Fluoxetine ameliorates Alzheimer’s disease progression and prevents the exacerbation of cardiovascular dysfunction of socially isolated depressed rats through activation of Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathway
Introduction
Depression is a mood disorder characterized by complex emotional and cognitive behaviors. The disease etiology may be due to genetic predisposition or environmental risk factors such as stressful life events, loneliness and social isolation [1], [2]. Social isolation (SI) is known to be a strong stressor for both rodents and humans. In humans, SI is associated with a higher risk of mental health problems, such as depression and anxiety [3], [4], besides it increased risk of mortality [5]. In rodents, social isolation induces anxiety and despair-like behaviors, aggression and memory impairments [6], [7], [8].
Importantly, several studies suggest that depression may be a risk factor for the development of both Alzheimer’s disease (AD) and cardiovascular diseases (CVD) [9], [10], [11], as patients with a history of depression were more likely to be affected by AD later in their life span [10]. Moreover, several studies proposed that there are across link between CVD and depression, and each of them can increase the risk of each other [12], [13].
Cardiovascular diseases and neurological disorders such as depression and dementia,…etc. share the same pathological mechanism in the upregulation of oxidative stress (OS) as well as inflammatory signaling [14], [15], [16], [17], [18], [19], [20].
Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor and master regulator of cell responses to OS via mediating of different antioxidant enzymes and proteins such as heme oxygenase-1 (HO-1) which acts as the important mediator of Nrf2 pathway [21], [22], [23]. Moreover, the Nrf2/HO-1 pathway favors cell survival and protection as several studies reported its neuroprotective effect in different neurological disorders [24], [25]. Interestingly, Nrf2/HO-1induction in rats’ brain showed a neuroprotection against OS, neuroinflammation, aging and other neurodegenerative diseases [26], [27], [28], [29]. Recently, Nrf2/HO-1 defense mechanism mediated peripheral disorders rather than neurological one [30], [31], [32].
The NLRP3 inflammasome is a polyprotein proinflammatory complex [33]. Recently, Yang et al., (2020) reviewed that there is a complex crosslink between the Toll-like receptor 4 (TLR 4) and inflammasome signaling pathway and targeting TLR-complement-NLRP3 inflammasome signaling can be a therapeutic and a preventive approach for most inflammatory disorders. TLR 4 plays an essential role in initiating the immune reaction that stimulates TLR4/NF-κB signaling cascade, contributing to the secretion of pro-inflammatory cytokines of IL-1β and IL-18 [34]. Therefore, inhibition of TLR-4/NLRP3 inflammasome activation has an important role in the prevention and treatment of most neuroinflammatory-dependent disorders [35], [36], [37], [38], [39].
Fluoxetine, is the most widely used antidepressant drug, it increases serotonergic neurotransmitters through selective inhibition of neuronal reuptake of serotonin [40]. Several studies reported fluoxetine antioxidant and anti-inflammatory properties which participating principally in its role of regarding antioxidant defense systems, cell survival, as well as neuronal trophicity [41], [42], [43]. Neuroprotective effects of fluoxetine have been confirmed by its capacity to control OS/neuroinflammation in central nervous system (CNS) and peripheral one through inhibition of TLR4/NF-κB/NLRP3 signaling pathway [42], [44], [45], [46], [47], [48], [49]. Moreover, fluoxetine increased brain derived neurotrophic factor (BDNF) protein levels, targeting Nrf2-signaling and increased brain autophagy in hippocampus and cortex of depressed mice which explained fluoxetine role in modulating the involved viscous cascades of prooxidant and inflammatory mediators [43], [50], [51], [52].
Therefore, the present study investigated the crosslink between depression, AD and cardiovascular risks considered depression is a risk factor for both AD and CVD. Moreover, role of fluoxetine in mitigating AD and cardiovascular disorders progression of socially isolated-depressed rats through activation of Nrf2/HO-1 and hindering NlRP3/TLR4 pathway were investigated too.
