Nutraceuticals: A strategy to mitigate neurotoxicity

Abstract

Increased evidence from epidemiological research and pre-clinical studies have presented a correlation between exogenous neurotoxicants (such as aluminum, arsenic, lead, cadmium, mercury and ethanol) and various neurobiological disorders which contribute to cognitive impairments. The existing data demonstrate that nutraceutical supplementation affords neuroprotective effects against neurotoxicity. Nutraceuticals improved learning and memory impairments, anxiety and depressive-like behavior, locomotor activity and neuropathic pain. The most common molecular and cellular mechanisms in nutraceutical therapy include attenuation of oxidative stress (by suppressing lipid peroxidation and increasing antioxidant enzymes and contents), suppression of apoptosis (by increasing B-cell lymphoma 2 (Bcl2) expression, and reduction in Bcl-2–associated X protein (Bax), caspase-3 and cytochrome c expression), suppression of neuroinflammation (by inhibiting inflammatory cytokines), inhibition of amyloid β (Aβ) plaque and neurofibrillary tangles, and increased synaptic plasticity (by increasing Brain-derived neurotrophic factor (BDNF), and regulating cholinergic and neurotransmitter systems.

1. Introduction

The central nervous system (CNS) is uniquely sensitive to exogenous neurotoxicants. Numerous critical periods of susceptibility exist during which exposure to environmental neurotoxicants can disrupt typical developmental processes. The specific timing and length of neurotoxicants exposure throughout developmental stages can lead to a diverse array of structural and functional impairments (Miodovnik, 2011). Neurotoxicants exhibit heightened effects during the prenatal period and throughout the early stages of childhood development (Cardenas-Iniguez et al., 2022). In addition to neurodevelopmental disorders, exposure to neurotoxicants leads to neurodegeneration (Nabi and Tabassum, 2022). Increasing evidence from epidemiological research has presented a correlation between exogenous neurotoxicants and various neurobiological disturbances which contribute to cognitive impairments and diminished quality of life (Iqubal et al., 2020). Neurotoxicants such as aluminum, arsenic, lead, cadmium and mercury cause neurodegeneration by inducing oxidative stress, neuroinflammation, myelin sheath disruption, and changes in blood-brain membrane permeability (Iqubal et al., 2020; Nabi and Tabassum, 2022). Some neurotoxic metals have been shown to associated with the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to their ability to produce amyloid plaques, α-synuclein and neurofibrillary tangles (NFTs) which, respectively, constitute the principal characteristic of these neuronal impairments (Sharma et al., 2020; Roy et al., 2024). In the last few years, the treatment and prevention of exogenous-induced neurotoxicity by nutraceuticals have attracted attention.

Nutraceutical, a term originating from the amalgamation of “nutrition” and “pharmaceutical,” denotes any product derived from botanical sources and nutrients employed not solely for nutritional but also for therapeutic applications. Nutraceuticals encompass a diverse array of bioactive compounds, including polyphenols, fatty acids, and vitamins. In recent years, nutraceuticals have experienced a notable surge in popularity, attributable to their physiological benefits and potential health effects, including anti-inflammatory, anti-cancer, antioxidant properties, as well as their role in the regulation of lipid metabolism (Caponio et al., 2022). Moreover, nutraceuticals have a significant beneficial impact on the CNS function (Gupta and Costa, 2021).

Current pre-clinical studies suggest that administration of diverse nutraceuticals provides neuroprotective effect against exogenous neurotoxic substances, which encompass hazardous metals and ethanol. Here, we evaluated the impacts of most common nutraceuticals on common exogenous-induced neurotoxicity.

2. Nutraceuticals and exogenous neurotoxic agents

2.1. Aluminum

Aluminum (Al) is a potent environmental toxin and it is the third most abundant element in the earth’s crust (Brough and Jouhara, 2020). Natural phenomena, the effect of acid rains and the expansion of industrialization of the world contribute to the dispersion of aluminum throughout the environment and its presence in water and food sources (Bondy, 2016). Aluminum ion has no known beneficial physiological function in metabolic processes (Igbokwe et al., 2019). Adverse effects of aluminum have been posited to alter some physiological and biochemical processes in the CNS, such as synaptic transmission, gene expression, protein synthesis and degradation, neurotransmitter synthesis, inflammatory responses, and oxidative stress mechanisms (Blaylock, 2024). It has been implicated in the initiation, development, and propagation of neurodegeneration and cognitive decline in several human neurodegenerative disorders, including Alzheimer’s disease (AD), autism spectrum disorder (ASD), Parkinson’s disease (PD), multiple sclerosis (MS), and dialysis encephalopathy (DE) (Bryliński et al., 2023). However, data to the contrary exist as well, thus it has yet to be fully characterized if aluminum is a potent neurotoxin. Several studies demonstrated neuroprotective effect of nutraceuticals supplementation in neurotoxicity induced by aluminum. They will be mentioned below.

2.2.1. Coenzyme Q10 and aluminum

The administration of Coenzyme Q10 (CoQ10) at 200 mg/kg/day, orally, for 4 weeks showed neuroprotective effect against neurotoxicity induced by aluminum in rats by reducing amyloid β (Aβ), inhibiting acetylcholinesterase (AchE) and suppressing oxidative stress (Ali et al., 2016). CoQ10 at 1200 mg/kg/day, orally, for 4 weeks decreased aluminum-caused neurotoxicity and oxidative damage in rats by inhibiting Reactive oxygen species’ (ROS) production and increasing the antioxidant system activity (Saeed et al., 2021). It at 8 and 12 mg/kg, i.p., for 4 weeks stimulated antioxidant activity by increasing glutathione (GSH), vitamin E, and activities of superoxide dismutase (SOD), catalase (CAT), and reducing lipid peroxidation (LPO) in the cerebral cortex of rats (Majumdar et al., 2014).

2.2.2. Omega-3 and aluminum

Omega-3 fatty acids at 20 mg/kg/day, orally, for 1 month lightened the neurotoxic effects of aluminum by activating antioxidant status, reducing LPO (Oda, 2016), and inhibiting apoptosis in rabbits (El-Kerdasy and Shaheen, 2021). Omega-3 at different dosages and treatment durations ((4000 mg/kg diet, for 40 days), (20 mg/kg, orally, for 2 months), and (0.4 g/kg and 0.8 g/kg, orally, for 90 days)) induced antioxidant status by increasing SOD, CAT and GSH levels, and reducing malondialdehyde (MDA) and ROS levels in the rats’ brain (El-Habibi et al., 2011; Ali et al., 2014; Mohammed and Ali, 2020). It at 20 mg/kg/day (orally, single daily dose, from day 14 of gestation until day 21 after birth) also suppressed apoptosis by inhibiting caspase-3 (El-Kerdasy and Shaheen, 2021; Albakoush et al., 2022). Moreover, omega-3 at 0.4 g/kg and 0.8 g/kg, orally, for 90 days decreased Aβ peptide levels in aluminum-treated rats (Mohammed and Ali, 2020).

2.2.3. Alpha-lipoic-acid and aluminum

Alpha-lipoic-acid (α-LA) at different dosages and treatment durations ((100 and 200 mg/kg/day, orally, for 2 weeks), (25 mg/kg/day, mixed in feed, for 12 days), and (20 mg/kg, i.p., for 2 weeks)) improved aluminum-induced learning and memory impairments assessed by Morris water maze test in rats (Abdullahi et al., 2023) via targeting cholinergic system by increasing muscarinic receptor genes M1, M2 and choline acetyltransferase (ChaT), and inhibiting AChE activities (Mahboob et al., 2016; Al-Otaibi et al., 2018). In addition, its administration (20 mg/kg, i.p., for 2 weeks) resulted in inhibition of aluminum-induced neurotoxicity and oxidative stress via increased GSH and SOD, and decreased LPO in rats (Al-Otaibi et al., 2018).

