Cannabidiol and the Canonical WNT/β-Catenin Pathway in Glaucoma

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway.


Introduction
Glaucoma is a progressive neurodegenerative disease that constitutes the main frequent cause of irreversible blindness. The number of people with glaucoma worldwide will increase from 76.5 million in 2020 to 111.8 million by 2040, mainly due to the aging of the population [1][2][3]. Glaucoma is characterized by loss of retinal ganglion cells (RGCs), thinning of the retinal nerve fiber layer, and cupping of the optic disc [4]. Glaucoma is a group of heterogeneous diseases characterized by varying clinical features. Aging, increased intraocular pressure (IOP), and genetic background are the main risk factors for glaucoma [4]. Primary open-angle glaucoma (POAG) is the main form in Western countries. Nevertheless, 30% of Caucasian patients with POAG, and a greater proportion of the Asian population show normal-tension glaucoma (NTG) [5]. The etiology of POAG is mainly described as mechanical and/or vascular processes. The mechanical process enhances compression of the axons due to elevation of IOP, whereas the vascular process highlights events in which blood flow and ocular perfusion pressure are diminished in the posterior pole [6,7]. Vascular or perfusion dysregulations in NTG present different clinical features, The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and age-related macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and age-related macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function B activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF- 22,3798 The TM dysfunction and the reduction of its cellularity are the fir sion glaucoma (HTG) onset, including POAG and also PACG glaucoma). Numerous factors, including OS and aging, as well a are implicated as the promotors of TM damage [40]. OS could b phological alterations of the TM of glaucomatous eyes, due to it st response. Chronic inflammation and OS modulate each other in a ing cellular responses. Cultures of TM present an NF-ϰB pathway nous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation re pression of the endothelial leukocyte adhesion molecule-1 (ELAM ELAM-1 belongs to selectin families, which are cell adhesion mo ELAM-1 in POAG is considered to be a factor in the onset of TM [42].
During glaucoma, a progressive loss of TM cells has been sh nation of both aging and stress conditions [43]. In HTG, the TM inflammation and tissue reprogramming mechanisms associated endothelial dysfunction [44]. Among the pro-inflammatory cytok alpha can induce ECM remodeling and alter cytoskeletal interactio TM [42]. The alterations in the protein patterns observed in the a POAG patients are the consequence of the progressive loss of TM The TM is the most sensitive tissue of the anterior segment of th [46]. Glaucomatous TM cells present POAG-typical molecular mod accumulation, cell death, dysregulation of the cytoskeleton, adva stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which oc sociated with oxidative degenerative processes damaging the hum (hTMEs). Chronic exposure of TM cells to OS leads to numerous c pathway responsible for autophagia [48], as well as cell senesce senescence-associated-galactosidase [49]. OS induces a lysosoma defective proteolytic stimulation of lysosomal enzymes with a sub tophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic n leads to hypoperfusion and to reperfusion damages [50]. IOP elev cause of retinal ganglion cells (RGCs) damage, resulting in a retr ade and the accumulation of neurotrophic factors at the lamina cr ing the RGC soma [51]. The POAG etiology is still unclear but s been observed as the causes of promoting its onset, such as eleva ethnicity, first-degree family history of glaucoma, oxidative stre vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several of the retina, such as glaucoma, occlusion of the central artery of th macular degeneration. They are enzymes, including the nicotina tide phosphate (NADPH) oxidase, the xanthine oxidoreductase, th mitochondrial cytochrome oxidase and the eNOS decoupled, w production of ROS in the tissues of the vascular system [53,54]. Ox hydrobioprotein (BH4) bioavailability, whereas it increases the B stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and agerelated macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function of the retina [58]. However, there are other pathogenic processes linked to glaucoma, including glutamate excitotoxicity [59], which are not necessarily associated with the elevated levels of IOP [56]. It seems that the death of RGCs during a glaucoma process stimulates ROS production in vitro [60]. It has been shown that ROS production controls the immune The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and age-related macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and age-related macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function B) stimulates several pro-inflammatory factors that activate COX-2 and inducible nitric oxide synthase (iNOS) [66]. Several studies have shown that NF-

