Curcumin as a potential therapeutic agent for treating neurodegenerative diseases

Neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function, posing a tremendous burden on health systems worldwide. Although the underlying pathological mechanisms for various neurodegenerative diseases are still unclear, a common pathological hallmark is the abundance of neuro-inflammatory processes, which affect both disease onset and progression. In this review, we explore the pathways and role of neuroinflammation in various neurodegenerative diseases and further assess the potential use of curcumin, a natural spice with antioxidant and anti-inflammatory properties that has been extensively used worldwide as a traditional medicine and potential therapeutic agent. Following the examination of preclinical and clinical studies that assessed curcumin as a potential therapeutic agent, we highlight the bioavailability of curcumin in the body and discuss both the challenges and benefits of using curcumin as a therapeutic compound for treating neurodegeneration. Although elucidating the involvement of curcumin in aging and neuro-degeneration has great potential for developing future CNS-related therapeutic targets, further research is required to elucidate the mechanisms by which Curcumin affects brain physiology, especially BBB integrity, under both physiological and disease conditions.


Introduction to neurodegenerative diseases
Neurological disorders are the number one contributor to disability and the second leading cause of death worldwide, impacting approximately 15% of the world's population (Van Schependom & D'Haeseleer, 2023).With the expansion of the elderly population, the burden of chronic neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is likely to double in the next two decades (Feigin et al., 2019).This trajectory raises a formidable challenge in maintaining accessible neurological care for an increasingly affected populace.The fact that the pathological mechanisms underlying these conditions are not fully understood accentuates the global socioeconomic impact.This impact has driven associations such as the UN's World Health Organization (WHO) to push for programs and solutions that ameliorate these effects (WHO, 2017(WHO, , 2023)).
Neurodegenerative diseases (NDDs) involve a progressive decrease in synapses and neurons, leading to functional deterioration.Despite their diverse origins, genetic profiles, progression patterns, and targeted brain regions, the commonality among all neurodegenerative diseases is the disruption of neuronal communication attributed to synapse dysfunction and/or degeneration.This heterogeneous group of disorders, marked by the gradual and selective loss of neurons, results in sensory, motor, and cognitive impairments.The quest for effective therapies is impeded by the intricate interplay of factors governing the etiology, pathophysiology, and progression of NDDs.Despite shared features across these disorders, their complex clinicopathological relationships pose a significant challenge in comprehending and addressing them (Dejanovic et al., 2024;Nie et al., 2023;Purushotham and Buskila, 2023;Stevenson et al., 2020;Vogel et al., 2023).Numerous studies have attempted to elucidate the multifactorial causes underlying the functional loss of neurons in age-related NDDs (Hambright et al., 2017;Ricke et al., 2020;Zhao et al., 2008).Genetic and environmental factors such as abnormal protein dynamics (Abeti et al., 2011;Ludtmann et al., 2018;Parra-Rivas et al., 2023), oxidative stress (Hambright et al., 2017;Petri et al., 2012), channel dysfunction (Buskila et al., 2019), mitochondrial dysfunction (Liu et al., 2020;Manczak et al., 2011), DNA damage (Naumann et al., 2018), neurotrophin dysfunction (Prakash & Kumar, 2014), astrocytic dysfunction (Stevenson et al., 2020(Stevenson et al., , 2023)), and neuroinflammatory processes have been reported (Gamage et al., 2023;Kovacs, 2018;Kwon and Koh, 2020).In addition to disorder-specific pathological hallmarks, emerging evidence underscores the pivotal role of neuroinflammation across various neurodegenerative conditions.This review focuses on the neuroinflammatory processes associated with various NDDs and curcumin as a potential therapeutic agent, exploring its role in modulating neuroinflammation and offering insights into how it might address the complexities of these challenging conditions.