Section snippets
Animals
Eighty-four male Sprague Dawley rats with 8-month ages (aged rats), weighing (200–250 g) were purchased from the National Institute for Research, (Cairo, Egypt). Rats were housed in an air-conditioned atmosphere, at a temperature of 25 °C with alternatively 12-h light and dark cycles, and kept on a standard diet and water ad libitum. One week before any experimental procedures, animals were acclimatized to laboratory conditions. All animal procedures and the experimental protocols were carried
Effects of fluoxetine on rats’ behaviors and cognition in the forced swim test and Morris water maze test of SI or/and AD rats
Depression-induced by SI for 12 weeks or AD induced by AlCL3 (70 mg/kg/day, i.p.) for 5 weeks into NC rats affected significantly p < 0.0001 rats’ behaviors in the FST via reduction of swimming score along with increase of their immobility score when compared to the NC group. Importantly, SI + AD rats exhibited more significant p < 0.0001 deterioration of detected rats’ depressive-like behavior in FST as compared to NC group and as compared to each disorder alone. Fluoxetine (10 mg/kg/day, p.o)
Discussion
Depression originated from loneliness and social disconnection is a strong risk factor for AD and CVD in human beings [75], [76], [77], [78]. The pathomechanisms responsible for the increased incidence of AD and CV dysfunction in depressive patients are poorly understood. Therefore, the current study investigated for the first-time the cross link between SI induced depression and AD as well as accompanied CV dysfunction risk alongside two possible involved mechanistic pathways using fluoxetine
Funding
This work did not receive funding from any organization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
None.
References (114)
- et al.
Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders
Neuropharmacology
(2012) - et al.
Social relationships, loneliness, and mental health among older men and women in Ireland: A prospective community-based study
J. Affect. Disord.
(2016) The vascular depression hypothesis: 10 years later
Biol. Psychiatry
(2006)- et al.
Is depression associated with increased oxidative stress? A systematic review and meta-analysis
Psychoneuroendocrinology.
(2015) - et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds
Pharmacol. Res.
(2016) - et al.
Pharmacological induction of hemeoxygenase-1 activity attenuates intracerebroventricular streptozotocin induced neurocognitive deficit and oxidative stress in rats
Eur. J. Pharmacol.
(2016) - et al.
Vincamine protects against cisplatin induced nephrotoxicity via activation of Nrf2/HO-1 and hindering TLR4/IFN-γ/CD44 cells inflammatory cascade
Life Sci.
(2021) - et al.
Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats
Brain Behav. Immun.
(2014) - et al.
NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model
Behav. Brain Res.
(2017)
TLR4 Cross-talk with NLRP3 inflammasome and complement signaling pathways in Alzheimer's disease
Front. Immunol.
Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment
Brain Behav. Immun.
Fluoxetine protects neurons against microglial activation-mediated neurotoxicity
Parkins. Relat. Disord.
The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients
Med. Hypotheses
Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: role of fluoxetine
Cell. Signal.
Nrf2-signaling and BDNF: a new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression
Neurosci. Lett.
Vinpocetine mitigates aluminum-induced cognitive impairment in socially isolated rats
Physiol. Behav.
Fluoxetine has neuroprotective effects after cardiac arrest and cardiopulmonary resuscitation in mouse
Resuscitation.
Effect of chronic handling and social isolation on emotion and cognition in adolescent rats
Physiol. Behav.
The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats
Pharmacol. Biochem. Behav.
Antidepressant-like effects of cytidine in the forced swim test in rats
Biol. Psychiatry
Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test
Eur. J. Pharmacol.
Immobility in the forced swim test is adaptive and does not reflect depression
Psychoneuroendocrinology.
Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice
Life Sci.
Developments of a water-maze procedure for studying spatial learning in the rat
J. Neurosci. Methods
Ibuprofen or piroxicam protects nigral neurons and delays the development of l-dopa induced dyskinesia in rats with experimental Parkinsonism: Influence on angiogenesis
Neuropharmacology
Further modification of a fluorometric method for analyzing brain amines
Microchem. J.
Determination of malonaldehyde precursor in tissues by thiobarbituric acid test
Anal. Biochem.
The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen
Biochem. Biophys. Res. Commun.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1β/JNK signaling pathway
Sci. Total Environ.
Counteracting role of nuclear factor erythroid 2-related factor 2 pathway in Alzheimer's disease
Biomed. Pharmacother.
New insights into the Nrf-2/HO-1 signaling axis and its application in pediatric respiratory diseases
Oxid. Med. Cell. Longevity
Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: novel cytoprotective mechanism against oxidative damage
Pharmacol. Res.
Upregulation of thioredoxin system via Nrf2-antioxidant responsive element pathway in adaptive-retinal neuroprotection in vivo and in vitro
Free Radical Biol. Med.
Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity
J. Nutrit. Biochem.
KEAP1 E3 ligase-mediated downregulation of NF-κB signaling by targeting IKKβ
Mol. Cell
Nrf2 induces IL-17D to mediate tumor and virus surveillance
Cell Rep.
NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings
Brain Behav. Immun.
Running opposes the effects of social isolation on synaptic plasticity and transmission in a rat model of depression
PLoS ONE
Attachment strength and relationship expectancies in the prediction of adolescent stress and depression
Edu. Develop. Psychol.
Social isolation, loneliness, and all-cause mortality in older men and women
Proc. Natl. Acad. Sci.
Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers
Neuropsychobiology.
Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress
Mol. Cell. Biochem.
Social isolation-induced increase in NMDA receptors in the hippocampus exacerbates emotional dysregulation in mice
Hippocampus.
Motivational symptoms of depression mask preclinical Alzheimer’s disease in elderly subjects
Dement. Geriatr. Cogn. Disord.
Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis
Arch. Gen. Psychiatry
Pharmacological treatment of depression in Alzheimer’s disease: a challenging task
Front. Pharmacol.
Midlife vs late-life depressive symptoms and risk of dementia: differential effects for Alzheimer disease and vascular dementia
Arch. Gen. Psychiatry
Interaction of systemic oxidative stress and mesial temporal network degeneration in Parkinson’s disease with and without cognitive impairment
J. Neuroinflam.
Cited by (20)
Impaired sleep is associated with tau deposition on <sup>18</sup>F-flortaucipir PET and accelerated cognitive decline, accounting for medications that affect sleep
2024, Journal of the Neurological SciencesCaenorhabditis elegans: A transgenic model for studying age-associated neurodegenerative diseases
2023, Ageing Research ReviewsHuangqin decoction mitigates hepatic inflammation in high-fat diet-challenged rats by inhibiting TLR4/NF-κB/NLRP3 pathway
2023, Journal of EthnopharmacologyCitation Excerpt :Meanwhile, blocking NLRP3 inflammasome is sufficient to alleviate these symptoms in NAFLD (Mridha et al., 2017). LPS-recognized TLR4 plays imperative roles in pathogen recognition and immune responses (Abu-Elfotuh et al., 2022). NF-κB dimers are activated once LPS binding with TLR4, triggering the TLR4/NF-κB pathway (Seki et al., 2010).
The NLRP3 inflammasome in depression: Potential mechanisms and therapies
2023, Pharmacological ResearchAgmatine-mediated inhibition of NMDA receptor expression and amelioration of dyskinesia via activation of Nrf2 and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling cascade in rotenone lesioned rats
2022, Life SciencesCitation Excerpt :The pyknotic neuronal cells (dead pyramidal dopaminergic neurons) were quantified in each section, where they identified morphologically on high power (40×), as triangular dark-stained neurons with shrinkage cytoplasm, condensed nuclei, and condensed chromatin surrounded by peri-neuronal vacuoles. To estimate the percent of pyknotic cells for each brain region; the number of pyknotic neurons from each section was divided by the total number of healthy neurons and then the percent of pyknotic cells was calculated, averaged and compared among different groups [36]. Paraffin blocks of SNpc (4-μm) were prepared and incubated with the following primary antibodies at dilution 1:100 for each: anti-TH antibody, anti-HMGB1, anti-TLR4, anti-NF-κB, and anti-caspase-3 antibodies (ABclonal co., USA, Cat No: A0028, A19529, A11226, A19653, A11953, respectively) as well as anti-MyD88 antibody (Cat No: AF5195, Affinity co., UK).
p-Coumaric acid mitigates passive avoidance memory and hippocampal synaptic plasticity impairments in aluminum chloride-induced Alzheimer's disease rat model
2022, Journal of Functional FoodsCitation Excerpt :These deleterious alterations are the main neuropathological markers of AD and are among the major underlying risk factors that lead to cognitive decline. Hence, AlCl3-induced AD in rats is used as a well-defined model to identify the underlying pathophysiological mechanisms of cognitive decline (Abu-Elfotuh, Al-Najjar, Mohammed, Aboutaleb, & Badawi, 2022; Cao et al., 2017; Chen et al., 2021; Elfiky et al., 2021; Khalil et al., 2020; Lin et al., 2015; Prema et al., 2017; Shunan et al., 2021; Singh et al., 2018; Weng et al., 2020). In recent years, phenolic compounds have provided a foundation for discovering and developing new neuroprotective agents against AD-induced cognitive decline (Andrade, Loureiro, & Pereira, 2021; Verma, Singh, & Kh, 2020; Wang, Wu, & Lu, 2021).