of 18
The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and age-related macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function B stimulates the expression of TNF-α, IL-6, IL-8, STAT3, COX-2, B-cell lymphoma 2 (BCL-2), metalloproteinases (MMPs), VEGF [66], and the ROS production [67]. Furthermore, iNOS, an enzyme catalyzing nitric oxide (NO), is activated during chronic inflammation [68].
Several pieces of research have shown the mechanism by which oxidative stress can lead to chronic inflammation [69]. The imbalance caused by oxidative stress leads to damage signaling in cells [70]. The ROS production plays a central role both upstream and downstream of NF-κB and TNF-α pathways, which are the main mediators of the inflammatory response. The hydroxyl radical is the most harmful of all the ROS. A vicious loop is observed between ROS and these pathways. ROSs are generated by NADPH oxidase (NOX) system. Moreover, the modified proteins by ROS could generate an initiation of auto-immune response to stimulate TNF-α and NOX [71]. Nuclear factor erythroid-2 related factor 2 (Nrf2) is mainly associated with oxidative stress in inflammation [69]. Nrf2 is a transcription factor that binds to the antioxidant response element (ARE) [72]. Several studies have shown that Nrf2 can present an anti-inflammatory role by regulating MAPK, NF-3 of 18 function and the reduction of its cellularity are the first steps to the high tena (HTG) onset, including POAG and also PACG (primary angle-closure umerous factors, including OS and aging, as well as environmental factors ed as the promotors of TM damage [40]. OS could be enhanced in the morlterations of the TM of glaucomatous eyes, due to it stimulating inflammatory ronic inflammation and OS modulate each other in a vicious circle influencesponses. Cultures of TM present an NF-ϰB pathway activation after exogetion including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant exhe endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ongs to selectin families, which are cell adhesion molecules. The presence of OAG is considered to be a factor in the onset of TM endothelial dysfunction glaucoma, a progressive loss of TM cells has been shown, due to the combith aging and stress conditions [43]. In HTG, the TM displays both chronic n and tissue reprogramming mechanisms associated with OS damage and ysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFuce ECM remodeling and alter cytoskeletal interactions in the glaucomatous alterations in the protein patterns observed in the aqueous humor (AH) of nts are the consequence of the progressive loss of TM cellular integrity [45]. e most sensitive tissue of the anterior segment of the eye to oxidative stress atous TM cells present POAG-typical molecular modifications, such as ECM n, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB and the release of inflammatory markers [41,47]. ndings may suggest that the IOP elevation, which occurs in glaucoma, is asoxidative degenerative processes damaging the human TM endothelial cells ronic exposure of TM cells to OS leads to numerous changes in the lysosomal ponsible for autophagia [48], as well as cell senescence with an increase in ssociated-galactosidase [49]. OS induces a lysosomal dysregulation and the teolytic stimulation of lysosomal enzymes with a subsequent decrease in aux and the promotion of cell senescence [9]. elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, operfusion and to reperfusion damages [50]. IOP elevation is considered as a nal ganglion cells (RGCs) damage, resulting in a retrograde transport blockaccumulation of neurotrophic factors at the lamina cribrosa instead of reachsoma [51]. The POAG etiology is still unclear but several risk factors have ed as the causes of promoting its onset, such as elevated IOP, aging, gender, st-degree family history of glaucoma, oxidative stress, systemic and ocular ors, and inflammation [52].
B, and PI3K pathways [73]. Thus, Nrf2 may play a major role against oxidative damages [74]. Furthermore, evidence also suggests that mitochondrial dysregulation has a significant role in the cancer mechanism [69].
Glutamate is an amino-acid responsible for the brain's primary excitatory neurotransmission [75]. Glutamatergic neurons are embedded in every brain circuit in comparison to dopamine and serotonin which are used by a small minority of neural cells in the brain. Glutamate is the main excitatory neurotransmitter in the brain and is present in more than 50% of synapses. This signaling plays a major role in neuronal plasticity, memory and learning [76]. Rapid neurotoxicity enhanced by neuronal excitotoxin has been observed with abnormal glutamate levels [77]. In neurons, glutamate is stored in synaptic vesicles from which it is released. Glutamate release increases glutamate concentration in the synaptic cleft to bind ionotropic glutamate receptors. The main consistent candidate gene in OCD is SLC1A1 (solute carrier, family 1, member 1) gene [78]. SLC1A1 encodes for the neuronal excitatory Na+-dependent amino acid transporter 3 (EAAT3). EAAT1 and EAAT2 are the main astrocyte glutamate transporters whereas EAAT3 is the major neuronal glutamate transporter. Glutamate is converted into glutamine in astrocytes. Then, glutamine is captured by the presynaptic neurons to be re-converted into glutamate [79]. The role of the EAAT3 is to control glutamate spillover (signification de spillover?) which affects pre-synaptic N-methyl-D-asparate (NMDA) and metabotropic glutamate receptors activity [80,81]. EAAT3 activity is dysregulated by the overexpression of GSK-3β [82].
In glaucoma, the glutamate toxicity could contribute to RGC death and appears to be mediated mainly by the NMDA receptor that, apart from promoting cell death, due to its greater Ca 2+ permeability, has a high affinity for glutamate and a slow inactivation [83,84]. Glutamate excitotoxicity is implicated in the mtDNA alteration or DNAoxidation-related mitochondrial dysregulation in retinal neurodegeneration [85]. Glutamate excitotoxicity over-activity leads to neuronal cell death through high levels of glutamate and the overactivation of NMDA receptors. The excitotoxic affection to RGCs may be involved by the increased glutamate synthesis or a decreased glutamate clearance [86].

WNT/β-Catenin Pathway
WNT name is derived from Wingless drosophila melanogaster and its mouse homolog Int. WNT/β-catenin pathway is involved in numerous signaling and regulating pathways, such as embryogenesis, cell proliferation, migration and polarity, apoptosis, and organogenesis [87]. However, during numerous pathological states, the WNT/β-catenin pathway can be dysregulated, such as inflammatory, metabolic and neurological disorders, tissue fibrosis and cancers [88].
Glycogen synthase kinase-3β (GSK-3β) is one of the main inhibitors of the WNT/βcatenin pathway [99][100][101][102][103][104]. As an intracellular serine-threonine kinase, GSK-3β is a key negative regulator of the WNT pathway [105]. It is involved in the regulation of several kinds of pathophysiological signaling, such as cell membrane signaling, cell polarity, and inflammation [106][107][108]. GSK-3β acts by inhibiting cytoplasmic β-catenin and stabilizes it to induce its nuclear migration. Inflammation is an age-related process associated with the increase of GSK-3β activity and the decrease of the WNT/β-catenin pathways [109].
Recent studies have observed that glaucoma patients present an increased GSK-3β activity and thus its inhibition could be an interesting treatment [110,111]. GSK-3β is a serine/threonine kinase that is involved in numerous intracellular signaling pathways. Dysfunction of GSK-3β is involved in the pathogenesis of several diseases, including neuropsychiatric disorders [112]. GSK3β is known to be the major inhibitor of the canonical WNT/β-catenin pathway [103,[113][114][115][116][117].