Neuroinflammation in NDDs
Neuroinflammation, a multifaceted phenomenon occurring within the central nervous system (CNS), has emerged as a pivotal player in the landscape of NDDs.Triggered by diverse factors, such as infection, trauma, toxin accumulation, and pathological injuries, neuroinflammation initially acts as a protective mechanism.This complex defense mechanism mainly involves the dynamic interplay of microglia and astrocytes, which are integral components involved in maintaining CNS homeostasis under nonpathological conditions.These mechanisms can falter when faced with abnormal conditions, leading to increased activation of these immune cells and the generation and release of inflammatory factors, revealing a dual faceted interaction of the immune system.Although neuroinflammation plays beneficial roles in promoting tissue repair and debris removal, the persistence of neuroinflammation poses risks, inhibiting regeneration and providing a potential gateway to the onset and progression of neurodegenerative diseases (Kwon and Koh, 2020;Lin et al., 2022;Sochocka et al., 2017).
The innate immune system forms the first barrier against any pathogen, and similar to macrophages in the body, microglia are the first line of defense in the CNS (Costantini et al., 2018).The role of glial cells in neuroinflammation and their role in NDDs has been extensively reviewed in the past decade (Gamage et al., 2023;Kekesi et al., 2019;Kwon and Koh, 2020;Lee et al., 2023;Mrak and Griffin, 2005;Stevenson et al., 2020Stevenson et al., , 2023;;Zhang et al., 2023), highlighting the key role that astrocytes and microglia play in this reactive state of the immune system within the CNS.
Astrocytes are the most prevalent glial cells in the mature mammalian brain and provide structural, metabolic, and tropic support for neurons (Song et al., 2002).They perform a wide range of homeostatic functions and play an important role in the formation and maintenance of the blood-brain barrier (BBB) (Lee et al., 2023).Astrocytes are key for the modulation of neuronal activity through neurotransmitter uptake, and they have been shown to control homeostasis through gap junctions activity, acting as a syncytium (Bellot-Saez et al., 2017).Moreover, astrocytes can store and supply energy, release trophic factors and actively engage in immune responses by interacting with microglia and peripheral immune cells (Zhou et al., 2019).
Microglia make up approximately 10-15% of the glial cell population of the adult brain (Subhramanyam et al., 2019).They are involved in numerous processes, including screening the extracellular matrix for changes and pathogens, executing physiological housekeeping tasks such as migrating to injured sites and maintaining myelin homeostasis, and facilitating protection against injurious stimuli such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (Kwon and Koh, 2020).In a healthy brain, glial cells can be activated by various substances, leading to immune responses and the production of inflammatory mediators.
While the pathophysiology of age-related neurodegenerative diseases remains to be elucidated, the immune system has emerged as a key player in their development, particularly in AD, PD, and ALS.In particular, circulating cytokines (including inflammatory-related cytokines, growth factors, and chemokines) are signaling molecules within the immune system that are associated with neuronal degeneration (Lee et al., 2023).This intricate network involves the overproduction of proinflammatory cytokines (such as interleukin-1β, IL-6, and tumor necrosis factor-α), anti-inflammatory cytokines (such as IL-1RA, IL-10, and IL-12), and various growth factors (such as nerve growth factors and stem cell growth factor), which collectively influence the progression of these age-related diseases (Yin et al., 2023).
Proinflammatory cytokines are activated by stress signaling pathways that ultimately regulate inflammatory responses.However, continued inflammatory reactions are harmful and impede the regeneration process (Sochocka et al., 2017).The persistence of inflammatory stimulation may arise from endogenous factors or environmental factors such as infection, trauma, and drugs.Indeed, these prolonged inflammatory responses in the central nervous system (CNS), mediated by microglia and astrocytes, have shown potential to contribute to the development of NDDs (Kwon and Koh, 2020).In the subsequent sections, we explore the role of neuroinflammation in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.Each of these NDDs presents unique challenges and manifestations of neuroinflammation.

Alzheimer's disease
Alzheimer's disease clinically manifests as a progressive cognitive decline accompanied by memory loss.Although associated with both genetic and environmental factors, the most common risk factor is age.Thus, it has been established as the prevalent cause of dementia in late adult life (Athar et al., 2021;Zhou et al., 2023).Decades of studies have proposed that amyloid beta (Aβ) overproduction and deposition, along with the formation of the intracellular aggregated phosphorylated protein tau, are the major pathological hallmarks of AD (Ismeurt et al., 2020;Zhou et al., 2022).The aberrant overexpression of these proteins is thought to initiate a cascade of cell signaling pathways that ultimately leads to synaptic dysfunction, neuronal damage, and neurodegeneration (Hong et al., 2016).For example, Aβ has been shown to enhance glucose uptake and glutamate release from astrocytes, leading to oxidative stress, overactivation of N-methyl-D-aspartate receptors (NMDARs), and synaptic disorders (Balu et al., 2019;Talantova et al., 2013).However, clinical and preclinical studies on the etiology of AD are limited.Indeed, other mechanisms have been proposed to contribute to its pathogenesis, such as oxidative stress-induced cytokine release, hypoglycemia, and vascular dysfunction, all of which lead to a chronic inflammatory response in the brain (Athar et al., 2021).Intriguingly, these contributors can be easily monitored and treated before AD clinical symptoms present; hence, they constitute a therapeutic target.
In exploring the complex landscape of preclinical AD, studies revealed early deterioration in the function of dendritic spines without evident cognitive impairment (Buskila et al., 2013;Crowe and Ellis-Davies, 2014).A study by Zou et al. in young deltaE9 mice revealed a failure to increase dendritic spine density under enriched environment conditions, disrupting novel neuronal connections.This deficiency, associated with early Aβ deposition, implicates BACE1 enzyme activity in decreasing Aβ plaques (Cole and Vassar, 2007) but fails to restore neural network reorganization.Significantly, anti-inflammatory interventions, including pioglitazone and interleukin-1 receptor antagonist (IL-1 RA), not only increase spine density but also remodel neural networks, highlighting the role of neuroinflammation in the impaired adaptive plasticity of layer V pyramidal neurons during preclinical AD (Zou et al., 2016).
Microglial and astrocytic activation plays a pivotal role in AD, influencing Aβ clearance and tau pathology development and exacerbating neurodegeneration.Janelidze et al. reported elevated levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 during preclinical and prodromal stages, which correlated with cerebrospinal fluid (CSF) tau in Aβ-positive individuals.These neuroinflammatory and cerebrovascular dysfunction biomarkers, particularly YKL-40 expressed by microglia and astrocytes, offer promising insights into monitoring neuroinflammation in AD (Janelidze et al., 2018).Moreover, Yin et al. demonstrated that cytokines are associated with an increased risk of AD, highlighting the protective role of IL-5 and the proinflammatory nature of elevated IL-12 (Yin et al., 2023).Neuroimaging studies have linked IL-12 with network functional connectivity, revealing its potential impact on brain function and further emphasizing the proinflammatory milieu in AD.
In response to tauopathy, a recent study by Zhou et al. showed that astrocytes lose their neurosupportive functions, contributing to impairments in the neuronal network and inducing AD-like symptoms.The inhibitory adenosine receptor A1R, which is posttranscriptionally regulated by tau via miR-133a-3p, was found to be upregulated in AD and implicated in glial reactivity, inflammatory responses, impaired synaptic plasticity, and memory deficits (Zhou et al., 2023).By abrogating A1R signaling, this study suggested an amelioration of the inflammatory response, particularly in aged mice, highlighting the crucial role of A1R activation/upregulation in neuron-glial crosstalk in individuals with AD.Notably, the study emphasized the localization of upregulated A1Rs in neurons with disrupted synaptic morphology surrounded by reactive astrocytes and neuroinflammation in individuals with AD (Zhou et al., 2023).Another study aimed at resolving glial contributions to AD using single-nuclei RNA sequencing (snRNA-seq) identified global and subtype-specific transcriptomic changes in astrocytes from AD brains (Sadick et al., 2022).These studies raise the question of the potential posttranscriptional mechanisms mediating aberrant protein and cytokine release alterations in AD.Correcting abnormalities in these signaling pathways may offer therapeutic potential, leading to improvements in glial reactivity, inflammatory responses, synaptic plasticity, and the mitigation of learning and memory deficits in the context of AD.

