Cadmium-induced Neurotoxicity Research Articles

Assessment of Protective Roles of Aqueous Seed Extract of Sour-Sop (Annona muricata) in Cerebellum Following Cadmium-induced Neurotoxicity of Adult Wistar Rats

Cadmium, a deleterious heavy metal that pervades the environment, has the potential to accumulate in the body and cause health complications. In the domain of traditional medicine, medicinal plants have been employed to combat the toxicity of heavy metals and treating of many diseases in traditional medicine.
 Aim: To access the protective impact of Annona muricata seed extract on cadmium-triggered neurotoxicity in the cerebellum of albino wistarrat.
 Place of Study: Department of Anatomy, Faculty of Basic Medical Sciences Olabisi Onabanjo University, Ogun State between June 2022 and June 2023
 METHODOLOGY: After a period of 14 days of acclimatization, 40 healthy male wistar rats were randomly allocated to four groups, group1(2ml/kg of distilled water), group2 cadmium only(2g/kg SC), group3 (2g/kg cadmium + 100mg/kg extract of Annona muricata) and group4(2g/kg cadmium + 200mg/kg extract of Annona muricata) The rats were subjected to cadmium subcutaneously followed by the oral administration of aqueous seed extract of Annona Muricata for fifteen consecutive days.
 Results: The impact of the extract on antioxidant enzymes activities of the cerebellum, cerebellar weight, as well as the histology of the cerebellum were scrutinized. The data revealed that the aqueous seed extract of Annona muricata, in a dose-dependent manner, augmented the levels of superoxide dismutase (SOD) (P=0.005) and catalase (CAT) (P=0.027) in contrast to the cadmium-only group. The relative weight of the cerebellum exhibited a significant increasein the treated groups compared to the cadmium-only group.
 The histology of the cerebellum delineated pathological changes arising from the exposure to cadmium, while Annona muricata brought about regenerative changes.
 Conclusion: In summary, the study posits that owing to the presence of phytochemicals in Annona muricata aqueous seed extract, it was efficacious in mitigating the neurotoxicity induced by cadmium in the cerebellum of male rats.

Targeting Autophagy, Apoptosis, and Oxidative Perturbations with Dapagliflozin Mitigates Cadmium-Induced Cognitive Dysfunction in Rats.

Cognitive decline and Alzheimer-like neuropathology are common manifestations of cadmium toxicity. Thanks to its antioxidant/anti-apoptotic features, dapagliflozin has demonstrated promising neuroprotective actions. However, its effect on cadmium-induced neurotoxicity is lacking. The present work aimed to examine whether dapagliflozin could protect rats from cadmium-evoked cognitive decline. In this study, the behavioral disturbances and hippocampal biomolecular alterations were studied after receiving dapagliflozin. Herein, cadmium-induced memory/learning decline was rescued in the Morris water maze, novel object recognition task, and Y-shaped maze by dapagliflozin. Meanwhile, the hippocampal histopathological abnormalities were mitigated. The molecular mechanisms revealed that dapagliflozin lowered hippocampal expression of p-tau and Aβ42 neurotoxic proteins while augmenting acetylcholine. The cognitive enhancement was triggered by hippocampal autophagy stimulation, as indicated by decreased SQSTM-1/p62 and Beclin 1 upregulation. Meanwhile, a decrease in p-mTOR/total mTOR and an increase in p-AMPK/total AMPK ratio were observed in response to dapagliflozin, reflecting AMPK/mTOR cascade stimulation. Dapagliflozin, on the other hand, dampened the pro-apoptotic processes in the hippocampus by downregulating Bax, upregulating Bcl-2, and inactivating GSK-3β. The hippocampal oxidative insult was mitigated by dapagliflozin as seen by lipid peroxide lowering, antioxidants augmentation, and SIRT1/Nrf2/HO-1 pathway activation. In conclusion, dapagliflozin's promising neuroprotection was triggered by its pro-autophagic, anti-apoptotic, and antioxidant properties.

Nano-selenium alleviates cadmium-induced neurotoxicity in cerebrum via inhibiting gap junction protein connexin 43 phosphorylation.

Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.