2.2.3. Vitamins and aluminum

Vitamin B6 at 8 mg/kg/day (orally, for 1 month) improved spatial memory in T-maze test, reversed the structural impairment, and increased the number of branch out points and axonal length in hippocampus in aluminum-caused neurotoxicity in rats (Sreekumaran and Ramakrishna, 2002; Sreekumaran et al., 2003).

Vitamin C (50 mg/kg/day, orally, for 2 weeks), D3 (0.0125 mg/kg/day, i.p., for 2 weeks) and E (2.5 mg/kg/day, orally, for 2 weeks) led to improvement in aluminum-induced memory loss assessed by Y-maze test in rats (Rashad et al., 2022). Mechanistically, treatment with vitamin C at 50–400 mg/kg/day, orally reduced AChE activity (Rashad et al., 2022) and LPO, and increased CAT and glutathione peroxidase (GPx) levels in rats (Anane and Creppy, 2001; Jankeer, 2015; Abayomi et al., 2021). It (5 mg/l, once daily, for 180 days) also decreased the aluminum concentration, and increased dopamine and GABA in Nile catfish’s brain (Khalil and Hussein, 2015).

Vitamin E at 300 IU/kg/day, orally, for 12 weeks prevented aluminum-induced neurotoxicity in rats by increasing antioxidants and inhibiting LPO, and reducing AChE activity (El-Fattah et al., 1998; El-Nahrery, 2015). Administration of vitamin E at 2.5–100 mg/kg/day, orally improved brain neurotoxicity via inhibition of AChE activity, and reduction in MDA, ROS and Aβ content, and enhancement in SOD, CAT and GSH in aluminum-treated rats (Abubakar et al., 2004; El-Demerdash, 2004; Adedosu et al., 2018; Inneh and Eiya, 2023). In addition, the neuroprotective effect of vitamin E (150 mg/kg/day,orally,for 45 days) against aluminum-induced neurotoxicity in rats might be due to its inhibitory effects on neuroinflammation amyloid plaques and neurofibrillary tangles (Jabeen et al., 2023).

Vitamin D at 400 IU/kg/day, p.o., for 6 weeks ameliorated hippocampal degenerative changes in AD rat model induced by aluminum (Bashraheel et al., 2023). Vitamin D at 150 IU/day, p.o., for 2 months protected against aluminum-induced cognitive decline assessed by the Morris water maze and novel object recognition test, neuronal dystrophy and neuronal loss, activation of glial, and oxidative stress in rats (Faccinetto-Beltrán et al., 2024). It improved oxidative stress status induced by aluminum via enhancement of GSH and SOD levels, and reduction of MDA level. In addition, vitamin D at 500 IU/kg/day, p.o., for 6 weeks decreased AChE and neurofilament light chain plasma levels, and enhanced dopamine level AD rat model induced by aluminum (Alnefaie and Bawazir, 2024).

2.2.4. Polyphenols and aluminum

Several studies have documented that quercetin treatment significantly decreased aluminum-induced neurotoxicity. Administration of quercetin 10 mg/kg/day, p.o., for 12 weeks in aluminum-treated rats improved cognition, anxiety, muscle coordination, locomotion and initial exploratory patterns in different behavioral tests such as motor function test, shuttle avoidance, aggressometer, Morris water maze, open field and elevated plus maze tests (Sharma et al., 2013). Quercetin (10 mg/kg/day, p.o., for 12 weeks) suppressed neurotoxicity induced by aluminum in rats via reduction in ROS levels, LPO, mitochondrial DNA oxidation, and citrate synthase activity (Shar ma et al., 2013; Shar ma et al., 2015). In addition, it increased SOD activity and GSH levels, AChE activity, and ATP levels (Sharma et al., 2013). Quercetin also prevented aluminum-induced neurodegenerative changes by inhibiting translocation of cyt-c, reducing Bax, p53 and caspase-3 expression, and increasing Bcl-2 expression (Sharma et al.,2016).Elreedy et al.(2022) reported that treatment with quercetin at 50 mg/kg/day, p.o., for 28 and 56 days reversed aluminum-induced increase in the AChE levels, and decrease in the dopamine level. Another study also demonstrated that supplementation with quercetin at 50 mg/kg/day, p.o., for 42 days decreased AChE activity, and oxidative stress in cortex and hippocampus of (Jadhav and Kulkarni, 2023). Finally, quercetin (25–50 mg/kg/day, p.o., for 1–2 months) also decreased Aβ plaques aggregation, amyloid precursor protein levels (APP), presenilin I (PSEN1), APH1 and β-amyloid converting enzyme 1 (BACE1), and enhanced ADAM10 and ADAM17 expression in the rats’ hippocampus (Elfiky et al., 2021; Elreedy et al., 2023).

Administration of curcumin at different dosages and treatment durations ((30 mg/kg/day, p.o., for 6 months), and (30, 60 mg/kg/day, p.o., for 6 weeks)) in aluminum-treated rats improved cognition deficits assessed by the Morris water maze, open field test and elevated plus maze test (Kumar et al., 2009; Sethi et al., 2009a). It at 30–175 mg/kg/day, p.o., in rats (30 mg/kg for an acute model, and 175 mg/kg for a chronic model), and at 0.2 and 0.5 mg/kg diet in drosophila melanogaster showed a neuroprotective effects might be due to its role in regulation of oxidative stress, including enhanced SOD and CAT activities and GSH content, reduced mitochondrial dysfunction (Sood et al., 2011; Oyetayo et al., 2020; ELBini-Dhouib et al., 2021; Laabbar et al., 2021), reduced LPO and ROS production (Zhang et al., 2018). Curcumin administration at 100 mg/kg/day, i.p., for 8 weeks also inhibited DNA fragmentation and AChE in the hippocampus of aluminum-treated rats (Kumar et al., 2009; Oyetayo et al., 2020; Mohamed et al., 2023). Moreover, curcumin decreased inflammation via reduction in the nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α) gene and protein expression (Sood et al., 2012). Additionally, it (100 mg/kg/day, p.o., for 20/40 days) decreased NO in cortex (Sethi et al., 2009b). Curcumin (5 μg/mL, for 3 h) inhibited aluminum-induced apoptosis by inhibiting the activities of cytochrome c and caspase-3 in rat brain synaptosomes (Kar et al., 2019). Jiang et al. (Jiang et al., 2012) reported that curcumin (10 μM, for 3 days) inhibited Aβ₄₂ fibrillation and the binding of aluminum with Aβ₄₂ - concomitant in PC12 cells. Administration of curcumin at 30 mg/kg and aluminum also maintained a higher locomotor activity, and dopaminergic levels in substantia nigra pars compacta (SNc) in rats (Laabbar et al., 2019).

Administration of resveratrol at 20 mg/kg/day, p.o., for 6 weeks to aluminum-exposed rats inhibited neuronal necrosis (Hammoud and Shalaby, 2019). Treatment with rutin at 30 mg/kg/day, p.o., for 6 weeks enhanced the antioxidant activity (by reduction in MDA and enhancement in GSH levels), and decreased inflammation (by inhibiting the excessive nitrate and TNF-α production) in rats (Kessas et al., 2024). Administration of chrysin (10, 30, and 100 mg/kg/day, p.o., for 90 days) improved cognitive impairment in mouse model of neurotoxicity induced by chronic exposure to aluminum as well as normalized the AChE and butyrylcholinesterase activities in the hippocampus. In addition, its administration prevented against the oxidative damage via reduction in LPO and enhancement in CAT and SOD (Campos et al., 2022).

Chronic administration of naringin (40–80 mg/kg/day, p.o.) improved cognitive dysfunction assessed using Morris water maze and elevated plus maze tests, and reduced mitochondria oxidative damage (by increasing GSH content, SOD, CAT, GPx and GST activities), LPO, ROS formation, AChE activity, and aluminum concentration in aluminum-exposed rats (Prakash et al., 2013; Tayo et al., 2024). Naringin (25, 50, and 100 mg/kg/day, p.o., for 30 days) in aluminum-intoxicated rats, improved spontaneous locomotors and exploratory activities and memory performance tasks assessed using the Morris water maze, open field, radial arm maze and rotarod tests via reduction in AChE activity and MDA level, and increased SOD and CAT activities (Prabhakar, 2020).