Parkinson's disease
Parkinson's disease, the second most common neurodegenerative disease, is characterized by the formation of α-synuclein deposits leading to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Stevenson et al., 2020).Phosphorylated α-synuclein in these aggregates results in the formation of Lewy bodies, a hallmark lesion in the brain of PD patients (Iwatsubo, 2003).Ludtmann et al. showed that α-synuclein oligomers induced mitochondrial dysfunction, leading to neuronal death through the activation of the mitochondrial permeability transition pore (PTP) (Ludtmann et al., 2018).Conversely, another study revealed that mitochondria contribute to α-synuclein aggregation through different mechanisms involving mutations in α-Syn and mitochondria-generated reactive oxygen species (mROS) that promote further oligomerization of α-Syn, creating a self-amplifying cycle in which mitochondrial dysfunction exacerbates α-Syn aggregation and vice versa (Choi et al., 2022).
Following this amplifying cycle, mROS can promote neuroinflammation by activating microglia and astrocytes, leading to the release of proinflammatory cytokines and chemokines (Park et al., 2015).Wang et al. compared the differential number and strength of ligand-receptor interactions among major cell types between control individuals and PD patients.They observed a global decrease in cell communications in neurons but increased communications for microglia, pericytes, endothelial cells, and fibroblasts (Wang et al., 2024).Neuroinflammation can exacerbate mitochondrial dysfunction through various mechanisms, including the production of nitric oxide (NO) and other reactive species that impair mitochondrial function and further contribute to oxidative stress, protein aggregation and neurodegeneration (Nakamura and Lipton, 2020).Therefore, the interplay between mitochondrial dysfunction, α-synuclein aggregation, and neuroinflammation creates a vicious cycle that contributes to the progression of PD pathology; thus, the amelioration of neuroinflammatory processes may disrupt this rotation.

Amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS), the predominant motor neuron disorder, is classified as a rare condition due to its low occurrence rate, with approximately 2-3 cases per 100 000 individuals in Europe (Obrador et al., 2020).ALS involves the gradual deterioration of motor neurons in the cortex, brainstem, and spinal cord (Stevenson et al., 2020).Numerous studies in human patients and mouse models have suggested that neuroinflammation is an active player contributing to the pathogenesis of ALS (Johann et al., 2015), and recently, Guttenplan and colleagues showed that the elimination of glial factors that induce reactive astrocytes markedly extends the survival of a mouse model of ALS (Guttenplan et al., 2020).Indeed, a common characteristic observed in patients with this disease is the abnormal proliferation of astrocytes surrounding motor neurons (MNs) (Buskila et al., 2019;Do-Ha et al., 2018;Stevenson et al., 2023).The canonical hypothesis is that in ALS, V. Perales-Salinas et al. the supportive function astrocytes typically provide to the MN is diminished during disease progression.A pilot study revealed increased levels of IL-6 in astrocyte-derived exosomes from the plasma of sporadic ALS patients compared to healthy controls, which were positively associated with the rate of disease progression, particularly in patients at an earlier disease stage.This study further suggested that measuring IL-6 levels in astrocyte-derived exosomes could be useful for revealing the pathophysiology of ALS (Chen et al., 2019).Furthermore, previous research within our group showed that astrocytes in the primary motor cortex have a significantly reduced K + clearance rate in an ALS mouse model, which was accompanied by changes in astrocytic morphology and impaired conductivity via Kir4.1 channels, suggesting a diminished supportive function of astrocytes to motoneurons during disease progression (Stevenson et al., 2023).These alterations in astrocytic function and morphology indicate that significant modifications occur during ALS, contributing to neuroinflammation and disease pathology.