Arrestin domain-containing protein 1-mediated microvesicles (ARMMs) protect against cadmium-induced neurotoxicity

Exposure to environmental heavy metals such as cadmium (Cd) is often linked to neurotoxicity but the underlying mechanisms remain poorly understood. Here we show that Arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs)–an important class of extracellular vesicles (EVs) whose biogenesis occurs at the plasma membrane–protect against Cd-induced neurotoxicity. Cd increased the production of EVs, including ARMMs, in a human neural progenitor cell line, ReNcell CX (ReN) cells. ReN cells that lack ARMMs production as a result of CRISPR-mediated ARRDC1 knockout were more susceptible to Cd toxicity as evidenced by increased LDH production as well as elevated level of oxidative stress markers. Importantly, adding ARMMs back to the ARRDC1-knockout ReN cells significantly reduced Cd-induced toxicity. Consistent with this finding, proteomics data showed that anti-oxidative stress proteins are enriched in ARMMs secreted from ReN cells. Together our study reveals a novel protective role of ARMMs in Cd neurotoxicity and suggests that ARMMs may be used therapeutically to reduce neurotoxicity caused by exposure to Cd and potentially other metal toxicants.

Disturbance of gut microbiota aggravates cadmium-induced neurotoxicity in zebrafish larvae through V-ATPase

Cadmium (Cd) is a harmful environmental pollutant that causes damage to the nervous system, and exposure to Cd also disrupts the gut microbiota. However, it is still unclear whether Cd-induced neurotoxicity is related to alteration of the microbiota. In this study, we first established a germ-free (GF) zebrafish model to avoid the effects of gut microbiota disturbances caused by Cd exposure, and found that Cd-induced neurotoxic effects were weak in GF zebrafish. RNA sequencing showed that expression levels of V-ATPase family genes (atp6v1g1, atp6v1b2, and atp6v0cb) were significantly decreased in Cd-treated conventionally reared (CV) zebrafish, while this inhibition could be avoided in GF zebrafish. Overexpression of atp6v0cb in the V-ATPase family could partially rescue Cd-induced neurotoxicity. Our study shows that the disturbance of gut microbiota aggravates Cd-induced neurotoxicity, and that this may be associated with the expression of several genes in the V-ATPase family.

Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.

Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington's disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 µM CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin-proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.

JAK2/STAT3 Signaling Pathway and Klotho Gene in Cadmium-induced Neurotoxicity In Vitro and In Vivo.

Cadmium (Cd), a common heavy metal in the environment, is associated with cognitive impairment. In the present study, we carried out a preliminary inquiry to explore whether Cd causes neurotoxicity by regulating the JAK2/STAT3 signaling pathway and affecting the expression of klotho genes in vivo and in vitro, providing clues for the mechanism of Cd-induced cognitive dysfunction. The rat samples were injected with Cd chloride solution for 14weeks, and the memory function of the rats was detected. Different concentrations of Cd and JAK2/STAT3 signaling pathway inhibitors were used to treat PC12 cells and thus detect the apoptosis rate. The protein expression levels of JAK2, p-JAK2, STAT3, p-STAT3, and klotho in rat and PC12 cell were detected by ELISA and Western blot, respectively. With the increase in exposure dose, the memory function of rats was severely impaired. The expression of p-JAK2 and p-STAT3 proteins was significantly up-regulated, whereas that of klotho was significantly down-regulated both in vivo and in vitro (p < 0.05). In comparison with the high-dose Cd exposure group, after adding tyrphostin AG490 (AG490), the apoptosis rate of PC12 cells increased, whereas the phosphorylation levels of JAK2 and STAT3 in the cells decreased significantly (p < 0.05). Cd exposure may cause neurotoxicity by regulating the JAK2/STAT3 signaling pathway and down-regulating klotho protein expression, leading to cognitive dysfunction.

Minocycline Protects PC12 Cells Against Cadmium-Induced Neurotoxicity by Modulating Apoptosis.

Cadmium (Cd) is a well-known heavy metal and a neurotoxic agent. Minocycline (Mino) is an anti-microbial agent with a lipophilic structure that crosses the blood-brain barrier and enters the cerebral tissue. In recent studies, Mino has been introduced as an antioxidant and anti-apoptotic chemical compound, and therefore, it was examined as a protective candidate against Cd-induced neurotoxicity. In this study, PC12 cells were exposed to Cd alone, or after being pre-treated with Mino. Initially, the cell viability and oxidative stress were analyzed using the MTT assay and fluorimetry, respectively. Then, Cd-induced apoptosis and Mino anti-apoptotic effect were evaluated in both intrinsic and extrinsic pathways using western blot analysis. Exposing PC12 cells to Cd for 24h decreased cell viability and increased production of reactive oxygen species in comparison with the control group. Cd (35μM) also elevated the level of caspase-8, Bax/Bcl-2, and caspase-3 proteins in the cells. Mino pre-treatment for 2h (100nM) increased the number of viable cells and decreased the production of reactive oxygen species, and the level of all apoptotic markers in comparison to Cd-treated cells. Considering all the evidence, it appears that Mino holds promising antioxidant and anti-apoptotic activity and can protect cells against Cd-induced oxidative stress and prevent apoptotic cell death.