WNT/β-Catenin Pathway in Glaucoma
Recent studies have shown that the WNT/β-catenin pathway is involved in the pathophysiology of TM cells. This pathway could serve as a regulator of IOP [118]. Secreted frizzled-related protein 1 (sFRP1), a WNT inhibitor, is elevated in the glaucomatous TM. Exogenous sFRP1 involves high IOP [119,120]. In sFRP1-perfused human eyes, the level of β-catenin is decreased [119]. sFRP1 is associated with cell stiffness [120]. TM cells have multiple responses to the stimulus by different concentrations of sFRP1 [120]. It has been illustrated that sFRP1 is elevated in normal TM cells grown on substrates simulating the stiffness of the glaucomatous TM. Increased stiffness of the TM involves the aqueous humor outflow resistance and is leading to elevated IOP [120]. Moreover, the GSK3β, another WNT inhibitor, can decrease the activity of the WNT/β-catenin pathway and lead to ocular hypertension in association with sFRP1 [119]. It has been shown that there are two effects of WNT in glaucoma [118]. The glaucoma gene myocilin (MYOC) has been shown to be a regulator of WNT/β-catenin pathway [121]. Nevertheless, the damages induced by MYOC mutation on the WNT pathway remain unclear in the TM. The aqueous humor outflow resistance is damaged by the change in adhesion junctions and cell contact, and then IOP is dysregulated [118]. The WNT/β-catenin pathway is believed to be a novel interventional target for the treatment of glaucoma [122][123][124]. Several WNT target genes are expressed in the TM, and the WNT ligand WNT3a is dysregulated [118,119]. The overexpression of both sFRP1 or Dkk1 can increase IOP in perfusion-cultured human eyes and in mouse eyes [118,119]. Moreover, the cotreatment with a small-molecule WNT pathway activator can downregulate sFRP1-induced OHT in mouse eyes. The activation of WNT/β-catenin pathway in the TM using lithium chloride decreases the production of some ECM and matricellular proteins [125,126]. WNT/β-catenin signaling and K-cadherin expression are major for the control of IOP, and the downregulation of this pathway leads to IOP elevation in glaucoma [127]. Recent studies have shown that active WNT/β-catenin pathway inhibits fibrosis-associated proteins in the TM and that the POAG-associated WNT antagonist sFRP1 increases ECM deposition, TM cell stiffness [120] and IOP [118,119]. Moreover, recent findings have shown that the WNT/β-catenin can regulate TM homeostasis and IOP by a cross-inhibit circle with TGF-β signaling [126].

WNT/β-Catenin Pathway and Oxidative Stress
FoxO (Forkhead box class O) transcription factors are the main intracellular controllers of numerous metabolic signaling such as glucose production, and the cellular response to oxidative stress [128]. ROS production is associated with the inhibition of the WNT pathway by diverting β-catenin from TCF/LEF to FoxO [129]. This leads to the accumulation and binding of β-catenin to FoxO as a cofactor, and in increasing FoxO transcriptional activity in the nucleus [130,131]. FoxO stimulates apoptotic genes [132][133][134]. FoxO3a stops the cell-cycle by stimulation of the production of the cyclin-dependent kinase inhibitor p27 kip1 and the inhibition of cyclin D1 expression [135,136]. The activation of FoxO induces apoptosis [137]. However, the activation of the WNT pathway can downregulate FoxO3a in the cytosol to prevent the loss of mitochondrial membrane permeability, cytochrome c release, Bad phosphorylation, and activation of caspases which activates ROS production and oxidative stress [138].