Huntington's disease (HD)
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat in the huntingtin gene, leading to the formation of aggregates and posttranslational modifications that affect huntingtin function (Zheng and Diamond, 2012).This dysfunction can lead to neuronal loss through a range of molecular mechanisms, including transcriptional dysregulation, mitochondrial dysfunction, and oxidative stress (Jurcȃu, 2022).Notably, HD myeloid cells exhibit a proinflammatory phenotype, suggesting a major role for neuroinflammation in this disease (Miller et al., 2016).
HD primarily affects medium spiny neurons (MSNs) in the striatum (Bergonzoni et al., 2021), but there are also subtle changes in many other cell types.A recent study identified thousands of differentially expressed genes across most striatal cell types, including genes related to transcriptional changes in glial populations that are potentially driven by partial loss of function of PRC2 (Malaiya et al., 2020).
In HD, there is an increase in the expression of proinflammatory genes in the brain.For example, Crotti et al. reported that the level of SPI1 (PU.1), a key factor in myeloid fate determination, is elevated in both the striatum and cortex of HD individuals, along with increased levels of IL6, IRF1, and TLR2 mRNA in the striatum and a trend toward increased levels of IL6, TNFα, and TLR2 in the cortex.They also performed immunostaining of postmortem samples from HD patients and showed an increase in microglia numbers and PU.1 expression.These observations suggest a consistent inflammatory profile in HD (Crotti et al., 2014).Moreover, a recent study by the Khakh group revealed a core disease-associated astrocytic molecular signature comprising 62 genes, which could be reversed by decreasing the expression of the mutant huntingtin protein in astrocytes (Diaz-Castro et al., 2019).These findings collectively underscore the importance of transcriptional dysregulation in HD, particularly in myeloid cells, and suggest potential targets for therapeutic intervention.

Curcumin as a potential therapeutic for NDDs
Understanding the role that neuroinflammation plays during the onset and progression of brain disorders is crucial for developing novel treatment strategies.Over the past two decades, observational studies have suggested a potential link between nonsteroidal anti-inflammatory drug (NSAID) use and a reduced risk of NDDs.A clinical study by Côté et al. revealed a significant association between NSAID use and a decreased incidence of AD (Côté et al., 2012).Conversely, other groups have shown that anti-inflammatory drugs do not yield discernible improvements, especially in cognitive measures (Jaturapatporn et al., 2012).
On the other hand, cytokine-suppressive inflammatory drugs (CSAIDs) are a class of compounds that target specific cytokines that regulate cellular responses to inflammatory stimuli.These compounds have demonstrated high selectivity and efficacy as anti-inflammatory agents in animal disease models (Denkert et al., 2003).Given their ability to modulate inflammatory responses, CSAIDs have garnered interest as potential therapeutic agents for NDDs.Curcumin, a well-known CSAID, exerts its anti-inflammatory effects by regulating the activity of various transcription factors and their associated proinflammatory signaling pathways, such as the STAT, NF-κB, and AP-1 pathways (Ullah et al., 2017).This makes curcumin a promising candidate for the treatment of NDDs, as illustrated in Fig. 1.

Composition, natural source, and definition of CSAID
Turmeric spices, which are derived from the rhizomes of the Curcuma longa L. plant in the ginger family, have been utilized in traditional medicine for centuries (Fadus et al., 2017).The primary active compound in turmeric is curcumin, which comprises 2-5% of its composition (Ullah et al., 2017).Curcumin, a polyphenolic compound, exhibits a wide range of pharmacological properties, including antioxidant, anti-inflammatory, antiviral, and antibacterial activities (Venigalla et al., 2016).Curcumin can exist in different forms, with the enolate form displaying radical scavenging abilities, contributing to its antioxidant effects.The various tautomeric structures of curcumin derivatives play a significant role in determining their molecular targets and clinical applications (Ullah et al., 2020).

Historical usage in traditional medicine
Curcumin has been extensively used as a traditional medicine in many societies, especially among Asian communities within India, Thailand, Persia and China (Akaberi et al., 2021).Monographs from the Islamic Traditional Medicine (ITM) textbooks describe curcumin as a cooling agent that is predominantly used in the management of inflammatory-related conditions (Razi, 1968).In Indian medicine, topical curcumin has been used to treat various skin conditions, such as scabies, herpes, and wound healing (Charles and Charles, 1992;Kundu et al., 2005;Organization, 1999); however, it has also been used for the treatment of cardiovascular (i.e., tachycardia) and neurological diseases, such as epilepsy and paralysis (Ayati et al., 2019;Jorjāni, 2006).
In ancient Hindu medicine, curcumin extracts have also been applied externally to alleviate sprains and swelling, skin infections, eczema, arthritis, and abdominal pain-related conditions (Fadus et al., 2017;Shrishail et al., 2013).Similarly, turmeric is used in traditional Thai medicine to treat conditions such as anal and vaginal hemorrhoids, gastrointestinal ulcers, and skin and ringworm diseases, as well as to prevent common cold and sexually transmitted diseases such as gonorrhea (Mahady et al., 2006;Prasad and Aggarwal, 2011).
In Chinese medicine, turmeric tubers, which are bitter and spicy, are used for treating hepatitis and liver cirrhosis, relieving menstrual pain and managing neurological illnesses such as epilepsy and mania.Tumeric rhizomes, on the other hand, have been utilized to treat amenorrhea, postpartum abdominal pain, diabetic wounds and jaundice.In addition, it is important to mention that in all of the above communities, turmeric is used extensively as a spice in cooking curries, to some extent due to its ability to combat bacterial, viral and fungal infections, as it is known for its antioxidant, anticancer, neuroprotective, and cardioprotective properties (R Vasanthi and P Parameswari, 2010;Sumathi et al., 2017), as well as for being an analgesic and wound-healing agent (Bone and Mills, 2012;Zhou et al., 2016).