Attenuation of Oxidative Stress and Cognitive Impairment in Cadmium Chloride-Exposed Wistar Rats Pre-treated with Ethanolic Turmeric Root Extract

Background: Turmeric (Curcuma longa), belonging to the Zingiberaceae family, is a widely used spice in cuisines of African, Asian and other countries globally. Despite the enormous pharmacological benefits of turmeric, there is very little experimental evidence to demonstrate its protective activity against cadmium-induced neurotoxicity. Accordingly, this study is aimed at investigating such activity in Wistar rats and its possible mechanisms of action. Methods: Y-maze and Novel object recognition tests were utilized to evaluate memory impairments while antioxidants activity and lipid peroxidation were evaluated to outline the antioxidant mechanism of action following pre-treatment of rats with ethanolic turmeric root extract (200 mg/kg body weight) 1 hour before cadmium administration for 21 consecutive days. In addition, the histology of the cerebrum and hippocampus was investigated to determine possible anatomical alterations across experimental groups. Results: The ethanolic extract of turmeric root at the dose of 200 mg/kg significantly improved the memory of rats and protected against the impairments induced by cadmium. In addition, the extract significantly increased cerebral and hippocampal antioxidant enzyme activities (SOD, GPx and CAT), decreased lipid peroxidation (MDA) and protected against the degenerative changes observed in the cerebrum and hippocampus of rats treated with cadmium alone. Conclusion: Taken together, these findings suggest that the ethanolic extract of turmeric root protected against the cognitive impairments induced by cadmium possibly through the attenuation of the oxidative damaging activity of cadmium.

Neuroprotective effects of carvacrol against cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis.

Cadmium (Cd), is a heavy metal reported to be associated with oxidative stress and inflammation. In this paper, we investigated the possible protective effects of carvacrol against Cd-induced neurotoxicity in rats. Adult male Sprague Dawley rats were treated orally with Cd (25mg/kg body weight) and with carvacrol (25 and 50mg/kg body weight) for 7 days. Carvacrol decreased the levels of malondialdehyde (MDA), glial fibrillary acidic protein (GFAP) and monoamine oxidase (MAO), and significantly increased the levels of glutathione (GSH) and activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in brain tissue. Additionally, carvacrol alleviated the in levels of inflammation and apoptosis related proteins involving p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), B-cell lymphoma-3 (Bcl-3), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), myeloperoxidase (MPO), prostaglandin E2 (PGE2), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), cysteine aspartate specific protease-3 (caspase-3) and Bcl-2 associated X protein (Bax) in the Cd-induced neurotoxicity. Carvacrol also decreased the mRNA expression of matrix metalloproteinases (MMP9 and MMP13), as well as 8-hydroxy-2'-deoxyguanosine (8 - OHdG) level, a marker of oxidative DNA damage. Collectively, our findings indicated that carvacrol has a beneficial effect in ameliorating the Cd-induced neurotoxicity in the brain of rats.

Cordycepin exacerbates cadmium-induced neurotoxicity via promoting endoplasmic reticulum stress-associated apoptosis

• Exposure of Cor deteriorated Cd-induced learning and memory deficits in mice. • Cor promoted Cd-induced neuronal apoptosis both in vivo and vitro. • The ER stress pathway was involved in the increased Cd- and Cor-induced neurotoxicity. Cordycepin (Cor) is a potent bioactive constituent of Cordyceps militaris , which has been used as a daily tonic food and herbal medicine in Asia. Cadmium (Cd) is a widespread neurotoxic environmental contaminant, and it has been detected as a pollutant in Cordyceps militaris . However, the potential effects of Cor on Cd neurotoxicity remains unknown. This study aimed to investigate the effects and possible mechanisms of Cor on neurotoxicity in Cd-induced cell and preclinical models. It was observed that Cor administration aggravated Cd-induced cognitive impairment and neurotoxicity in mice, exerted synergistic growth inhibition, and promoted apoptosis of SH-SY5Y cells. These effects were found to be mediated through the activation of endoplasmic reticulum (ER) stress. Overall, our findings suggest that Cor can increase Cd-induced neurotoxicity via promoting ER stress-associated apoptosis. These observations may support the implementation of stricter criterion for the detection of Cd in Cordyceps militaris , to keep the consumers safe.