WNT/β-Catenin Pathway and Inflammation
The stimulation of the WNT pathway cascade restrains inflammation and leads to neuroprotection via interactions between microglia/macrophages and astrocytes [139,140].
Several studies have shown negative crosstalk between WNT/β-catenin pathway and NF-3 of 18 function and the reduction of its cellularity are the first steps to the high tena (HTG) onset, including POAG and also PACG (primary angle-closure umerous factors, including OS and aging, as well as environmental factors d as the promotors of TM damage [40]. OS could be enhanced in the morlterations of the TM of glaucomatous eyes, due to it stimulating inflammatory ronic inflammation and OS modulate each other in a vicious circle influencesponses. Cultures of TM present an NF-ϰB pathway activation after exogetion including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant exhe endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ongs to selectin families, which are cell adhesion molecules. The presence of OAG is considered to be a factor in the onset of TM endothelial dysfunction glaucoma, a progressive loss of TM cells has been shown, due to the combith aging and stress conditions [43]. In HTG, the TM displays both chronic n and tissue reprogramming mechanisms associated with OS damage and ysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFuce ECM remodeling and alter cytoskeletal interactions in the glaucomatous alterations in the protein patterns observed in the aqueous humor (AH) of nts are the consequence of the progressive loss of TM cellular integrity [45]. e most sensitive tissue of the anterior segment of the eye to oxidative stress atous TM cells present POAG-typical molecular modifications, such as ECM n, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB nd the release of inflammatory markers [41,47]. ndings may suggest that the IOP elevation, which occurs in glaucoma, is asoxidative degenerative processes damaging the human TM endothelial cells ronic exposure of TM cells to OS leads to numerous changes in the lysosomal ponsible for autophagia [48], as well as cell senescence with an increase in ssociated-galactosidase [49]. OS induces a lysosomal dysregulation and the teolytic stimulation of lysosomal enzymes with a subsequent decrease in auand the promotion of cell senescence [9]. elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, operfusion and to reperfusion damages [50]. IOP elevation is considered as a nal ganglion cells (RGCs) damage, resulting in a retrograde transport blockaccumulation of neurotrophic factors at the lamina cribrosa instead of reachsoma [51]. The POAG etiology is still unclear but several risk factors have B pathway, one of the main markers of inflammation [141]. The NF- 22,3798 The TM dysfunction and the reduction of its cellularity are the first steps to th sion glaucoma (HTG) onset, including POAG and also PACG (primary ang glaucoma). Numerous factors, including OS and aging, as well as environmen are implicated as the promotors of TM damage [40]. OS could be enhanced in phological alterations of the TM of glaucomatous eyes, due to it stimulating infl response. Chronic inflammation and OS modulate each other in a vicious circl ing cellular responses. Cultures of TM present an NF-ϰB pathway activation a nous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a sign pression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and ELAM-1 belongs to selectin families, which are cell adhesion molecules. The p ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial d [42].
During glaucoma, a progressive loss of TM cells has been shown, due to nation of both aging and stress conditions [43]. In HTG, the TM displays bo inflammation and tissue reprogramming mechanisms associated with OS da endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 alpha can induce ECM remodeling and alter cytoskeletal interactions in the glau TM [42]. The alterations in the protein patterns observed in the aqueous hum POAG patients are the consequence of the progressive loss of TM cellular inte The TM is the most sensitive tissue of the anterior segment of the eye to oxida [46]. Glaucomatous TM cells present POAG-typical molecular modifications, su accumulation, cell death, dysregulation of the cytoskeleton, advanced senescen stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glauc sociated with oxidative degenerative processes damaging the human TM endot (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the pathway responsible for autophagia [48], as well as cell senescence with an i senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulatio defective proteolytic stimulation of lysosomal enzymes with a subsequent decr tophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (O leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is consi cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transp ade and the accumulation of neurotrophic factors at the lamina cribrosa instea ing the RGC soma [51]. The POAG etiology is still unclear but several risk fa The TM dysfunction and the reduction of its cellularity are the fir sion glaucoma (HTG) onset, including POAG and also PACG glaucoma). Numerous factors, including OS and aging, as well a are implicated as the promotors of TM damage [40]. OS could b phological alterations of the TM of glaucomatous eyes, due to it st response. Chronic inflammation and OS modulate each other in a ing cellular responses. Cultures of TM present an NF-ϰB pathwa nous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation re pression of the endothelial leukocyte adhesion molecule-1 (ELAM ELAM-1 belongs to selectin families, which are cell adhesion mo ELAM-1 in POAG is considered to be a factor in the onset of TM [42].
During glaucoma, a progressive loss of TM cells has been sh nation of both aging and stress conditions [43]. In HTG, the TM inflammation and tissue reprogramming mechanisms associated endothelial dysfunction [44]. Among the pro-inflammatory cytok alpha can induce ECM remodeling and alter cytoskeletal interacti TM [42]. The alterations in the protein patterns observed in the a POAG patients are the consequence of the progressive loss of TM The TM is the most sensitive tissue of the anterior segment of th [46]. Glaucomatous TM cells present POAG-typical molecular mod accumulation, cell death, dysregulation of the cytoskeleton, adva stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which oc sociated with oxidative degenerative processes damaging the hum (hTMEs). Chronic exposure of TM cells to OS leads to numerous c pathway responsible for autophagia [48], as well as cell senesce senescence-associated-galactosidase [49]. OS induces a lysosoma defective proteolytic stimulation of lysosomal enzymes with a sub tophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic n leads to