Curcumin bioavailability in the body and BBB
Although curcumin is well known for its wide range of therapeutic properties, it has few characteristics that reduce its bioavailability in the body, such as poor water solubility, high instability, rapid degradation, and rapid metabolism, which essentially limits its potential as an oral medication (Ghalandarlaki et al., 2014;Tsai et al., 2011).Upon ingestion, curcumin undergoes rapid metabolism and biotransformation in the small intestine, liver, and kidneys, which leads to the formation of curcumin conjugates, namely curcumin sulfate, curcumin glucuronide, and methylated curcumin, as illustrated in Fig. 2A (Jankun et al., 2016;Pan et al., 1999;Vareed et al., 2008).A further reduction in free curcumin is mediated by gut microbes, which reduce curcumin to other metabolites, such as dihydrocurcumin, tetrahydrocurcumin and hexahydrocurcumin (Hassaninasab et al., 2011;Vareed et al., 2008).The free form of curcumin is considered as the most bioactive form of all the curcumin metabolites, hance it is important to mention that enzymes such as β-glucuronidase and sulfatases convert the glucuronide and sulfated conjugates back to the free active form of curcumin (Fig. 2).
While this substantial increase in free curcuminoids has great potential as a therapeutic agent, it also raises concerns about overdosing.Indeed, while toxicological studies in animals and phase-1 human clinical trials revealed that curcumin formulations are safe even up to 12 g/day and even when taken for an extended period of 6 months (Aggarwal et al., 2003;Lao et al., 2006;Peng and Qian, 2014), recent reports have raised concerns about their hepatotoxicity and liver injury potential, especially when they are administered with peperine, which increases its bioavailability (Halegoua-DeMarzio et al., 2023).Due to these reports, the Australian Therapeutic Goods Administration (TGA) published a safety advisory on the risk of liver injury for medicines containing turmeric or curcumin (Australia, 2023).
Several studies have shown that curcumin is capable of crossing the blood-brain barrier (BBB), which is the main gatekeeper for transporting therapeutics into the brain (Askarizadeh et al., 2020;Hamada et al., 2020).There are various pathways that regulate the movement of molecules across the BBB, including the paracellular aqueous pathway, the transcellular lipophilic pathway, the transport protein, cell-mediated transcytosis, and absorptive transcytosis, as illustrated in Fig. 2 (Abbott et al., 2006).Since curcumin is lipophilic in nature, it may cross the BBB via the trancellular lipophilic pathway, however this still remains obscure and unexplored (Barry et al., 2009).Indeed, modified curcumin preparations provide superior BBB permeability, with gluco-oligosaccharide and nano delivery systems showing their ability to cross the BBB most effectively (Askarizadeh et al., 2020;Hamada et al., 2020).While several in vivo and in vitro studies have suggested that curcumin formulations alleviate neurodegenerative symptoms, more studies are needed to investigate the efficacy of these formulations in humans.Moreover, β-glucuronidase, which converts glucuronide and sulfated conjugates back to the free active form of curcumin, has been reported to be released during inflammatory conditions from reactive microglia and astrocytes, especially in diseased conditions (Antunes et al., 2012;Kroh and Renkawek, 1973).However, the exact role and expression of these enzymes, specifically their potential to affect BBB function during neurodegenerative diseases during which the BBB is more permable is not clear as of yet.Furthermore, the form of curcumin that exists in the target tissues is not known, and the ability of these curcumin conjugates to reach the brain has yet to be fully elucidated.