Potentilla anserine L. polysaccharide protects against cadmium-induced neurotoxicity

Cadmium is a toxic metal that can damage the brain and other organs. This study aimed to explore the protective effects of Potentilla anserine L. polysaccharide (PAP) against CdCl2-induced neurotoxicity in N2a and SH-SY5Y cells and in the cerebral cortex of BALB/c mice. In addition, we aimed to identify the potential mechanisms underlying these protective effects. Relative to CdCl2 treatment alone, pretreatment with PAP prevented the reduction in cell viability evoked by CdCl2, decreased rates of apoptosis, promoted calcium homeostasis, decreased ROS accumulation, increased mitochondrial membrane potential, inhibited cytochrome C and AIF release, and prevented the cleavage of caspase-3 and PARP. In addition, PAP significantly decreased the CdCl2-induced phosphorylation of CaMKII, Akt, and mTOR. In conclusion, PAP represents a potential therapeutic agent for the treatment of Cd-induced neurotoxicity, functioning in part via attenuating the activation of the mitochondrial apoptosis pathway and the Ca2+-CaMKII-dependent Akt/mTOR pathway.

The protective effects of chitosan oligosaccharide (COS) on cadmium-induced neurotoxicity in Wistar rats

The aim of the study was to investigate the influence of chitosan oligosaccharide (COS) on some antioxidant and cytokine levels in the rat hippocampus as well as synaptophysin (SYP) immunoreactivity in the cerebral cortex of the cadmium (Cd) exposed rats. Thirty-two male albino Wistar rats were divided randomly into four equal groups as control (C; n = 8), Cd (n = 8), COS (n = 8), and Cd + COS (CdCOS; n = 8). The rats in the Cd and CdCOS groups received Cd chloride (CdCl2) (2 mg/kg/d) orally by gastric gavage three times a week for 4 weeks. Besides, COS (200 mg/kg/d) was administered to COS and CdCOS groups five times a week for 4 weeks. Then, they were decapitated and hippocampal/cerebral cortex tissue samples were taken for measurement of GSH levels, CAT and SOD activities, MDA values, TNF-α, IL-6, and IL-10 levels as well as SYP immunoreactivity. Although tissue GSH levels were determined the lowest in the Cd group, these values were attenuated with COS treatment in the CdCOS group (p < .01). In addition, TNF-α levels were alleviated by COS treatment in the CdCOS group when compared to Cd (p < .01). SYP-positive cells were investigated in the cerebral cortex and found mild in the CdCOS group. COS exhibits potential protective effects on Cd-induced neurotoxicity in rats.

Gisenoside Rg1 attenuates cadmium-induced neurotoxicity in vitro and in vivo by attenuating oxidative stress and inflammation.

Gisenoside Rg1 is a potent neuroprotectant in ginseng. The aim of this study was to investigate the elimination effect of Rg1 on cadmium (Cd)-induced neurotoxicity. A cumulative Cd exposure mouse model was established. Also, the toxicity of Cd and the protective effect of Rg1 were examined in vitro using cultured neurons and microglia. We found that Cd-intoxicated mice exhibited significant injury in the liver, kidney, small intestine, and testis, along with cognitive impairment. Antioxidant enzymes such as SOD, GSH-Px and CAT were reduced in the blood and brain, and correspondingly, the lipid peroxidation product MDA was elevated. In the brain, astrocytes and microglia were activated, characterized by an increase in inflammatory factors such as TNF-α, IL-1β and IL-6, as well as their protein markers GFAP and IBA1. However, Rg1 eliminated Cd-induced toxicity and restored oxidative stress and inflammatory responses, correspondingly restoring the behavioral performance of the animals. Meanwhile, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the Rg1-mediated elimination of Cd-induced toxicity. Rg1 is a promising agent for the elimination of Cd-induced toxicity.

Protective effects of oral melatonin against cadmiuminduced neurotoxicity in Wistar rats

Protective effects of oral melatonin against cadmiuminduced neurotoxicity in Wistar rats

Potentilla anserine L. polysaccharide inhibits cadmium-induced neurotoxicity by attenuating autophagy

Cadmium (Cd), a heavy metal with cytotoxicity, can activate autophagy. This study aimed to explore the effects and mechanisms of Potentilla anserine L. polysaccharide (PAP) on autophagy in N2a cells, primary neurons, and the brain of BALB/c mice exposed to Cd. The CCK-8 assay results showed that the cell viability decreased and the number of acidic vesicular organelles, autophagic vacuoles, lysosomes, and dysfunctional mitochondria increased in the cytoplasm of Cd-exposed N2a cells and primary neurons, as revealed by acridine orange staining, monodansylcadaverine staining, and transmission electron microscopy. PAP mitigated Cd-induced neuronal death and characteristic changes in autophagy. The expression of LC3 IILC3 II, Bcl-2, p62, Beclin-1, and PI3K class III was examined by Western blot analysis. Furthermore, the PI3K inhibitor (LY294002 or 3-MA) and/or PAP reversed the Cd-induced upregulated expression of LC3 II, Beclin-1, and PI3K class III, with a synergy between PI3K inhibitor and PAP against Cd-induced autophagy. The findings suggested that PAP partially prevented Cd-induced autophagic cell death in neurons by inhibiting the PI3K class III/Beclin-1 signaling pathway in vitro and in vivo.