Administration of Epigallocatechin-3-gallate (EGCG) at 10 mg/kg/day, i.p., for 4 weeks during aluminum-induced neurotoxicity decreased Aβ, AChE, MDA together with the increased SOD (Ali et al., 2016). Na-noEGCG administration at 10 mg/kg/day, i.p., for 30 days improved neurobehavioral impairments assessed using the Morris water maze, open field and novel object recognition tests, and decreased neuritic plaques and neurofibrillary tangles in aluminum-treated rats (Singh et al., 2018a). An in vitro study showed that its nanoformulation (21.82 mM) also decreased Aβ42 fibrillation in aluminum-exposed SH-SY-5Y cells (Singh et al., 2018b).

2.2. Arsenic

Arsenic-toxicity is one of the major public health problems affecting millions of people worldwide (Ganie et al., 2024). The toxicity of arsenic has been linked to its chemical speciation; as organic arsenic represents a lower level of toxicity than inorganic forms (Thakur et al., 2021). Arsenic and its related compounds are associated with various cancers, neurological and coronary diseases (Thakur et al., 2021). Due to its easy passage through the blood-brain barrier, arsenic can accumulate in different areas of the brain, has harmful effects on the morphology and physiological changes in brain cells, and ultimately lead to various neurological complications and cognitive deficits (Uttara et al., 2009). The undesirable long-term effects triggered by arsenic exposure, resulted from several mechanisms included, mitochondrial dysfunction, neuroinflammation, oxidative stress, and molecular and neurochemical alterations, which converge and lead to impact on critical processes such as the establishment of neural networks, migration, proliferation, plasticity, ultimately leading to cell death, neurodegeneration and cognitive dysfunction (Vázquez Cervantes et al., 2023). Several studies have demonstrated that nutraceuticals supplementation significantly improved arsenic-induced behavioral and cognitive deficits through some molecular mechanisms.

CoQ10 decreased LPO and SOD levels, and increased AChE, butyrylcholinesterase (BChE) activities and GSH in arsenic-induced neurotoxicity in mice (Sharma et al., 2018). In addition, it (200 mg/kg/day, p.o., for 30 days) improved neuroinflammation by targeting the expression IL-10, TNF-α and interferon gamma (IFN-γ) (Mwaeni et al., 2021). Moreover, α-LA at 70 mg/kg/day, i.p., for 2 weeks improved arsenic-induced neurotoxicity and memory dysfunction assessed by the Morris water maze and elevated plus maze in rats (Dixit et al., 2020). The neuroprotective effect of the α-LA at 70 mg/kg/day, i.p., for 12 days was associated with reduction in apoptosis by inhibiting Bax and enhancing Bcl-2 in the hippocampus of rats exposed to Arsenic (Dixit et al., 2015). Vitamin E at 125 mg/kg, p.o., for 1 week inhibited oxidative stress in Arsenic-induced neurotoxicity in rats by increasing Mn-SOD, Cu/Zn-SOD, CAT, GPx and GSH, reducing LPO (Kumar and Reddy, 2017). It (5–50 mg/kg/day) also showed beneficial effects in rats and mice by targeting cholinergic system (Chinthirla et al., 2018; Sharma et al., 2018).

Quercetin administration (50 mg/kg/day, p.o., for 4 weeks) decreased brain arsenic concentration in arsenic-exposed rats (Alahmari et al., 2017). In a model of Arsenic-exposed rats, administration of quercetin at 50 mg/kg/day, p.o., for 18 days increased total antioxidant status, total thiols, SOD, CAT, GPx, GR, and aryl esterase, in contrast decreased MDA, advanced oxidation protein product and plasma NO levels (Yousuf et al., 2023). Liposomal quercetin (2.71 mg/kg, s.c., twice a week, for 4 months) downregulated cytochrome c expression, decreased brain Lipohydroperoxide content, arsenic concentration, and oxidative damage in arsenic-induced neurotoxicity in rats (Ghosh et al., 2011). It at 20 mg/kg/day, for 15 days reversed behavioral dysfunction evaluated by rotarod and hot plate tests by reducing oxidative damage via inhibition of LPO level, and enhancement of SOD, CAT and GPx activities (Nageshwar et al., 2019).

Curcumin at 100 mg/kg/day, p.o., for 28 days improved locomotor activity and cognitive dysfunction assessed by rotarod test, and improved oxidative stress status (by reduction in MDA, and increment in SOD activity, GSH and GPx levels) in arsenic-exposed rats (Yadav et al., 2009; Pandey et al., 2025). In addition, the neuroprotective effect of curcumin at 100 mg/kg/day, p.o., for 28 days in rats exposed to arsenic might be related to reduction in the NO levels and increment in the levels of biogenic amines (dopamine, epinephrine, norepinephrine, serotonin, 3,4-dihydroxyphenylacetic acid, homovanillic acid) in corpus striatum, frontal cortex and hippocampus (Yadav et al., 2010). Another studies showed that curcumin at 100 mg/kg/day, p.o., for 28 days inhibited oxidative damage by reduction in ROS formation, glutathione disulfide (GSSG) and MDA and enhancement in SOD, GSH and CAT activities in the brain (Yadav et al., 2012; Sankar et al., 2016). It also increased dopamine, and decreased 5-HT (Yadav et al., 2012). Curcumin protected against arsenic-induced neurotoxicity via inhibition of ROS generation, inhibition of apoptosis via increasing in Bcl2 expression, and decreasing Bax and caspase-3/7 expression. In addition, it (400 mg/kg, for 28 days) decreased the expression of pJNKs and p-p38, and increased the expression of nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase (HO)-1,Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 signaling, SOD-1, and GPX-1 levels in the frontal cortex and hippocampus of ducks (Srivastava et al., 2014; Khodadadi et al., 2020; Wu et al., 2021). Curcumin decreased arsenic concentrations and inflammatory mediators such as TNF-α, IL-1β, IL-18, IL-2, IL-6, inducible nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2) were decreased by curcumin administration (Wu et al., 2021). Administration of curcumin for 28 days attenuated inflammation (Toll-like receptor (TLR)-4, NF-κB, TNF-α, IL-2, and IL-6) and pyroptosis (Caspase-1, IL-18, IL-1β) by modulating NF-κB/NLRP3 signaling pathways in ducks hypothalamus which exposed to arsenic trioxide (Gan et al., 2023). Moreover, it increased blood brain barrier (BBB) tight junction proteins (occludin and ZO-1) (Wu et al., 2021; Gan et al., 2023). Curcumin (100 mg/kg/day, p.o., for 45 days) contributed to maintenance of myelin structure and upregulation of myelin basic protein (MBP) expression in the white matter of cerebellar in arsenic-treated rats (Kaushal et al., 2014; Mehta et al., 2020). Curcumin at 100 mg/kg, p.o., for 28 days also modulated BDNF/DARPP32/CREB axis in the corpus striatum of arsenic-treated rat (Srivastava et al., 2018a). It activates BDNF by mediating PI3k/Akt/GSK3β pathway in arsenic-exposed rat (Srivastava et al., 2018b).

Administration of resveratrol at 40 mg/kg/day, p.o., for 45 days in arsenic-treated rats reduced anxiety levels, increasing locomotion, learning and memory function. These behavioral impairments were accompanied by modulation of estrogen-NMDAR-BDNF pathway via upregulation of estrogen receptor (ERα) expression in the hippocampus (Mehta et al., 2021b). Pretreatment with resveratrol (3–20 mg/kg/day, p.o.) upregulated antioxidants (GSH) and attenuated ROS and MDA production and accumulation of arsenic in the cerebral cortex of arsenic-treated rats (Cheng et al., 2014; Taheri Zadeh et al., 2021). Resveratrol at 40 mg/kg/day, p.o., for 45 days upregulated expression levels of Bcl-2 proteins and downregulated of Bax in the brain of arsenic-treated mice (Mehta et al., 2021a).