hypoperfusion and to reperfusion damages [50]. IOP elev cause of retinal ganglion cells (RGCs) damage, resulting in a retr ade and the accumulation of neurotrophic factors at the lamina cr The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport block- The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a B signaling [143]. Moreover, by interacting with the PI3K, β-catenin inhibits the functional activity of NF- 22,3798 The TM dysfunction and the reduction of its cellularity are the first steps to sion glaucoma (HTG) onset, including POAG and also PACG (primary a glaucoma). Numerous factors, including OS and aging, as well as environm are implicated as the promotors of TM damage [40]. OS could be enhanced phological alterations of the TM of glaucomatous eyes, due to it stimulating in response. Chronic inflammation and OS modulate each other in a vicious cir ing cellular responses. Cultures of TM present an NF-ϰB pathway activation nous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a si pression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β a ELAM-1 belongs to selectin families, which are cell adhesion molecules. The ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial [42].
During glaucoma, a progressive loss of TM cells has been shown, due t nation of both aging and stress conditions [43]. In HTG, the TM displays inflammation and tissue reprogramming mechanisms associated with OS endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL alpha can induce ECM remodeling and alter cytoskeletal interactions in the g TM [42]. The alterations in the protein patterns observed in the aqueous hu POAG patients are the consequence of the progressive loss of TM cellular in The TM is the most sensitive tissue of the anterior segment of the eye to oxi [46]. Glaucomatous TM cells present POAG-typical molecular modifications, accumulation, cell death, dysregulation of the cytoskeleton, advanced senesc stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glau sociated with oxidative degenerative processes damaging the human TM end (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in th pathway responsible for autophagia [48], as well as cell senescence with an senescence-associated-galactosidase [49]. OS induces a lysosomal dysregula defective proteolytic stimulation of lysosomal enzymes with a subsequent de tophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head ( The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9]. B activity has been observed in numerous cell types, such as fibroblasts, epithelial cells, hepatocytes and osteoblasts [141]. In parallel, the overactivation of GSK-3β leads to an inhibition of the β-catenin and then an activation of the NF-3 of 18 M dysfunction and the reduction of its cellularity are the first steps to the high tenlaucoma (HTG) onset, including POAG and also PACG (primary angle-closure ma). Numerous factors, including OS and aging, as well as environmental factors plicated as the promotors of TM damage [40]. OS could be enhanced in the morgical alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory se. Chronic inflammation and OS modulate each other in a vicious circle influencllular responses. Cultures of TM present an NF-ϰB pathway activation after exogetimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant exon of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. -1 belongs to selectin families, which are cell adhesion molecules. The presence of -1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction uring glaucoma, a progressive loss of TM cells has been shown, due to the combiof both aging and stress conditions [43]. In HTG, the TM displays both chronic mation and tissue reprogramming mechanisms associated with OS damage and helial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFcan induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous 2]. The alterations in the protein patterns observed in the aqueous humor (AH) of patients are the consequence of the progressive loss of TM cellular integrity [45]. M is the most sensitive tissue of the anterior segment of the eye to oxidative stress laucomatous TM cells present POAG-typical molecular modifications, such as ECM ulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB lation and the release of inflammatory markers [41,47]. hese findings may suggest that the IOP elevation, which occurs in glaucoma, is ased with oxidative degenerative processes damaging the human TM endothelial cells s). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal ay responsible for autophagia [48], as well as cell senescence with an increase in ence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the B pathway [145]. The potential protective action of β-catenin was due to the activation of PI3K/Akt pathway and thus the reduction of TLR4-driven inflammatory response in hepatocytes [146]. NF- The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal B activation leads to the diminution of the complex β-catenin/TCF/LEF by the upregulation of LZTS2 in cancer cells [147]. DKK, a WNT inhibitor, was a target gene of the NF- The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is as-B pathway leading to negative feedback to diminish the β-catenin signaling [148]. Activated B-catenin inhibits the NF- The TM dysfunction and the reduction of its cellularity are the first steps to the high t sion glaucoma (HTG) onset, including POAG and also PACG (primary angle-clos glaucoma). Numerous factors, including OS and aging, as well as environmental fact are implicated as the promotors of TM damage [40]. OS could be enhanced in the m phological alterations of the TM of glaucomatous eyes, due to it stimulating inflammat response. Chronic inflammation and OS modulate each other in a vicious circle influe ing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exo nous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant pression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [ ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunct [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the com nation of both aging and stress conditions [43]. In HTG, the TM displays both chro inflammation and tissue reprogramming mechanisms associated with OS damage a endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TN alpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomat TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH POAG patients are the consequence of the progressive loss of TM cellular integrity [ The TM is the most sensitive tissue of the anterior segment of the eye to oxidative str [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as EC accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF stimulation and the release of inflammatory markers [41,47]. The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM B pathway [149,150].

