Cd-induced Neurotoxicity Research Articles

High cadmium exposure impairs adult hippocampal neurogenesis via disruption of store-operated calcium entry

Cadmium (Cd) is a neurotoxicant that gradually accumulates in the human body with age. High Cd burden is correlated with adult hippocampal neurogenesis (AHN) and memory deficits in mammals. However, little knowledge is known about the mechanism by which Cd exposure impairs neurogenesis and cognition. Here, we investigated the roles of store-operated calcium entry (SOCE)-mediated calcium dyshomeostasis in Cd-induced AHN and memory deficits as well as therapeutic potential for the prevention of Cd-induced neurotoxicity. To achieve this goal, 8 weeks-old C57BL/6 J mice were subjected to different concentrations of cadmium chloride (0, 5, 10, 20 ppm) in drinking water for 8 weeks, we then examined the AHN, calcium homeostasis, SOCE channel and memory in Cd-exposed mice by using immunohistochemistry, calcium imaging, Y-maze and fear conditioning test. Our results indicated that chronic Cd exposure markedly increased Cd levels in serum and cerebrospinal fluid by almost 10-fold, and inhibited the proliferation and differentiation of hippocampal adult neural stem cells in a dose-dependent manner. Additionally, Cd exposure impaired the maturation of hippocampal neural stem cells without inducing gliosis. Transcriptome analysis revealed that Cd exposure inhibited the proliferation of neuroblastoma via alteration of calcium signaling pathway, and attenuated SOCE channels played a pivotal role in mediating Cd-induced cytoplasmic calcium overload and depletion of endoplasmic reticulum calcium stores. Activation of SOCE by hyperforin, a natural derivative from medicinal plant, restored intracellular calcium homeostasis and improved AHN and memory in Cd-exposed mice. Together, this study provided novel insights into the mechanism that Cd exposure impaired AHN and memory by prompting neuronal SOCE-mediated calcium dyshomeostasis, and offered a new therapeutic approach for prevention of Cd-induced neurotoxicity.

Effects of Laurus extract against cadmium-induced neurotoxicity in rats

Cadmium (Cd) is a hazardous heavy metal with widespread environmental presence, posing significant threats to human and animal health. This study investigates the neurotoxic effects of Cd exposure and explores the therapeutic efficacy of Laurus nobilis L. in counteracting these adverse effects. Cd exposure induces oxidative stress and neurotoxicity, leading to neuronal damage and histopathological alterations. Laurus, known for its antioxidant properties, is assessed for its potential in mitigating Cd-induced neurotoxicity through in vitro antioxidant assays, GC–MS analysis, HPLC profiling, and experimental animal models. Results demonstrate that Laurus ethanolic extract exhibits significant antioxidant activity, attributed to its phenolic and flavonoid constituents. GC–MS analysis reveals various bioactive compounds in the extract, including Hexadecanoic acid methyl ester and (Z)-13-Docosenamide, which posses neuroprotective properties. HPLC analysis identifies phenolic compounds such as ellagic acid and flavonoids like rutin and kaempferol in the extract. In vivo studies in rats exposed to Cd demonstrate that Laurus extract administration mitigates Cd-induced alterations in body and brain weight, hematological parameters, liver and kidney function, oxidative stress markers, and acetylcholinesterase (AchE) activity. Histopathological examination confirms the protective effects of Laurus against Cd-induced neuronal damage. The SOD model, validated with high resolution (2.05 Å) and strong R values (work: 0.192, free: 0.236, observed: 0.194), shows strong structural stability (C-score: 0.30). Docking studies reveal high binding affinities of kaempferol (−8.1 kcal/mol) and rutin (−8.7 kcal/mol) with SOD with kaempferol demonstrating superior solubility, lipophilicity, and drug-likenessSimulation analysis confirms the protein’s flexibility and adaptability, highlighting its therapeutic potential, especially with kaempferol. These findings suggest the therapeutic potential of Laurus. as a natural remedy for Cd-induced neurotoxicity, highlighting its antioxidant and neuroprotective properties.

Quetiapine attenuates cadmium neurotoxicity by suppressing oxidative stress, inflammation, and pyroptosis.

Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied. QTP was administered in 10 and 20mg/kg doses, while Cd was given in a dose of 6.5mg/kg. In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and β-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1β and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels. In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.