Rutin (2 g/L, via the drinking water, for 6 weeks) increased body weight gain, open field motility; decreased latency of the cortical evoked potentials and enhanced peripheral nerve conduction velocity in arsenic-treated rats (Sárközi et al., 2015). Pretreatment with apigenin in PC12 cells intoxicated by arsenic, diminished neuroinflammation, oxidative stress, and apoptotic cell death. The neuroprotective effect of apigenin might be due to upregulation of Nrf2 (Almeer and Alyami, 2023). Luteolin administration (20 μM, for 24 h) prevented against apoptosis in the dopaminergic PC12 cells exposed to arsenic. In addition, it decreased ROS production, decreased caspase-3 activity and γ-H2AX expression as well as expression of α-Synuclein (α-Syn) level (Wu et al., 2017). An in vitro study showed that treatment with the naringenin (10–100 μM) inhibited arsenic-induced oxidative stress (Peruru and Dodoala, 2017). Epicatechin administration at 25–100 mg/kg/day, p.o., for 2 weeks in arsenic-treated mice resulted in reducing LPO, and NO concentration, and enhanced the levels of antioxidant factors. Furthermore, it reduced pro-inflammatory cytokines including TNF-α and NF-κB and increased Nrf2 expression (Shariati et al., 2024).

2.3. Ethanol

Ethanol is a main component of alcohol. Alcohol consumption is a serious public health issue worldwide (Zeng et al., 2024). The severity of pathological effect are a function of the dose, period and frequency of its consumption (Fernandes et al., 2017). One of the detrimental effects of chronic alcohol consumption, is neurotoxicity, leading to cognitive and memory impairment and develops neurodegenerative disorders such as AD and PD (Agirre et al., 2021). Ethanol exposure affects the brain through activating immune cells, altering synaptic plasticity and neurotransmitter systems, dysregulating oxidative stress, neuroinflammation, mitochondria dysfunction (Anand et al., 2023). Supplementation with nutraceuticals supplementation was shown to decrease the adverse effects of ethanol exposure on animal brain.

The neuroprotective effect of CoQ10 (50–100 mg/kg, p.o., for 10 weeks) in neuropathic pain induced by ethanol has been reported. It also decreased endogenous calcium levels, oxidative stress and neuroinflammation in rat model (Kandhare et al., 2013). The administration of omega-3 (720 mg/kg, a single dose, 15 min after the last alcohol injection) improved anxiety-like behaviors induced by acute ethanol in pre-juvenile rats (Balaszczuk et al., 2019). It (30 mg/100 g/day, with modified liquid diet) inhibited apoptosis by reducing the levels of cytochrome c, caspase-3, calpain and cathepsin B in ethanol-treated rats (Kusat Ol et al., 2016). Omega-3 at 50–150 mg/kg, for 5 weeks improved memory dysfunction assessed using the Morris water maze and passive avoidance tests, in adolescent in ethanol-treated rats by balancing oxidative stress and neuroinflammation (Haidary et al., 2024). Additionally, an in vitro study showed that the administration of α-LA (0.1 mM) in ethanol-intoxicated hippocampal cells decreased neurotoxicity and oxidative stress (Pirlich et al., 2002).

Vitamin B1 at 25 mg/kg/day, p.o., for 30 days decreased ethanol-neurotoxicity in rats via regulation of oxidative stress by increasing SOD, CAT and GPx (Vidhya et al., 2013). In ethanol-induced neurotoxicity in mice, treatment with vitamin B3 (0.25, 0.5, and 1 g/kg) inhibited both caspase-3 and PARP-1, and neurodegeneration (Ieraci and Herrera, 2018). Vitamin B3 (0.25, 0.5, and 1mg/g, s.c., for 4 times) also inhibited ethanol-induced neuronal apoptosis by reducing caspase-3 activation, cytochrome-c in adult mice (Ieraci and Herrera, 2006). The administration of Vitamin B5 (100–200 mg/kg/d, p.o., by Lieber-Decarli liquid diet for 4 weeks and 4 months) prevented the tremor in ethanol-treated rats (Newland et al., 1992).Vitamin B5 (200 mg/kg, i.p., or i.v.) increased ACh synthesis in female squirrel monkey (Rivera-Calimlim et al., 1988). Vitamin B9 (75 μM) decreased the ethanol-induced behavioral defects (Cadena et al., 2020; Marengo et al., 2023). It (60 mg/kg/day, p.o.) also improved anxiety evaluated by open field test and elevated plus maze test in prenatal alcohol exposure in mice (Shrestha and Singh, 2013). Vitamin B9 (60 mg/kg/day) inhibited apoptotic cell death by targeting caspase-3, calpain and cytochrome c in rats (Sogut et al., 2017). Moreover, it inhibited ethanol-induced teratogenesis by increasing Hoxa1 and reducing miR-10a expression (Wang et al., 2009). Vitamin B12 (1.5 mg/kg, s.c.) improved learning and memory impairments assessed using the Morris water maze and passive avoidance test via reduction of oxidative stress, GFAP and AChE activity, and enhancement of BDNF in ethanol-treated rats (Akbari et al., 2023).

Vitamin E (100, 200 and 400 mg/kg/day, p.o., from the GD 0 until weaning) improved cognitive dysfunctions measured using the Morris water maze, and increased BDNF in perinatal ethanol-exposure rats (Mahdinia et al., 2021). It (50 μM) also increased the expression of BDNF in ethanol-exposure cultured cerebellar granule cells (Heaton et al., 2004a). Vitamin E at wide range of dosage protected against neuronal loss induced by ethanol (Mitchell et al., 1999; Heaton et al., 2000; Marino et al., 2004). It also enhanced survival in neuronal cells by increasing anti-apoptotic proteins such as Bcl-xl, Bcl-2 and pAkt, and reducing apoptotic protein such as caspase-3 (Heaton et al., 2004b; Siler-Marsiglio et al., 2004), and regulating oxidative stress (Shirpoor et al., 2009a). Vitamin E also ameliorated brain atrophy and DNA damage in ethanol-treated offspring rats (Shirpoor et al., 2009b). Vitamin C (150 and 350 μmol/L, for 8 h) decreased Hsp70, COX-2 and PGE2 synthesis in ethanol-treated rats (Sánchez-Moreno et al., 2003). It decreased ethanol-induced oxidative stress, neuroinflammation and apoptotic neuronal loss via reducing ROS, activated microglia and astrocytes, NF-κB, Bax/Bcl-2 ratio, cytochrome-c, caspase-9, caspase-3, and PARP-1 activities (Peng et al., 2005; Ahmad et al., 2016).