Preclinical studies implicating curcumin as a potential therapeutic
Broadly, curcumin has been shown to reduce the expression of inflammatory mediators such as TNF-α and IL-1β and to affect mitochondrial dynamics and epigenetic changes (Hatami et al., 2019).Curcumin also upregulates the transcription factor Nrf2 and its downstream target HO-1, which are involved in the cellular response to oxidative stress (Yang et al., 2009).Furthermore, it inhibits the activation of NF-κB, a key transcription factor involved in proinflammatory gene expression (Jobin et al., 1999).Finally, curcumin has been shown to increase the activity of sirtuins, particularly SIRT1, which play a role in the protective effects of curcumin against neurological disorders (Zendedel et al., 2018).Multiple preclinical trials on the potential of curcumin for the treatment of neurodegenerative disease have been conducted over the years, and promising results on its bioavailability, anti-inflammatory effects, and disease progression delay have been reported (Table 1).
An in vitro and in vivo study performed in mice revealed measurable brain curcumin levels of ~1.1 μM after 1 h of injecting 50 μM curcumin into the right carotid artery, suggesting that this polyphenol can cross the blood-brain barrier (BBB) (Yang et al., 2005).In vitro, this study also revealed that curcumin inhibits the formation of Aβ oligomers, and its effects are not determined by the specific order of amino acids in Aβ but rather by the overall structure of the fibrils.This indicates that curcumin likely influences cellular processes and functions through mechanisms that occur after gene expression and protein synthesis, such as modifying protein structure or activity or regulating protein interactions.Lim et al. found that both low and high doses (160 and 5000 ppm, respectively) of curcumin had beneficial effects on reducing inflammation and oxidative stress in transgenic mouse models of AD that were fed for 6 months.Specifically, curcumin decreased the levels of IL-1β and oxidized proteins while also reducing soluble and insoluble Aβ levels, particularly with low-dose treatment (Lim et al., 2001).Furthermore, Teter and colleagues also conducted a study on Tg2576 transgenic mice treated with different doses of curcumin and reported that curcumin could modulate the expression of innate immune genes such as TREM2 and CD33 to promote the phagocytic clearance of amyloid plaques and restore neuroinflammatory networks involved in neurodegenerative diseases.At a low dose (160 ppm), curcumin decreased CD33 and increased TREM2 expression, stimulating microglial migration and phagocytosis of amyloid plaques and acting as an immunomodulatory treatment similar to an anti-Aβ vaccine (Teter et al., 2019).Curcumin at low doses has also been shown to increase the level of sirtuins (Grabowska et al., 2016).Sirtuins are evolutionarily conserved proteins that are dependent on nicotinamide adenine dinucleotide (NAD+) and are known for regulating the activity of various enzymes and transcription factors through deacetylation (Jia et al., 2016).These Fig. 2. Metabolism of curcumin in the body upon oral administration.A) Curcumin undergoes rapid metabolism and biotransformation reactions in the stomach, liver and kidneys.Upon oral ingestion, it is converted to curcumin sulfates and curcumin glucuronides due to the action of the enzymes β-glucuronidase and sulfatase.In addition, it is reduced to dihydrocurcumin, tetrahydrocurcumin and hexahydrocurcumin by gut microbes.Curcumin and its metabolites are available in the systemic circulation; however, the forms of curcumin that are capable of crossing the well-protected physical barrier of the BBB and the pathways through which they enter the brain are still unclear.B) Schematic diagram depicting the possible pathways through which curcumin crosses the BBB under normal (top) and neurodegenerative (bottom) conditions.Some of the pathways that control the trafficking of molecules across the BBB include i) passive diffusion through tight junctions; ii) transcellular lipophilic pathways; iii) transport proteins and efflux pumps; iv) receptor-mediated and adsorptive transcytosis; and v) cell-mediated transcytosis, as reviewed by (Abbott et al., 2010).Owing to the lipophilic characteristics of curcumin, it most likely enters the brain via the transcellular lipophilic pathway (Barry et al., 2009).Curcumin is also known to interact with and regulate the expression of P-gp (Anuchapreeda et al., 2002;Sreenivasan et al., 2013), an efflux pump that plays a role in brain detoxification and is downregulated during various NDDs (Bartels et al., 2008); thus, it has the potential to affect BBB permeability during disease conditions where the BBB is leaky.Portions of the figure utilized images from Servier Medical Art, licensed under the Creative Commons Attribution 4.0 Unported License (Servier; https://smart.servier.com/).genes are categorized into five classes in mammals.Among these proteins, SIRT1, primarily located in the nucleus, interacts with numerous partners and targets for deacetylation (Zendedel et al., 2018).Studies have shown that SIRT1 plays a crucial role in maintaining motor neuron health (Herskovits and Guarente, 2014).SIRT1 expression decreases with age, but overexpressing SIRT1 has been shown to slow age-related degeneration of motor neuron presynaptic sites at neuromuscular junctions.This effect is particularly significant in mouse models of ALS, where SIRT1 overexpression delays disease progression (Herskovits et al., 2018).These findings suggest that interventions targeting aging-related mechanisms may also slow the progression of ALS.In PD, overexpression of SIRT1 increased the lifespan of a mouse model of A53T α-synuclein mutation by reducing α-synuclein aggregates (Donmez et al., 2012).Overall, SIRT1 has been implicated in directly deacetylating proteins involved in neurodegenerative disorders, further highlighting its potential therapeutic role (Montie et al., 2011).The link between these findings and the role of curcumin as a CSAID lies in its potential to modulate SIRT1 activity, possibly by mitigating neurodegeneration through anti-inflammatory and neuroprotective mechanisms.
Another study showed that the process of phagocytosis, followed by the activation of NADPH oxidase in microglia, contributes to the neuronal damage induced by aggregated α-synuclein in PD.Thus, targeting microglia, particularly NADPH oxidase, is proposed as a potential therapeutic strategy to intervene in PD progression (Zhang et al., 2005).Indeed, the role of curcumin as a CSAID has been linked to its ability to modulate microglial activation (Karlstetter et al., 2011) and oxidative stress (Parada et al., 2015), potentially mitigating neuroinflammation and neuronal damage in PD.Furthermore, curcumin has been shown to attenuate mitochondrial oxidative damage through SIRT1 activation, suggesting a potential role in improving mitochondrial function (Yang et al., 2013).As mentioned above, mitochondrial dysfunction is a critical factor in PD, leading to the loss of dopaminergic neurons (Stevenson et al., 2020).A recent study revealed that despite severe mitochondrial dysfunction, dopaminergic neurons in the substantia nigra maintain a high mitochondrial inner membrane potential to counterbalance constant calcium influx.However, this imbalance in the mitochondrial redox system ultimately leads to neuronal death (Ricke et al., 2020).The potential of curcumin as a CSAID agent can modulate mitochondrial function and redox balance, potentially protecting dopaminergic neurons from degeneration in PD patients.
In vitro and in vivo studies have also shown the beneficial effects of curcumin on astrocytic function (Daverey and Agrawal, 2016;Wang et al., 2013).An in vitro study on human cell lines with induced oxidative stress revealed that astrocytes were activated in a dose-and time-dependent manner (Daverey and Agrawal, 2016).Daverey et al. reported that at elevated concentrations or with prolonged exposure to hydrogen peroxide (H 2 O 2 ), GFAP expression decreases, suggesting that GFAP upregulation may serve as an initial defense mechanism against oxidative stress.Interestingly, when treating the cells with curcumin, they observed that it mediates its protective effect by blocking both extrinsic and intrinsic apoptosis pathways through the suppression of caspase 1 upregulation.Caspase-1 triggers various pathways leading to the breakdown of mitochondria, causing the production of ROS, loss of mitochondrial membrane potential, permeabilization of mitochondria, and fragmentation of the mitochondrial network (Yu et al., 2014).Its activation also leads to the release of proinflammatory cytokines (Chai et al., 2022), revealing the multiple pathways through which curcumin mediates the transcriptional regulation of important players in neurodegeneration, such as astrocytes.Moreover, Wang et al. reported that curcumin effectively ameliorated spatial memory deficits in a rat model of induced AD.While the injection of Aβ1-40 into the hippocampus led to the upregulation of GFAP mRNA transcription, a high-dose intraperitoneal injection of curcumin downregulated GFAP mRNA expression V. Perales-Salinas et al. (Wang et al., 2013).These findings suggest that curcumin may exert its beneficial effects on spatial memory in AD through its ability to modulate astrocytic function and GFAP expression levels.Glutamate excitotoxicity is another key factor in neurodegeneration and is influenced by oxidative stress, neuroinflammation, and impaired glial glutamate uptake (Heneka et al., 2014).In conditions such as AD, PD, HD and ALS, excessive glutamate release leads to overactivation of glutamate receptors, particularly NMDA receptors, resulting in calcium influx and subsequent neuronal damage or death (Carvajal et al., 2016).
In an in vitro study on primary cortical neurons, glutamate induced significant cell death and apoptosis, but these effects were blocked by pretreatment with curcumin (Jia et al., 2016).The authors attributed the neuroprotective effect of curcumin to SIRT1-mediated deacetylation of PGC-1α, a key coactivator that plays a central role in a network dictating the transcriptional regulation of mitochondrial biogenesis and respiratory function (Scarpulla, 2011).Nonetheless, Miller et al. reported that the overexpression of PGC-1α leads to a decrease in the levels of NADPH, a key molecule involved in redox metabolism, resulting in a more oxidized state.This study also highlights the existence of distinct nuclear and cytosolic pools of NADPH, which respond independently to the status of PGC-1α, which suggests a complex regulatory mechanism involving multiple cellular compartments (Miller et al., 2019).The ability of curcumin to inhibit DNA methyltransferases and regulate histone modifications suggests its potential role in modulating NADPH activity (Liu et al., 2011); however, the precise mechanisms by which curcumin, known for its pleiotropic effects, regulates these coactivators and molecules remain to be fully elucidated.