Cadmium exposure induced neuronal ferroptosis and cognitive deficits via the mtROS-ferritinophagy pathway

Exposure to environmental cadmium (Cd) is known to cause neuronal death and cognitive decline in humans. Ferroptosis, a novel iron-dependent type of regulated cell death, is involved in various neurological disorders. In the present study, Cd exposure triggered ferroptosis in the mouse hippocampus and in the HT22 murine hippocampal neuronal cell line, as indicated by significant increases in ferroptotic marker expression, intracellular iron levels, and lipid peroxidation. Interestingly, ferroptosis of hippocampal neurons in response to Cd exposure relied on the induction of autophagy since the suppression of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) substantially ameliorated Cd-induced ferroptosis. Furthermore, nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin was required for the Cd-induced ferroptosis of hippocampal neurons, demonstrating that NCOA4 knockdown decreased intracellular iron levels and lipid peroxidation and increased cell survival, following Cd exposure. Moreover, Cd-induced mitochondrial reactive oxygen species (mtROS) generation was essential for the ferritinophagy-mediated ferroptosis of hippocampal neurons. Importantly, pretreatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated Cd-induced hippocampal neuronal death and cognitive impairment in mice. Taken together, these findings indicate that ferroptosis is a novel mechanism underlying Cd-induced neurotoxicity and cognitive impairment and that the mtROS-ferritinophagy axis modulates Cd-induced neuronal ferroptosis.

Integrated metabolomic and transcriptomic analysis reveals perturbed glycerophospholipid metabolism in mouse neural stem cells exposed to cadmium

Cadmium (Cd) is a ubiquitous heavy metal with neurotoxicity. Our previous study reported that Cd could inhibit the proliferation of mouse neural stem cells (mNSCs). However, the underlying mechanisms are obscure. In recent years, the rapid growth of multi-omics techniques enables us to explore the cellular responses that occurred after toxicant exposure at the molecular level. In this study, we used a combination of metabolomics and transcriptomics approaches to investigate the effects of exposure to Cd on mNSCs. After treatment with Cd, the metabolites and transcripts in mNSCs changed significantly with 110 differentially expressed metabolites and 2135 differentially expressed genes identified, respectively. The altered metabolites were mainly involved in glycerophospholipid metabolism, arginine and proline metabolism, arginine biosynthesis, glyoxylate and dicarboxylate metabolism. Meanwhile, the transcriptomic data demonstrated perturbed membrane function and signal transduction. Furthermore, integrated analysis of metabolomic and transcriptomic data suggested that glycerophospholipid metabolism might be the major metabolic pathway affected by Cd in mNSCs. More interestingly, the supplementation of lysophosphatidylethanolamine (LPE) attenuated Cd-induced mitochondrial impairment and the inhibition of cell proliferation and differentiation in mNSCs, further supporting our analysis. Overall, the study provides new insights into the mechanisms of Cd-induced neurotoxicity.

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.

Mirtazapine attenuated cadmium-induced neuronal intoxication by regulating Nrf2 and NF-κB/TLR4 signals

Cadmium (Cd) is one of the most hazardous metals to the environment and human health. Neurotoxicity is of the most serious hazards caused by Cd. Mirtazapine (MZP) is a central presynaptic α2 receptor antagonist used effectively in treating several neurological disorders. This study investigated the anti-inflammatory and antioxidant activity of MZP against Cd-induced neurotoxicity. In this study, rats were randomly divided into five groups: control, MZP (30 mg/kg), Cd (6.5 mg/kg/day; i.p), Cd + MZP (15 mg/kg), and Cd + MZP (30 mg/kg). Histopathological examination, oxidative stress biomarkers, inflammatory cytokines, and the impact of Nrf2 and NF-κB/TLR4 signals were assessed in our study. Compared to Cd control rats, MZP attenuated histological abrasions in the cerebral cortex and CA1 and CA3 regions of the hippocampus as well as the dentate gyrus. MZP attenuated oxidative injury by upregulating Nrf2. In addition, MZP suppressed the inflammatory response by decreasing TNF-α, IL-1β, and IL-6 mediated by downregulating TLR4 and NF-κB. It is noteworthy that MZP's neuroprotective actions were dose-dependent. Collectively, MZP is a promising therapeutic strategy for attenuating Cd-induced neurotoxicity by regulating Nrf2, and NF-κB/TLR4 signals, pending further study in clinical settings.

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.

Cadmium induces mitochondrial dysfunction via SIRT1 suppression-mediated oxidative stress in neuronal cells.