Chronic treatment with quercetin at 10–40 mg/kg, p.o, for 10 weeks resulted in reducing allodynia, hyperalgesia, and increased motor coordination and nerve conduction velocity along with reduction in the level of membrane-bound Na⁺/K⁺-ATPase. It also attenuated NO, MDA and myeloperoxidase (MPO) levels. In addition, quercetin-treatment diminished the extent of DNA fragmentation (Raygude et al., 2012). Chronic administration of curcumin (15–60 mg/kg, p.o.) in ethanol-treated rats improved cognitive deficit which might be related to reducing AChE activity, neuroinflammation and apoptosis in both cerebral cortex and hippocampus of brain rat pups (Tiwari and Chopra, 2012; Tiwari and Chopra, 2013a). The cytoprotective effect of curcumin (200 nM, for 2 h) administration reduced ethanol-induced neurotoxicity and cell death through attenuating activation of p38 mitogen-activated protein kinases (p38 MAPK), and increasing activation of Mitogen-Activated Protein Kinase Phosphatase 1 (MKP-1) (Pae et al., 2009). Curcumin administration at 50 mg/kg/day, i.p., for 6 weeks protected against ethanol-induced oxidative stress by increasing Nrf2. Also, it attenuated the activation of astrocytes and microglia by inhibiting expression of TLR4/RAGE. Furthermore, it rescued apoptotic cell death, synaptic dysfunction, and improved memory impairment in mice brains via Nrf2/TLR4/RAGE Signaling (Ikram et al., 2019). The protective effects of curcumin pretreatment (40 mg/kg/day, i.p.) in acute ethanol-exposed mice, ameliorated the memory deficits. Its effects might be due to manipulation of the NOS/NO signaling pathway. Curcumin suppressed the NOS activity and NO production in the prefrontal cortex, hippocampus, and amygdala of mice brain (Yu et al., 2013). Curcumin in a dose dependent manner (10, 20, 40 and 60 mg/kg, i.p., for 21 days), suppressed alcohol-induced apoptosis, oxidative stress, inflammation and behavioral impairment. These protective effects are mediated via CREB-BDNF signaling pathway. Curcumin attenuated LPO and oxidative stress by reduction in GSSG, and elevation in GSH, GPx, GR and SOD activities. It also suppressed neuroinflammation by inhibition of pro-inflammatory cytokines levels such as IL-1β and TNF-a, and inhibited apoptosis by inhibition of Bax and Bax/Bcl-2 ratio expression in rats (Motaghinejad et al., 2017). Curcumin-treatment at 40 mg/kg/day, i.p., for 7 days during the peri–adolescence period, improved cognition impairment in prenatal and lactational alcohol-exposure mice. Also, it reduced expression of pro-inflammatory mediators (such as IL-6 and TNF-α protein expression) as well as the activity of astrogliosis and microglia activation (Cantacorps et al., 2020).

Resveratrol (30 μM/L) inhibited oxidative/nitrosative stress by reduction in ROS formation, MDA and NO level, and enhancement in GSH content and SOD activity ethanol-exposed embryonic dorsal root ganglion (DRG) neurons (Yuan et al., 2013b). It (0.1 to 100 μM) also decreased cell death and DNA damage in the ethanol-treated primary astrocyte cells (Gonthier et al., 2012). Resveratrol (0.1, 1, 10, 30 μmol/L) improved cell viability, inhibited apoptosis, increased the mRNA and protein levels of BDNF and GDNF and decreased NGF in ethanol-induced toxicity in Schwann cells (Yuan et al., 2013a). Pretreatment with resveratrol (20 mg/kg, i.p.) in postnatal mice exposed to ethanol attenuated the impairment in hippocampal neurogenesis and apoptosis (Xu et al., 2015). It (100 mg/kg) reduced apoptosis by reduction in ROS formation, MDA and total thiol in the external granule layer of the cerebellum and enhanced cerebellar granule cells survival. In addition, restored the level of Nrf2 associated to downstream gene targets such as NADPH quinine oxidoreductase 1 and SOD expression and activity in cerebellum (Kumar et al., 2011). Treatment of rats with resveratrol (100 mg/kg/day, i.p.) attenuated spatial memory impairment assessed using the Morris water maze, and neuroinflammation by decreasing microglial activation and reducing inflammatory cytokines levels including IL-1β, IL-6 and TNF-α. In addition, it inhibited TLR2-MyD88-NF-κB signal pathway (Qi et al., 2018). Resveratrol administration (5–20 mg/kg, p.o.) improved cognitive and locomotor deficits assessed using the Morris water maze, elevated plus maze, open field and novel object recognition tests, inhibited activation of NF-Kb, inflammatory cytokines, oxidative-nitrosative stress, AChE activity and apoptosis in ethanol-exposed rats (Tiwari and Chopra, 2011; Tiwari and Chopra, 2013b; Navarro-Cruz et al., 2024). Additionally, it (30 mg/kg, p.o., for 4 days) inhibited neurodegeneration via mediating AMPK/SIRT1/p38 signaling pathway via upregulation of AMPK and SIRT1 protein expression, and inhibition of pro-apoptotic protein expression of p38 (Gu et al., 2018).

Song et al. pointed out that the protective effects of rutin (1 μg/ml) in ethanol-neurotoxicity HT22 cells might be related to inhibition of apoptosis by inhibition of Bax, cytochrome-c expression and caspase-3 activity, and enhancement of Bcl-2 and Bcl-xL protein expression. Concomitantly, it increased aldehyde dehydrogenase 2 (ALDH2) expression (Song et al., 2014). Naringenin at 50 mg/kg/day, p.o., for 55 days ameliorated cognitive dysfunction in ethanol-exposed rats by targeting Nrf2/NAD(P)H quinone oxidoreductase 1, anti-oxidant capacity (enhancement in Nrf2, GSH, NQO1, reduction in MDA), necroptosis (reduction in RIPK3, MLKL and pGSK-3β, and enhancement in CNTF) (Soliman et al., 2023). Epigallocatechin-3-gallate (25, 50, and 100 mg/kg, p.o., for 10 weeks) prevented all the cognitive dysfunction assessed using the Morris water maze and elevated plus maze test, biochemical and molecular alterations in the different brain regions of ethanol-treated rats in a dose-dependent manner. It at 50 and 100 mg/kg, p.o., for 3 days suppressed the AChE activity, oxidative–nitrosative stress, inflammatory cytokines (TNF-α and IL-1β), NF-κB, and caspase-3 levels in both the cortex and hippocampus (Tiwari et al., 2010; Uniyal et al., 2021). The protective effect of epigallocatechin-3-gallate against alcoholicneuropathic pain in rats was also reported. Its beneficial effects at 25–100 mg/kg, p.o., for 6 weeks might be related to inhibition of oxidative-nitrosative stress and inflammatory mediators (TNF-α, IL-1β and TGF-β1 levels) (Tiwari et al., 2011).

2.4. Lead

Lead is the second most noxious metal which enters the human body through ingestion, inhalation, and skin contact. 0.002 percent of the earth’s crust consists of lead (Tripathy et al., 2022). Improper nutrition, especially protein, calcium, zinc, and iron deficiency, enhances the risk of adverse effects of chronic exposure of lead (Mostafa et al., 2009). Lead can dysregulate several biological processes such as apoptosis and its downstream pathway, energy metabolism, metal transport, oxidative stress, and cell signaling pathway (Gudadhe et al., 2024). Excess exposure to lead, results in morphological, structural and functional alternations in brain, leading to neurocognitive, neuropsychological and neurobehavioral impairments and develops neurodegenerative disorders (Singh et al., 2024). It has been proposed that nutraceuticals supplementations may serve as neuroprotective strategies to decrease lead-related brain damage.

The administration of CoQ10 at 10 mg/kg, i.p., for 7 days following lead exposure contributed to antioxidants status through reduction of ROS and LPO, and enhancement of GSH, CAT, SOD and GPx. It also activated Nrf2/HO-1 axis. In addition, treatment with CoQ10 showed anti-inflammatory response by reducing TNF- and IL-1β (S. Yousef et al., 2019). Omega-3 at 300–750 mg/kg/day, p.o. improved behavioral deficits assessed using the Morris water maze and elevated plus maze test, and inhibited lead-induced oxidative stress in neurons by inhibiting LPO and ROS production and increasing GPx, CAT and SOD activities (Singh et al., 2016; Kumar Singh et al., 2018; Singh et al., 2019). The administration of α-LA at 20 mg/kg/day, i.p., for 3 weeks protected against lead-induced neurotoxicity and cognitive dysfunctions by inhibiting LPO, and increasing GSH content, NO production, AChE activity, dopamine, 5- HT and ATP production in rats (Abd-Ella et al., 2016; Abd-Ella et al., 2017). Folic-acid (0.4 mg/kg/day, p.o.) decreased lead-induced neurotoxicity and apoptosis by targeting Bc1–2, Bax, NO synthesis and blood levels of lead in rats (Quan et al., 2015). Vitamin B12 (45 μg/kg/day, i.p., for 7 days) decreased long-term potentiation (LTP) and Pb2+ concentration in hippocampus in lead-exposed rats (Chen et al., 2007).