Current applications in modern healthcare
A series of clinical studies have explored the potential of curcumin for treating different neurodegenerative diseases with mixed results.Despite encouraging effects regarding the potential therapeutic benefits of curcumin, most early placebo-controlled trials in humans have shown unsatisfactory outcomes (Table 2).However, this could be due to the use of curcumin formulations with restricted bioavailability.
In 2012, Hishikawa et al. conducted a case study to investigate the effects of turmeric treatment on the behavioral and psychological symptoms of dementia (BPSD) in AD patients.Three cases were examined, each of whom demonstrated significant improvements in BPSD, including agitation, depression, and irritability, following turmeric administration (764 mg/day for 12 weeks) without any adverse effects.This study suggested that turmeric treatment may offer a safer alternative to conventional pharmacological treatments for BPSD in AD patients, potentially reducing the need for antipsychotic drugs.The authors speculate that the modulatory effects of turmeric on neurotransmitters and its antioxidant and anti-inflammatory properties may contribute to the observed therapeutic effects.In addition, they found that combining turmeric with donepezil resulted in additional improvements, indicating its potential as an adjunctive therapy (Hishikawa et al., 2012).However, larger clinical trials should be conducted to validate these findings.
In a randomized, double-blind, placebo-controlled trial, participants received either curcumin or placebo treatment.Curcumin was administered at a dose of ~80 mg daily (Longvida® Optimized Curcumin).The aim of this study was to investigate the effects of curcumin on cognition, mood, and coping with mental health challenges in healthy older adults.The findings showed that acute and chronic curcumin treatment improved performance on tasks assessing sustained attention and working memory compared to placebo.Chronic curcumin treatment for four weeks also reduced fatigue and enhanced resilience to psychological stress, while no significant improvements were observed in tasks assessing executive function.These results suggest that curcumin supplementation, even at 4 weeks, may hold promise for preventing agerelated cognitive decline, reducing fatigue, and mitigating the affective impact of psychological stress in older adults (Cox et al., 2015).
Conversely, Rainey-Smith et al. studied the effect of curcumin (1500 mg/day) in a healthy cohort and found no significant differences after 12 months.The authors suggested that the lack of visible effects may be due to the healthy cohort in question and that, if performed in diseased patients, the effect could be clearer (Rainey-Smith et al., 2016).Nevertheless, a 24-week double-blind placebo-controlled trial assessing the tolerability of Curcumin C3 Complex® in individuals with mild-to-moderate AD failed to detect significant plasma levels of native curcumin, potentially due to its limited bioavailability and extensive metabolism in the gastrointestinal tract.While the study suggested a possible peripheral anti-inflammatory effect of curcumin, challenges related to curcuminoids penetrating the blood-brain barrier have been acknowledged.Even with high levels of glucuronidated curcuminoids in plasma, no significant clinical or biochemical evidence of its efficacy against AD was observed (Ringman et al., 2012).Despite its observed antioxidant, anti-inflammatory, and anti-amyloid effects in vitro and in animal models, these findings align with other studies that also failed to demonstrate significant clinical benefits of curcumin in AD patients (Baum et al., 2008), and while no significant differences between treated and placebo groups were observed, Baum et al. reported a significant increase in plasma vitamin E levels and serum Ab40 levels.The authors suggested that curcumin may promote the disaggregation of Aβ deposits in the brain, resulting in their subsequent release into the bloodstream (Baum et al., 2008).
In another randomized, double-blind, placebo-controlled clinical trial, taking Theracurmin (180 mg/day) led to significant memory improvement over 18 months, as measured by both the Buschke SRT and the Consistent Long-Term Retrieval score, which reflects the ability to consolidate and recall information over time (Small et al. 2018).The observed improvements in cognitive functioning were supported by significant differences in the scores on the Trail Making Test Part A between the curcumin and placebo groups.Additionally, curcumin consumption was associated with reduced FDDNP binding in brain regions such as the amygdala and hypothalamus, which are involved in memory processing, emotional responses, and neurodegeneration associated with Alzheimer's disease.Chico et al. investigated the effects of a curcumin-based dietary supplement, Brainoil, on ALS patients over a 6-month period.The trial consisted of a double-blind phase for the first three months, followed by an open-label phase.The results showed that while there were no significant differences between groups in overall ALS-FRS-r, MRC, or BMI parameters, Group B, which received Brainoil for the entire 6 months, exhibited a milder decline in respiratory function than Group A (receiving placebo for 3 months before transitioning to Brainoil).Intragroup analysis revealed stabilization or improvement of the ALS-FRS-r and MRC scores in patients treated with Brainoil, particularly in Group B. Additionally, Brainoil supplementation appeared to stabilize BMI, suggesting a potential protective effect on muscle mass loss.Notably, brain oil intake was associated with reduced oxidative stress levels, as evidenced by decreased AOPP levels in Group B compared to Group A and healthy controls.Their findings suggest a potential therapeutic benefit in ALS, particularly in preserving respiratory function and reducing oxidative stress (Chico et al., 2018).In accordance with these results, a double-blind, randomized, placebo-controlled trial in 54 patients with ALS showed improved survival probabilities, especially in patients with bulbar symptoms (Ahmadi et al., 2018).Using a formulation with nanomicelles, Ahmadi et al. measured the safety and survival outcomes of curcumin as an add-on treatment for ALS.Further research is needed to explore different curcumin formulations and their efficacy in NDD treatment, considering potential differences between animal models and human biology, as well as variations in curcumin metabolism, formulations, dosage, and clinical experimental design.