WNT/β-Catenin Pathway and Glutamatergic Pathway
β-catenin activates EAAT2 and glutamine synthetase (GS) at the transcriptional level in progenitor-derived astrocytes through the activation of TCF/LEF [151]. The knockdown of β-catenin leads to the diminution of EAAT2 and GS expression in the prefrontal cortex [152]. In astrocytes, the inhibition of β-catenin is associated with diminution of both EAAT2 and GS expression [153]. The dysregulation of the WNT/β-catenin pathway induces glutamate excitotoxicity resulting in the increase of both inflammation and exudative stress [153].

Cannabidiol
Cannabinoids refer to a heterogeneous group of compounds classified into three major groups: endogenous, synthetic and phytocannabinoids [31,154]. CBD is a nonpsychotomimetic phytocannabinoid derived from Cannabis sativa plant. The Cannabis sativa plant produces more than 66 compounds, such as delta9-tetrahydrocannabinol (THC), responsible for anxiogenic effects, and CBD, the major non-psychotomimetic compound in the plant [155]. CBD attenuates brain damage associated with neurodegeneration. Humans tolerate a high dose of CBD [156]. Moreover, CBD can interact with synaptic plasticity and induces neurogenesis. The mechanisms of the CBD effects remain unclear but have multiple pharmacological targets. Traditional medicines use Cannabis sativa for centuries. CBD, one of the main compounds of Cannabis sativa, has recently presented numerous interesting actions in many neuropsychiatric disorders [157]. CBD presents a large spectrum of possible therapeutic properties such as anxiolytic, antidepressant, neuroprotective, anti-inflammatory and immunomodulatory [31]. Cannabinoids could be considered as a new class of drugs because of their possible actions on neuropsychiatric disorders [158]. CBD has a potential therapeutic role in neuropsychiatric disorders such as schizophrenia, epilepsy, addiction and neonatal hypoxic-ischemic encephalopathy [159]. CBD can activate WNT/β-catenin and PI3K/Akt pathways and produces therapeutic effects in schizophrenia [160][161][162].

Cannabinoids in Glaucoma
CBs could have a major role in IOP control through the interaction with the ciliary muscle and Schlemm's canal, and by the modulation of cyclooxygenase-2 (COX-2) [163]. These actions are obtained by the interaction with CB1 receptor but also by the modulation of cyclooxygenase (COX) pathway [164]. CB1 is expressed in both retina and anterior eye structures including TM, Schlemm's canal, iris, ciliary body muscle, and ciliary pigmented epithelium. Several pathways could be implicated in the IOP lowering action of CBs by the regulation of aqueous humor production and outflow (trabecular and uveoscleral) [165]. Activation of the CB1 receptor in the ciliary muscle could also induce vasodilatation with consequent reduction of aqueous humor production [166]. Nevertheless, the exact role of CBs in the regulation of IOP remains unclear [27]. In parallel, CBs inhibit glutamate and nitric oxide release by the activation of pre-synaptic CB receptors leading to higher neuronal excitability and synaptic plasticity [28]. Glutamate pathway can regulate the RGC death through the stimulation of nitric oxide synthase and the increase in oxidative damages. Glutamate pathway in glaucoma is well investigated [27]. The anti-inflammatory actions of CBs could also have a role in neuroprotection. Stimulation of CB1 and CB2 receptors in the retina and CNS downregulates the production of nitric oxide and inflammatory cytokines which are responsible for OS and RGC death [167]. In the TM, the reduction of OS could also be obtained by ROS blockage without any CB receptor activation, such as activation of the WNT pathway [168].
Nevertheless, CBD could have an opposing effect on IOP by increasing or decreasing it [169]. The increase of IOP by CBD could be the result of the antagonist role of CBD on CB1 receptor [169]. The absence of the effect of CBD on IOP could be due to the direct and indirect activity at GPR18 receptor and CB1 receptor which could be both deleted. CBD is activated on GPR18 [170] to interrupt the activity of FAAH [171], responsible for the elevation of acylethanol-amines, such as AEA, one of the precursor of GPR18 [172]. Diurnal action of CB1 and activation of GPR18 remain unstudied. Time of day and broadly speaking pressure, which is higher during the day, regulate the pressure in the eye. Mice present a nocturnal and reversed cycle of GPR18 which participate in lowering eye pressure. Thus, diurnal signaling should have a major role in the ocular response of CBD, which is different between humans and mice [173]. Moreover, gender different effects could be involved in IOP-response to CBD, by interacting with GPR119 ligand. Female mice show lower ocular pressure under CBD administration, whereas it is not the case for male mice [174]. Furthermore, a low dose of CBD administration may have no significant IOP-lowering effect [27,175]. However, these different mechanisms remain unclear.

Activation of the Canonical WNT Pathway by Cannabidiol: A Potential Therapeutic
Strategy for the Altered Pathways in Glaucoma 9.1. Cannabidiol and WNT Pathway Dysfunction of GSK-3β is involved in the pathogenesis of several diseases, including neuropsychiatric disorders [112]. GSK-3β is a regulator of several pathways such as inflammation, neuronal polarity or either cell membrane signaling [107]. GSK3β is known to be the main inhibitor of the WNT/β-catenin signaling [103,113,114,117]. GSK-3β downregulates the canonical WNT/β-catenin pathway by inhibiting β-catenin cytosolic stabilization and its translocation in the nucleus [176]. Moreover, several studies have shown a link between neuro-inflammation and the increase of the GSK-3β activity and in parallel the decrease of the WNT/β-catenin pathway and the protein kinase B (Akt) pathway [99]. CBD downregulates the expression of GSK-3β through the promotion of the PI3K/Akt signaling [100,177]. PI3K/Akt signaling regulates GSK-3β activity [178]. Cannabinoids control the PI3K/Akt/GSK-3β axis [179,180]. Genes encoding for the PI3K/Akt pathway is increased in CBD-GMSCs (mesenchymal stem cells derived from gingiva treated by CBD) [100].