The administration of Vitamin C (120 mg/kg/day, p.o., for 3 weeks), Vitamin B12 (1 mg/kg/day, p.o., for 3 weeks), Omega-3 (1000 mg/kg/day, p.o., for 3 weeks) prevented lead-induced cognitive impairment (Moosavirad et al., 2016). Vitamin C administration (150 mg/kg/day, p.o., for 3 months) decreased synaptic plasticity impairment, and oxidative stress induced by lead in the rat hippocampus (Karamian et al., 2015). Vitamin E at 10, 25, 50 μg/rat, p.o., for 30 days improved cognitive dysfunction assessed using the passive avoidance learning, induced by chronic exposure to lead in rats (Khodamoradi et al., 2015). Vitamin E at 54 and 150 mg/kg/day, p.o., for 4 weeks decreased synaptic plasticity impairment, and improved oxidative stress induced by lead in the rat hippocampus. It improved oxidative stress by upregulation of TAC, GSH, SOD and GPx levels and downregulation of MDA, 8- OHDG and TOS levels (Sawan and Nagy, 2009; Salehi et al., 2015). The neurotoxicity of lead in rats decreased by Vitamin D at 1000 IU/kg/day, i.p., for 4 weeks via inhibition of LPO and ROS, and increased GSH, CAT and SOD activities. It also decreased the gene expression of Nrf2 and NF-κB (Hosseinirad et al., 2021).

Quercetin in a dose-dependent manner (15 and 30 mg/kg/day, p.o., for 3 months), decreased brain lead content, increased NO production and PKA activity, suppressed oxidative stress, increased the phosphorylations of Akt, CaMKII, nNOS, eNOS, and CREB in lead-induced neurotoxicity mice model (Liu et al., 2013). Quercetin (50 and 100 mg/kg/day, p.o., for 5 days) improved behavioral dysfunctions assessed using the adhesive removal test, and mitigated the neurotoxic effects in lead-exposed rats via inhibition of oxidative burden, downregulation of Bak and Hsp-70 expressions and upregulation of Bcl-2 expression (Chander et al., 2014). It (25 and 30 mg/kg/day, i.p.) improved locomotor activity, and learning and memory function by inhibition of oxidative stress (via enhancement in CAT, GSH, SOD, GPx, and ALA-D levels, and reduction in MDA levels), inhibition of apoptosis (by reducing Bax expression and increasing Bcl-2 expression), and inhibition of neuroinflammation (by reducing IL-1β and TNF-α levels) (Adewole and Ayoka, 2009; Zahid et al., 2022) A study reported that post-treatment of quercetin at 30 mg/kg in lead-exposed rats reduced hippocampal lead concentration and improved synaptic plasticity impairment via increasing long-term potentiation (LTP) in dentate gyrus area in rats (Hu et al., 2008).

Curcumin (100 and 200 mg/kg, p.o., for 38 days) improved locomotor and memory deficit assessed using the water maze swimming and forced swimming tests, cholinergic dysfunction and neuroinflammation in mice (Benammi et al., 2017; Changlek et al., 2022). Resveratrol (50 mg/kg/day, p.o.) decreased cognitive damage, increased neurogenesis and improved cell proliferation in the pups. lead-induced injury via targeting SIRT1 pathway by enhancement in SIRT1, BDNF, CREB mRNA and protein expression. In addition, it reduced the expression of Ki-67, NeuN and caspase-3 expression (Wang et al., 2021). Rutin (50 μM) pretreatment ameliorated lead-induced cell death, inflammation, oxidative stress, and increased cell survival. Moreover, it activated antioxidant signaling (Nrf2, ARE, HO-1, GCLC and NQO1) (Li et al., 2024). Apigenin (20 mg/kg/day, p.o., for 4 weeks) reduced oxidative stress, AChE activity, and neuroinflammation in cerebellum of lead-exposed rats (Alfwuaires et al., 2023). Luteolin (50 mg/kg/day, p.o., for 7 days) decreased the lead concentration, neuronal LPO, NO production, neuroinflammatory response (IL-1β and TNF-α), and enhanced the antioxidant enzymes (SOD, CAT, GSH, GPx, GR) in cortical tissue of lead-exposed rats. In addition, it decreased cortical cell death by reduction in proapoptotic (Bax and caspase-3) and elevation in antiapoptotic protein (Bcl-2) (Baty et al., 2020). Naringenin (50 mg/kg/day, p.o., for 4 weeks) inhibited oxidative stress caused by lead through reduction of MDA levels, and increasing SOD, GSH and CAT activities in the rats brain (Erİșİr et al., 2018; Mansour et al., 2023). Additionally, it (50 mg/kg/day, p.o., for 4 weeks) decreased inflammation (by reducing NF-κβ and increasing) IL-10 and apoptosis (by reducing caspase-3, and increased Bcl-2). Also, it upregulated the levels of the neurotransmitters NE, DA and 5-HT (Mansour et al., 2023). Epigallocatechin-3-gallate (10, 25 and 50 mg/kg, i.p.) increased GSH, SOD activity, and LTP amplitude in CA1, reduced MDA levels, inhibited apoptosis, and inhibited ROS accumulation induced by lead (Yin et al., 2008; Suresh et al., 2011).

2.5. Cadmium

Cadmium is recognized as a non-essential environmental pollutant which is listed as the seventh most dangerous chemical for human health (Support document to the 2022 substance pr ior ity list (candidates for toxicological profiles) agency for toxic substances and disease reg istry - NCTR. In addition to occupational exposure, cadmium may gain access to the general population through cosmetics, cigarette smoke, diet, and polluted air and water (Hartwig and Jahnke, 2017). The neurotoxicity mechanisms of cadmium exposure, entail destruction of metal-ion homeostasis, oxidative stress and ROS generation, inflammation, mitochondr ial impair ment, neurotransmitter signaling and synapse dysfunction, immune responses in the CNS, epigenetic changes, and dysregulation of cell death (Dhilleswara Rao et al., 2024). Because of toxic effects of cadmium at very low concentrations, low excretion rate, and prolonged biological half-life, exposure to cadmium is considered as a health hazard (Wen and Wang, 2024). Albeit acute exposure to this metal heavy is attenuated by the BBB, chronic exposure to cadmium has been shown to enhance BBB permeability and promote its entry (Branca et al., 2020). The prolonged accumulation of cadmium salts results in adverse effects on several organs, such as bones, lungs, pancreas, liver, kidney, reproductive organs, and cardiovascular and nervous systems (Arsenic, 2012). These disruptive alterations in the CNS, may underlie etiopathophysiologies in neurodegenerative and neurodevelopmental dysfunction like PD, AD, chronic traumatic encephalopathy and amyotrophic lateral sclerosis (ALS) (Branca et al., 2018; Forcella et al., 2020). Several studies have addressed the neuroprotective effects of nutraceuticals supplementation in the ameliorating cadmium neurotoxicity.

Omega-3 at 100 mg/kg/ p.o., for 6 days reduced LPO, Hsp70, 8OHdG, NF-Kb and IFN-γ, and normalized AChE, SOD, CAT, GST and monoamine oxidase (MAO) levels within the rat brains exposed by Cadmium (Alnahdi and Sharaf, 2019). α-LA at 50 mg/kg/day, p.o., for 12 weeks attenuated the cadmium-induced upregulation of neuronal ER chaperone proteins, including BiP, p-eIF2α, ATF4, and CHOP, and restored the Cd-evoked upregulation of the Bax/Bcl-2 ratio, activation of caspase-12 and −3, and apoptotic morphological changes. Also, it inhibited the Cadmium-induced, ER stress-associated eIF2α-ATF4 pathway, and oxidative stress (Yuan et al., 2019). Vitamin C at 50–100 mg/kg/day, p.o. ameliorated the oxidative damage in rats that exposed to cadmium by reducing MDA level, and increasing SOD, CAT, GPx and GSH (El-Sokkary and Awadalla, 2011) (Elkhadragy et al., 2018). Vitamin C (10–100 mg/kg/day, p.o.) improved myelin integrity, neuronal loss, learning and memory impairments, anxiety and depressive-like behavior in the cadmium induced neurotoxicity in rats (Afifiand Embaby, 2016; Adebiyi et al., 2022). Vitamin B12 at 500 μg/kg/day, i.p., for 2 weeks improved cognitive dysfunctions in cadmium-induced neurotoxicity in mice due to its anti-inflammatory and antioxidative potential. It activated p-Akt signaling pathway along with inhibiting the NF-κB, TNF-α and IL-1β (Yousaf et al., 2023). Vitamin E injection at 5 and 30 mg/kg/day decreased neurotoxicity induced by cadmium in rats via regulation of oxidative stress (Nemmiche et al., 2007; Shukla et al., 1988).