Cadmium is a widespread environmental contaminant and its neurotoxicity has raised serious concerns. Mitochondrial dysfunction is a key event in Cd-induced nervous system disease; however, the exact molecular mechanism involved has not been fully elucidated. Increasing evidences have shown that Sirtuin 1 (SIRT1) is the key target protein impaired in Cd-induced mitochondrial dysfunction. In this study, the role of SIRT1 in Cd-induced mitochondrial dysfunction and cell death and the underlying mechanisms were evaluated in vitro using PC12 cells and primary rat cerebral cortical neurons. The results showed that Cd exposure caused cell death by inhibiting SIRT1 expression, thus inducing oxidative stress and mitochondrial dysfunction in vitro. However, inhibition of oxidative stress by the antioxidant puerarin alleviated Cd-induced mitochondrial dysfunction. Furthermore, activation of SIRT1 using the agonist Srt1720 significantly abolished Cd-induced oxidative stress and mitochondrial dysfunction and ultimately alleviated Cd-induced neuronal cell death. Collectively, our data indicate that Cd induced mitochondrial dysfunction via SIRT1 suppression-mediated oxidative stress, leading to the death of PC12 cells and primary rat cerebral cortical neurons. These findings suggest a novel mechanism for Cd-induced neurotoxicity.

Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction

Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl2) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl2 (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA Gm10532 (lnc-Gm10532) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl2 for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl2-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-Gm10532 increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of Fis1 mRNA. Moreover, lnc-Gm10532 was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.

Cerebellar injury induced by cadmium via disrupting the heat-shock response.

Cadmium (Cd) is a food contaminant that poses serious threats to animal health, including birds. It is also an air pollutant with well-known neurotoxic effects on humans. However, knowledge on the neurotoxic effects of chronic Cd exposure on chicken is limited. Thus, this study assessed the neurotoxic effects of chronic Cd on chicken cerebellum. Chicks were exposed to 0 (control), 35 (low), and 70 (high) mg/kg of Cd for 90days, and the expression of genes related to the heat-shock response was investigated. The chickens showed clinical symptoms of ataxia, and histopathology revealed that Cd exposure decreased the number of Purkinje cells and induced degeneration of Purkinje cells with pyknosis, and some dendrites were missing. Moreover, Cd exposure increased the expression of heat-shock factors, HSF1, HSF2, and HSF3, and heat-shock proteins, HSP60, HSP70, HSP90, and HSP110. These changes indicate that HSPs improve the tolerance of the cerebellum to Cd. Conversely, the expressions of HSP10, HSP25, and HSP40 were decreased significantly, which indicated that Cd inhibits the expression of small heat-shock proteins. However, HSP27 and HSP47 were upregulated following low-dose Cd exposure, but downregulated under high-dose Cd exposure. This work sheds light on the toxic effects of Cd on the cerebellum, and it may provide evidence for health risks posed by Cd. Additionally, this work also identified a novel target of Cd exposure in that Cd induces cerebellar injury by disrupting the heat-shock response. Cd can be absorbed into chicken's cerebellum through the food chain, which eventually caused cerebellar injury. This study provided a new insight that chronic Cd-induced neurotoxicity in the cerebellum is associated with alterations in heat-shock response-related genes, which indicated that Cd through disturbing heat-shock response induced cerebellar injury.

Metformin attenuates cadmium-induced degeneration of spiral ganglion neuron via restoring autophagic flux in primary culture

Cadmium (Cd), a common environmental and occupational toxicant, is an important risk factor for hearing loss. After exposure, Cd accumulates in the inner ear and induces spiral ganglion neuron (SGN) degeneration; however, the underlying mechanisms are poorly understood. Dysfunctional autophagy has been implicated in many neurodegenerative diseases, including Cd-induced neurotoxicity. Metformin has been validated to confer not only anti-hyperglycaemic but also neuroprotective effects. However, the relationship between autophagy dysfunction, SGN degeneration, and the effect of metformin on Cd-induced SGN neurotoxicity has not yet been established. In this study, we demonstrate that metformin notably attenuates Cd-evoked SGN degeneration by restoring impaired autophagy flux, as evidenced by the suppression of Cd-induced elevation of autophagy markers microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and autophagy substrate protein p62 in degenerated SGN. Blockage of autophagy flux by chloroquine abolished metformin-induced neuroprotection against Cd-induced neurotoxicity in SGN. The results of this study reveal that autophagy dysfunction is an important component of Cd-induced SGN degeneration, and metformin may be a potential protective agent for attenuating SGN degeneration following Cd exposure.

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.

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.