Cannabidiol and Oxidative Stress
Energy and glucose metabolisms involved during oxidative stress are mainly controlled by the intracellular FOXO transcription factors (FOXO1, 3a, 4) [128]. The interaction between β-catenin and FOXO transcription factors promotes cell quiescence and cell cycle arrest. B-catenin blocks its transcriptional complex with TCF/LEF through the interaction with FOXO-induced ROS [129]. B-catenin does not translocate to the nucleus and thus accumulates in the cytosol to inactivate the WNT/β-catenin pathway [130,131].
CBD can reduce the redox balance through the modification of both the level and activity of oxidants and antioxidants [181]. CBD stops the free radical chain reactions through the capture of free radicals and then by reducing their activities [182]. CBD downregulates the oxidative conditions through the prevention of the formation of superoxide radicals, generated by xanthine oxidase (XO), NADPH oxidase (NOX1 and NOX4) [183,184]. Moreover, CBD can enhance the diminution in NO levels in the liver of doxorubicin-treated mice [185]. CBD diminishes reactive oxygen species (ROS) production through the chelation of transition metal ions implicated in the Fenton reaction to form extremely reactive hydroxyl radicals [186]. CBD acts on the classic antioxidant butylated hydroxytoluene (BHT) to prevent the dihydrorodamine oxidation in the Fenton reaction [187].
The antioxidant activity of CBD is characterized by the activation of the redox-sensitive transcription factor which refers to the nuclear reythroid 2-related factor (Nrf2) [188] responsible for the transcription of cytoprotective genes [189]. Superoxide dismutase (SOD) and enzymatic activities of Cu, Zn and Mn-SOD, which are responsible for the metabolism of superoxide radicals, are increased by CBD [190]. Glutathione peroxidase and reductase are increased by CBD and decrease the malonaldehyde (MDA) levels [191]. Enzymatic activities are altered during oxidative modifications of proteins. CBD, by targeting glutathione and cytochrome P450, car inhibit their biological activity to decrease oxidative stress [185,192]. Moreover, through the diminution of ROS levels, CBD can prevent and protect non-enzymatic antioxidants [190], including vitamins A, E and C [193].

Cannabidiol and Inflammation
Cannabinoids present anti-inflammatory action by endogenous receptors, such as cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) [194]. N-Oleoyl glycine (OLGly), a lipoamino acid, increases adipogenic genes including PPARγ, a marker of inflammation, and the mRNA expression of CB1 receptor. The inhibition of CB1 receptor by its antagonist SR141716 downregulates the actions of OLGly on the expression of PPARγ.

Cannabidiol and Glutamatergic Pathway
Few studies have investigated the interaction between the endogenous cannabinoid system and the glutamatergic pathway in the brain [212]. CBD diminishes the glutamate release in neural signaling implicated in compulsive behavior [213]. Many studies highlighted that the actions of CBD on dopamine and GABA levels were correlated with its strong anti-oxidant properties through the modulation of nitric oxide synthase expression and the inhibition of ROS-generating NADPH oxidases [214]. However, endogenous cannabinoids can bind to the cannabinoid CB1 receptor and dampen presynaptic glutamate release [215]. Moreover, the inhibition of GSK-3β can decrease EAAT3 activity [82]. Nevertheless, the relation between CBD and the glutamatergic pathway remains unclear. CBD can block the actions of CB1R/CB2 combined receptor agonist [216] and can act as a CB1R antagonist [217].

Conclusions
Currently, even if CBs are well documented in the literature, few investigations have studied CBD as a possible alternative therapeutic way to treat glaucoma patients. Nevertheless, CBD could appear to be interesting in glaucoma by targeting both oxidative stress, inflammation and the glutamatergic pathway through the activation of the WNT/βcatenin pathway. The action of CBD is mainly involved by its negative interaction with GSK-3β, the main inhibitor of the WNT/β-catenin pathway. In glaucoma, the WNT/βcatenin is downregulated to allow the stimulation of oxidative stress, inflammation and glutamatergic pathway. Future prospective studies should focus on CBD and its different actions in glaucoma.

Conflicts of Interest:
The authors declare no conflict of interest.

GSK-3β
Glycogen synthase kinase-3β LRP 5/6 Low-density lipoprotein receptor-related protein 5/6 NF-3 of 18 unction and the reduction of its cellularity are the first steps to the high tena (HTG) onset, including POAG and also PACG (primary angle-closure umerous factors, including OS and aging, as well as environmental factors d as the promotors of TM damage [40]. OS could be enhanced in the morterations of the TM of glaucomatous eyes, due to it stimulating inflammatory ronic inflammation and OS modulate each other in a vicious circle influencesponses. Cultures of TM present an NF-ϰB pathway activation after exogetion including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant exe endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ngs to selectin families, which are cell adhesion molecules. The presence of OAG is considered to be a factor in the onset of TM endothelial dysfunction glaucoma, a progressive loss of TM cells has been shown, due to the combith aging and stress conditions [43]. In HTG, the TM displays both chronic and tissue reprogramming mechanisms associated with OS damage and ysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFuce ECM remodeling and alter cytoskeletal interactions in the glaucomatous alterations in the protein patterns observed in the aqueous humor (AH) of ts are the consequence of the progressive loss of TM cellular integrity [45]. e most sensitive tissue of the anterior segment of the eye to oxidative stress atous TM cells present POAG-typical molecular modifications, such as ECM , cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB nd the release of inflammatory markers [41,47]. ndings may suggest that the IOP elevation, which occurs in glaucoma, is asoxidative degenerative processes damaging the human TM endothelial cells ronic exposure of TM cells to OS leads to numerous changes in the lysosomal ponsible for autophagia [48], as well as cell senescence with an increase in ssociated-galactosidase [49]. OS induces a lysosomal dysregulation and the teolytic stimulation of lysosomal enzymes with a subsequent decrease in auand the promotion of cell senescence [9]. elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, perfusion and to reperfusion damages [50]. IOP elevation is considered as a al ganglion cells (RGCs) damage, resulting in a retrograde transport blockccumulation of neurotrophic factors at the lamina cribrosa instead of reachsoma [51]. The POAG etiology is still unclear but several risk factors have d as the causes of promoting its onset, such as elevated IOP, aging, gender, t-degree family history of glaucoma, oxidative stress, systemic and ocular ors, and inflammation [52].