Quercetin at 25 mg/kg/day, p.o., for 28 days prevented cadmium-intoxicated changes in the rat’s hippocampus and frontal cortex. It improved learning and memory assessed by passive avoidance test using a shuttle box, enhanced the binding of cholinergic–muscarinic receptors, ChAT and AChE mRNA and protein expression, and the expression of PKCβ1. In addition, it ameliorated mitochondrial dysfunction through increasing mitochondrial complexes activity. Quercetin inhibited apoptosis by reduction in Bax and caspase-3 and enhancement in Bcl-2. MAP kinase signaling, AP1, p38, JNK1/2, and JNK3 proteins also diminished by quercetin (Gupta et al., 2017). Administration of quercetin (15–100 mg/kg/day, p.o.) along with cadmium attenuated MDA level, enhanced the enzymatic antioxidants levels (SOD, GPx and CAT levels), neuronal degeneration, and caspase-3 in the frontal cortex tissue of rats and mice (Unsal et al., 2015; Halder et al., 2016; Kanter et al., 2016; Makwana et al., 2021). Quercetin (5, 25 or 50 mg/kg/day, p.o., for 45 days) treatment improved cadmium-induced neurotoxicity, memory impairment and anxiogenic-like behavior assessed using inhibitory avoidance task, open field, foot shock sensitivity test and elevated plus maze task, reduced ROS formation, protected against oxidative stress alterations, increased AChE, and Na+/K+-ATPase activities and δ-Aminolevulinic acid dehydratase (δ-ALA-D) activity in the cerebral cortex, hippocampus and hypothalamus of rat brain. In contrast, AChE activity was decreased in hypothalamus of rats (Abdalla et al., 2014). Moreover, quercetin attenuated cadmium-induced necroptosis by inhibiting the ROS/iNOS/NF-κB pathway. It (500 mg/kg/day, fed with the basal diet, for 60 days) also decreased the Receptor-interacting serine/threonine-protein kinase (RIPK)-1 and −3, and Mixed lineage kinase domain-like (MLKL) expression levels, and elevated Caspase-8 level. Furthermore, quercetin decreased cadmium accumulation, ROS formation, and MDA level, in contrast elevated the antioxidant enzymes (SOD, GPx, and CAT). In addition, it decreased iNOS activity and NO production, diminished inflammatory factors expression (NF-κB,TNF-α,COX-2,iNOS,prostaglandin E,and IL-1β), and also inhibited heat shock proteins (HSPs) (HSP27, HSP40, HSP60, HSP70, and HSP90) in Isa hens (Liu et al., 2021). Quercetin treatment at 25 mg/kg/day, p.o., for 30 days along with cadmium-intoxicated rats improved dental gyrus structure, the spatial and avoidance memories, reduced inflammation, oxidative stress, and apoptosis. It also increased GSH, SOD, Ach and BDNF levels,meanwhile downregulated AchE in the hippocampus. Furthermore, it activated SIRT1 and inhibited acetylation of Nrf2, NF-κB p65, and p53 (Alshammari et al., 2021). Quercetin at 25 mg/kg/day, p.o., for 28 days in cadmium-treated rats,decreased pyramidal neurons degeneration, increased NMDA receptor subunits (NR1, NR2A), enhanced NMDA-R levels associated with its downstream signaling proteins (Ca2+/calmodulindependent protein kinase II (CaMKIIα), Postsynaptic density protein 95 (PSD-95), Tropomyosin receptor kinase B (TrkB), BDNF, Phosphoinositide 3-kinases (PI3Ks), Protein kinase B (PKB), Extracellular signal-regulated kinase ½ (ERK1/2), Glycogen synthase kinase 3-beta (GSK3β), and cAMP-response element binding protein (CREB)) and decreased the levels of SynGap in hippocampus. In addition, it increased Nrf2 and HO1 signaling (Srivastava et al., 2023). An in vitro study in BRL-3A cells showed that quercetin (5 μmol/L, for 24 h) activated the Nrf2-Keap1 pathway via elevating Nrf2 and NAD(P)H quinone oxidoreductase 1 (NQO1), and reduction in Keap1 expression (Wang et al., 2022).

Curcumin (12.5–160 mg/kg/day, p.o.) improved locomotor abnormality, attenuated anxiety-like behaviors, spatial learning and memory impairment assessed using the open field, novel object recognition test, inhibitory avoidance, foot shock sensitivity test and y-maze, and neuronal abnormality in cadmium-treated rats (Akinyemi et al., 2017b; da Costa et al., 2017; Namgyal et al., 2020; Namgyal et al., 2021). It also upregulated antioxidant status via reduction in MDA levels, and elevation in SOD and CAT activities, and GSH content (Namgyal et al., 2020; Namgyal et al., 2021). In addition, it (20, 40, 80 and 160 mg/kg/day, p.o., for 60 days) promoted neurogenesis through CREB-BDNF signaling pathway in rats model (Namgyal et al., 2020). Curcumin (12.5, 25 and 50 mg/kg/day, p.o., for 7 days) also inhibited AChE activity in cadmium-exposed rats (Akinyemi et al., 2017a; Akinyemi et al., 2017b). Curcumin treatment (20, 40, 80 and 160 mg/kg/day, p.o., for 60 days) inhibited neuroinflammation via reducing the levels of TNF-α, IL-6 and increasing IL-10 level in cadmium intoxicated rats (Namgyal et al., 2021).

Resveratrol (300 mg/kg/day, p.o., for 45 days) reduced memory impairment in cadmium intoxicated rats. Mechanistically, it enhanced Sirtuin 1 (SIRT1)/ Adenosine monophosphate-activated protein kinase (AMPK)/Akt signaling pathway, inhibited apoptosis (via upregulating Bcl-2 and downregulating caspase-12 and caspase-3), reduced ROS generation, increased GSH level, and inhibited of ER stress (Shati, 2019). In an in vitro study resveratrol (100 μM, for 1 h) also attenuated cadmium-induced neuronal apoptosis via inhibition of mTORC1/2 pathways (Liu et al., 2022). Additionally, it blocked the phosphorylation of JNK, ERK1/2, p38, JNK and c-Jun as well as inactivated Akt/mTOR proteins (via inhibiting phosphorylation of Akt, S6K and 4E-BP1) and activating PTEN expression (Lin et al., 2015; Liu et al., 2015). Resveratrol exerted antagonistic action against the cadmium -induced cerebrum toxicity via decreasing the expression of CYP450 genes (Lv et al., 2023).

Treatment with rutin (25, 50 and 100 mg/kg/day, p.o.) increased antioxidant status by elevation in SOD and CAT activities, reduced ER stress and apoptosis in cadmium-exposed rats (Oboh et al., 2019; Mostafa et al., 2019). It also decreased AChE and BChE activities, and increased NO level (Oboh et al., 2020). Rutin hydrate (100 mg/kg/day, p.o., for 30 days) decreased cadmium-induced memory impairments and neural apoptosis in rats by increasing the levels of acetylcholine, suppressing JNK and ERK1/2 and activating mTOR signaling (Abdel-Aleem and Khaleel, 2018). Kaempferol (50 mg/kg/day, p.o., for 6 weeks) improved memory deficits in cadmium-exposed rats (El-Kott et al., 2020b). Kaempferol inhibited LPO and NO levels, while enhanced GSH content and the activities of GPx, GR, SOD, and CAT in cadmium-exposed rats. It (50 mg/kg/day, p.o., for 30 days) also suppressed inflammatory responses through reduction in TNF-α, IL-1β, IL-6, and NF-κB p65 levels and iNOS expression in rats. Furthermore, pro-apoptotic proteins included Bax and caspase-3 were decreased, while Bcl-2, the anti-apoptotic protein, was increased (Al-Brakati et al., 2021). It also reduced ROS formation, enhanced the Phosphatase and tensin homolog (PTEN) and AMPK activities, and decreased Akt and mTOR activities (El-Kott et al., 2020b). Kempferol (50 mg/kg/day, p.o., for 30 days) also increased nuclear activity and levels of SIRT1, and inhibited the nuclear activity and levels of Poly [ADP-ribose] polymerase 1 (PARP-1) in rats (El-Kott et al., 2020a).