Conclusions
The anticipated growth in the aging population worldwide implies a  NCT00164749 (Baum et al., 2008) Curcumin levels in plasma peaked at 1.5-4 h after ingestion, with glucuronidation being the primary metabolic pathway.Total curcuminoid levels tended to be higher with 4 g compared to 1 g, and higher with capsules compared to powder administration further increase in the number of people with neurodegenerative diseases and is expected to pose a tremendous burden on global health systems.In that regard, herbal nutraceuticals such as curcumin, which have been used for generations to treat a variety of illnesses and have beneficial impacts on various aspects of NDDs, may have clinical applications.However, while curcumin is considered as safe supplament, the exponential increase in its bioavailability via modified formulations poses a risk for side effects; hence, precautions must be taken, especially when it is consumed in large quantities for long periods or when it is combined with other medications.As some of the studies discussed above have shown conflicting evidence about the benefits of different doses of curcumin, considerable attention should be given to its beneficial effects on different age groups, as neuroinflammation and BBB impairment are more widespread in elderly individuals, which may affect the overall concentration of free curcumin in the brain.Indeed, elucidating the involvement of curcumin in aging and neurodegeneration has great potential for developing future CNS-related therapeutic targets.Further research is required to elucidate the mechanisms by which Curcumin affects brain physiology, especially BBB integrity, under both physiological and disease conditions.

Fig. 1 .
Fig. 1.Cellular and molecular processes effected by curcumin.Schematic diagram depicting five key pathways that are effected by curcumin, including modulation of anti-inflammatory processes, regulation of mitochondrial and cell survival processes, microglial phagocytic activity and oxidative stress.

Table 1
Summary of preclinical data assessing curcumin as a potential therapeutic agent for treating neurodegeneration, neuroinflammation and aging.Curcumin at low doses demonstrated anti-inflammatory and antioxidant effects, reducing markers of inflammation, amyloid burden, and oxidative damage.High doses did not show the same effects on insoluble Aβ levels.

Table 2
Summary of clinical trials on curcumin as a potential therapeutic agent for treating neurodegeneration, neuroinflammation and aging.