Effects of myricetin against cadmium-induced neurotoxicity in PC12 cells.

Cadmium (Cd) is one of the most prevalent toxic metals widely found in the environment. Cd induces toxicity and apoptosis in various organs and cells. The nervous system is one of the primary organs targeted by Cd. Cd toxicity is correlated with induction of severe oxidative stress. Myricetin, a natural product, has been found to exert protective effects against various disease conditions. The present study aimed to evaluate the potential protective effects of myricetin on Cd-induced neurotoxicity in PC12 cells. The cells were pretreated with myricetin in the absence and presence of Cd. The viability of cells was assessed using the MTT assay. Markers of oxidative stress were investigated by the lipid peroxidation (LPO), glutathione (GSH) content, and total antioxidant capacity (TAC). Moreover, activation of caspase 3 was examined by Western blot analysis. Myricetin could significantly enhance the viability of PC12 cells. Pretreatment of the cells with myricetin, prior to Cd exposure, showed a significant decrease in the levels of LPO whereas GSH and TAC levels were increased. In addition, the activity of caspase-3 was notably prevented by myricetin. These findings revealed that myricetin has protective effects on Cd-induced neurotoxicity in PC12 cells, which can be linked to its antioxidant potential, inhibition of LPO, and prevention of caspase-3 activation.

Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity

Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics analysis revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer’s disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl2 exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-l-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemical-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.

Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: Role of oxidative stress, inflammation and apoptosis

Environmental and occupational exposure to heavy metals, including cadmium (Cd), is associated with extremely adverse impacts to living systems. Antioxidant agents are suggested to eliminate Cd intoxication. In this paper, we investigated the potential neuroprotective effect of protocatechuic acid (PCA) against Cd-induced neuronal damage in rats. Adult male Wistar rats were randomly divided into control, PCA (100 mg/kg)-treated, CdCl2 (6.5 mg/kg)-treated, and PCA and Cd treatment groups. Pre-treatment with PCA significantly reduced Cd concentrations and increased cortical acetylcholinesterase activity and brain derived neurotrophic factor. Additionally, PCA also prevented CdCl2-induced oxidative stress in the cortical tissue by preventing lipid peroxidation and the formation of nitric oxide (NO), and significantly enhancing antioxidant enzymes. Molecularly, PCA significantly up-regulated the antioxidant gene expression (Sod2, Cat, Gpx1, and Gsr) that was down-regulated by Cd. It should be noted that this effect was achieved by targeting the nuclear-related factor 2 (Nfe2l2) mRNA expression. PCA also prevented the Cd-induced inflammation by reducing the pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. Moreover, PCA supplementation relieved the Cd-induced neuronal death by increasing Bcl-2 and decreasing Bax and Cas-3 levels in the cortical tissue. The improvement of the cortical tissue histopathology by PCA confirmed the biochemical and molecular data. Collectively, our findings indicate that PCA can counteract Cd-induced cortical toxicity by enhancing the antioxidant defense system and suppressing inflammation and apoptosis.

Effect of both selenium and biosynthesized nanoselenium particles on cadmium-induced neurotoxicity in albino rats.

Because cadmium (Cd) is not naturally degradable by ecosystems, it interferes with many types of food chains. Cd accumulates in the kidney, liver and in the nervous tissues, especially the brain. The neurotoxicity of Cd is very high, as it alters the integrity, and increases the permeability, of the blood-brain barrier. Cd penetrates and accumulates in neurons in the brains of rats. This study reveals that Cd decreases antioxidant enzymes and increases oxidative stress in the brain. In addition, Cd increases lipid peroxidation of brain tissues. Cd increases the expression of the Cu/Zn superoxide dismutase gene. It also affects cholinergic, glutamatergic, gamma-Aminobutyric acid (GABAergic), dopamine, serotonin and acetylcholine neurotransmitters in brain tissue. Consequently, Cd increases the formation of amyloid β, a neurotoxic index, and induces apoptosis by changing the quality and the quantity of Bcl-2, Bax and p53 proteins. In conclusion, both selenium and nanoselenium show potential antioxidant activity and promote recovery from the neurotoxic action of Cd.