Naringenin at 20 and 40 mg/kg/day, p.o., for 28 days improved memory impairment assessed by Morris water maze and elevated plus maze tests in cadmium-treated mice. It decreased oxidative stress via increasing GSH content and reducing MDA level in brain (Srivastava et al., 2021). An in vitro study showed that naringenin decreased cadmium-induced neurotoxicity via inhibition of oxidative stress by reducing ROS, mitochondrial mass, and membrane potential. Also, it reversed nuclear damage, G2/M phase arrest, and apoptosis (Priya et al., 2024). Epigallocatechin 3-gallate at 10, 50 or 100 μM decreased cadmium-induced mitochondrial dysfunction and mitochondrial LPO (Abib et al., 2011).

2.6. Mercury

Mercury is a volatile contaminant which currently listed as the third chemical of greatest public health concern. Distribution of this toxicant from human activities poses several hazardous effects to both human health and surrounded environment (Zafar et al., 2024). Three forms of mercury exist; elemental or metallic mercury, organic and inorganic mercury compounds. In the meantime, the organic form of this, is the most toxic type and causes neurological complications and developmental impairments. While inorganic compounds are soluble in water and can impair gastrointestinal tract, lungs, liver, kidneys and immune system (Chamoli and Karn, 2024; Zafar et al., 2024). Mercury is distributed to all organs of the body through the bloodstream (Crespo-Lopez et al., 2022). The main neurological symptoms of methylmercury exposed individuals include attention, learning and memory deficits, visual and verbal impairments and motor dysfunction (Santos-Sacramento et al., 2021). Other symptoms include tremors, irritability, hallucinations, headaches, and nausea (Chamoli and Karn, 2024). Molecular and cellular mechanisms of mercury neurotoxicity result from calcium, glutamate and GABA dyshomeostasis, mitochondrial malfunction, dysregulated oxidative stress, inflammatory responses, failure of synaptic support and cell death pathway (Novo et al., 2021; Leal-Nazaré et al., 2024). Several studies have addressed the neuroprotective effects of nutraceuticals supplementation in the ameliorating mercury neurotoxicity.

In a study, omega-3 at 0.5 g/kg/day, s.c., for 7 days was reported to elicit neuroprotective effects in mercury-induced neurotoxicity in mice by regulation of oxidative stress (Karapehlivan et al., 2014). α-LA at 35 μmol/kg/day, i.p., for 4 weeks was reported to protect against mercury-induced neurotoxicity in rats by regulating oxidative stress (Yang et al., 2015; Yang et al., 2017). It also prevented neurotoxicity due to mercury by inhibiting apoptosis via reduction of caspase 3 and Bax expression and increasing Bcl-2 expression in rats (Yang et al., 2020). An in vitro study showed that α-LA (12.5–100 μM, for 0.5–6 h) inhibited apoptotic rates, ROS formation, intracellular Ca²⁺ concentration and calpain activity in primary cultured neurons exposed to mercury (Yang et al., 2016).

Vitamin C (595 and 1190 mg/kg/day, p.o., for 3 weeks) ameliorated CA3 degeneration, learning and memory deficit assessed using the Morris water maze, in rats that exposed to mercury (Animoku et al., 2016). Vitamin E (50–500 mg/kg/day, p.o.) decreased Purkinje and DRG neurons degeneration, the neurotoxic effect of mercury on the development of glial cells, nerve fibers and fibroblasts, and behavioral impairments in mercury treated rats (Kasuya, 1975; Yip and Chang, 1982; Owoeye et al., 2018b; Owoeye et al., 2018a;). It (2.0 ppm) reduced neuronal damage and necrosis in mercury treated hamsters (Chang et al., 1978). Vitamin E (24 μmol/kg, i.p., single injection) showed neuroprotective effects by inhibiting oxidative stress in rats (Agarwal et al., 2010). Vitamin E at 500 mg/kg/day, p.o., for 14 days protected against mercury-induced oxidative in rats through reduction in MDA, and elevation in CAT, SOD, GSH (Owoeye et al., 2019). It (100 mg/kg/day, p.o., for 14 days) also inhibited apoptosis and neuroinflammation via inhibition of TNF-α, IL-6, MAPK expression, Bax and caspase-3 levels. Meanwhile, it increased BDNF and CREB protein expressions in rats (Fadda et al., 2020).

Quercetin reduced the excessive ROS formation, enhanced SIRT1 activity and SIRT1/PGC-1α signaling pathway, and increased mitochondrial biogenesis in mercury-induced neurotoxicity in mice (Liu et al., 2024). Curcumin improved cognitive dysfunction, depression, anxiety and locomotory activities assessed using the light-dark chambers, forced swimming, tail suspension, plus-maze and open-field tests in mercury-exposed mice (Abu-Taweel, 2019; Abu-Taweel and Al-Fifi, 2021). Mechanistically, it enhanced the levels of dopamine, 5-HT and AChE in forebrain (Abu-Taweel, 2019). Curcumin also increased Nrf2 and HO-1 expression (Yang et al., 2019). Administration of apigenin (40 and 80 mg/kg/day, p.o., for 21) improved neurobehavioral functions including learning memory, cognition, motor coordination, and grip strength which might be related to downregulation of c-JNK and p38MAPK signaling as well as the restoration of myelin basic protein within the brain. In addition, it inhibited neuronal apoptotic via reduction in Bax and caspase-3 and elevation in Bcl-2, restored neurotransmitter imbalance, decreased inflammatory markers through reduction in TNF-α and IL-1β, and alleviated oxidative damage (Akaras et al., 2023).

Luteolin (0.25, 0.5 and 1.0 mg/g feed, for 35 days) attenuated the mercury-induced locomotor deficits and enhanced the exploratory profiles assessed using the novel environment test, AChE activity, decreased LPO levels, but increased CAT and GST activities in rats (Adedara et al., 2016). Naringenin at 50 and 100 mg/kg/day, p.o., for 15 days improved cognitive impairments assessed using Morris water maze, prevented neuronal cell death, and oxidative stress in mercury intoxicationed mice (Chandran et al., 2019), and decreased the percentage of fragmented DNA in brain of both fetuses and pups (Mazhar et al., 2015).

3. Conclusions

Existing data demonstrate that nutraceutical supplementation affords protective effects against xenobiotics (e.g., metals, metalloids and ethanol). Nutraceuticals improved learning and memory impairments, anxiety and depressive-like behavior, locomotor activity and neuropathic pain. The protective mechanisms of nutraceutical treatments in various neurotoxic agents seem common (Fig. 1). The key mechanisms implicated are inhibition of oxidative stress (by suppressing LPO and increasing antioxidant enzymes and contents), suppression of apoptosis (by increasing Bcl2 expression, and reducing Bax, caspase-3 and cytochrome c expression), and neuroinflammation (by inhibiting inflammatory cytokines), inhibition of amyloid β (Aβ) plaque and neurofibrillary tangles, increased synaptic plasticity (by increasing BDNF), and restored cholinergic and neurotransmitter systems. Further research is needed to characterize the effects of nutraceuticals on the various molecular pathways in various exogenous neurotoxic agents.

Fig. 1.

Schematic representation of the effects of nutraceuticals on different signaling pathways in exogenous neurotoxicants.