Stress, Inflammation and Glutamate in Glaucoma
hanisms of ROS production are activated in several pathological conditions such as glaucoma, occlusion of the central artery of the retina and age-related eneration. They are enzymes, including the nicotinamide adenine dinucleote (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the l cytochrome oxidase and the eNOS decoupled, which catalyzes the overf ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetratein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein ting with BH4 to enhance eNOS [55]. the visual loss processes are not entirely elucidated in glaucoma, and ROS lays an important role in its development [56]. ROS production rates are intients with glaucoma in the aqueous humor but also in the blood serum [57]. ain factors for glaucoma risk is elevated IOP. A moderately elevated IOP S production levels, stimulates NOX2 expression, and endothelial dysregunal arteries, suggesting that IOP augmentation affects the vascular function The TM dysfunction and the reduction of its cellularity are the first steps to the high tension glaucoma (HTG) onset, including POAG and also PACG (primary angle-closure glaucoma). Numerous factors, including OS and aging, as well as environmental factors are implicated as the promotors of TM damage [40]. OS could be enhanced in the morphological alterations of the TM of glaucomatous eyes, due to it stimulating inflammatory response. Chronic inflammation and OS modulate each other in a vicious circle influencing cellular responses. Cultures of TM present an NF-ϰB pathway activation after exogenous stimulation including IL1 or H 2 O 2 . The NF-ϰB activation results in a significant expression of the endothelial leukocyte adhesion molecule-1 (ELAM-1), IL-1β and IL-6 [41]. ELAM-1 belongs to selectin families, which are cell adhesion molecules. The presence of ELAM-1 in POAG is considered to be a factor in the onset of TM endothelial dysfunction [42].
During glaucoma, a progressive loss of TM cells has been shown, due to the combination of both aging and stress conditions [43]. In HTG, the TM displays both chronic inflammation and tissue reprogramming mechanisms associated with OS damage and endothelial dysfunction [44]. Among the pro-inflammatory cytokines, IL6, IL1 and TNFalpha can induce ECM remodeling and alter cytoskeletal interactions in the glaucomatous TM [42]. The alterations in the protein patterns observed in the aqueous humor (AH) of POAG patients are the consequence of the progressive loss of TM cellular integrity [45]. The TM is the most sensitive tissue of the anterior segment of the eye to oxidative stress [46]. Glaucomatous TM cells present POAG-typical molecular modifications, such as ECM accumulation, cell death, dysregulation of the cytoskeleton, advanced senescence, NF-ϰB stimulation and the release of inflammatory markers [41,47].
These findings may suggest that the IOP elevation, which occurs in glaucoma, is associated with oxidative degenerative processes damaging the human TM endothelial cells (hTMEs). Chronic exposure of TM cells to OS leads to numerous changes in the lysosomal pathway responsible for autophagia [48], as well as cell senescence with an increase in senescence-associated-galactosidase [49]. OS induces a lysosomal dysregulation and the defective proteolytic stimulation of lysosomal enzymes with a subsequent decrease in autophagic flux and the promotion of cell senescence [9].
The IOP elevation, either at the lamina cribrosa or the optic nerve head (ONH) level, leads to hypoperfusion and to reperfusion damages [50]. IOP elevation is considered as a cause of retinal ganglion cells (RGCs) damage, resulting in a retrograde transport blockade and the accumulation of neurotrophic factors at the lamina cribrosa instead of reaching the RGC soma [51]. The POAG etiology is still unclear but several risk factors have been observed as the causes of promoting its onset, such as elevated IOP, aging, gender, ethnicity, first-degree family history of glaucoma, oxidative stress, systemic and ocular vascular factors, and inflammation [52].

Oxidative Stress, Inflammation and Glutamate in Glaucoma
The mechanisms of ROS production are activated in several pathological conditions of the retina, such as glaucoma, occlusion of the central artery of the retina and age-related macular degeneration. They are enzymes, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the xanthine oxidoreductase, the cytochrome P450, the mitochondrial cytochrome oxidase and the eNOS decoupled, which catalyzes the overproduction of ROS in the tissues of the vascular system [53,54]. Oxidation decreases tetrahydrobioprotein (BH4) bioavailability, whereas it increases the 7,8-dihydrobioprotein (BH2) competing with BH4 to enhance eNOS [55].
To date, the visual loss processes are not entirely elucidated in glaucoma, and ROS production plays an important role in its development [56]. ROS production rates are increased in patients with glaucoma in the aqueous humor but also in the blood serum [57]. One of the main factors for glaucoma risk is elevated IOP. A moderately elevated IOP increases ROS production levels, stimulates NOX2 expression, and endothelial dysregulation in retinal arteries, suggesting that IOP augmentation affects the vascular function