Puerarin alleviates cadmium-induced mitochondrial mass decrease by inhibiting PINK1–Parkin and Nix-mediated mitophagy in rat cortical neurons

Cadmium (Cd) has well-known central nervous system toxicity, and mitochondria are direct targets of Cd-induced neuronal toxicity. However, how Cd induces mitochondrial mass decrease in terms of its neurotoxic effects remains unknown. Puerarin, an isoflavone extracted from kudzu root, can cross the blood–brain barrier and exert protective effects in nervous system disease. The purpose of the study was to determine the mechanism of Cd-induced mitochondrial mass decrease and the protective role of puerarin in rat cortical neurons. The results indicated that Cd induced mitochondrial mass decrease by activating mitophagy mediated by the PTEN-induced putative kinase protein 1 (PINK1)–E3 ubiquitin ligase (Parkin) and Nip3-like protein X (Nix) pathways in rat cortical neurons. Puerarin improved the Cd-induced decrease in mitochondrial membrane potential (MMP) in vitro, and blocked PINK1–Parkin and Nix-mediated mitophagy, inhibiting Cd-induced mitochondrial mass decrease in rat cortical neurons in vitro and in vivo. In summary, our data clearly indicated that puerarin protects rat cortical neurons against Cd-induced neurotoxicity by ameliorating mitochondrial damage, inhibiting mitophagy-mediated mitochondrial mass decrease. Puerarin appears to have great potential as a neuroprotective agent.

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.

Developmental exposure to environmental levels of cadmium induces neurotoxicity and activates microglia in zebrafish larvae: From the perspectives of neurobehavior and neuroimaging

Cadmium (Cd) is a worldwide environmental pollutant that postures serious threats to humans and ecosystems. Over the years, its adverse effects on the central nervous system (CNS) have been concerned, whereas the underlying cellular/molecular mechanisms remain unclear. In this study, taking advantages of zebrafish model in high-throughput imaging and behavioral tests, we have explored the potential developmental neurotoxicity of Cd at environmentally relevant levels, from the perspectives of neurobehavior and neuroimaging. Briefly, Cd2+ exposure resulted in a general impairment of zebrafish early development. Zebrafish neurobehavioral patterns including locomotion and reactivity to environmental signals were significantly perturbed upon Cd2+ exposure. Importantly, a combination of in vivo two-photon neuroimaging, flow cytometry and gene expression analyses revealed notable neurodevelopmental disorders as well as neuroimmune responses induced by Cd2+ exposure. Both cell-cycle arrest and apoptosis contributed jointly to a significant decrease of neuronal density in zebrafish larvae exposed to Cd2+. The dramatic morphological alterations of microglia from multi-branched to amoeboid, the microgliosis, as well as the modulation of gene expression profiles demonstrated a strong activation of microglia and neuroinflammation triggered by environmental levels of Cd2+. Together, our study points to the developmental toxicity of Cd in inducing CNS impairment and neuroinflammation thereby providing visualized etiological evidence of this heavy metal induced neurodevelopmental disorders. It's tempting to speculate that this research model might represent a promising tool not only for understanding the molecular mechanisms of Cd-induced neurotoxicity, but also for developing pharmacotherapies to mitigate the neurological damage resulting from exposure to Cd, and other neurotoxicants.

Cadmium Impairs Autophagy Leading to Apoptosis by Ca2+-Dependent Activation of JNK Signaling Pathway in Neuronal Cells.

Autophagy, a process for self-degradation of intracellular components and dysfunctional organelles, is closely related with neurodegenerative diseases. It has been shown that cadmium (Cd) induces neurotoxicity partly by impairing autophagy. However, the underlying mechanism is not fully elucidated. In this study, we show that Cd induced expansion of autophagosomes with a concomitant abnormal expression of autophagy-related (Atg) proteins in PC12 cells and primary murine neurons. 3-MA, a classical inhibitor of autophagy, attenuated Cd-induced expansion of autophagosomes and apoptosis in the cells. Further investigation demonstrated that Cd activated JNK pathway contributing to autophagosome expansion-dependent neuronal apoptosis. This is supported by the findings that pharmacological inhibition of JNK with SP600125 or expression of dominant negative c-Jun markedly attenuated Cd-induced expansion of autophagosomes and abnormal expression of Atg proteins, as well as apoptosis in PC12 cells and/or primary neurons. Furthermore, we noticed that chelating intracellular free Ca2+ ([Ca2+]i) with BAPTA/AM profoundly blocked Cd-elicited activation of JNK pathway and consequential expansion of autophagosomes, abnormal expression of Atg proteins, and apoptosis in the neuronal cells. Similar events were also seen following prevention of [Ca2+]i elevation with EGTA or 2-APB, implying a Ca2+-dependent mechanism involved. Taken together, the results indicate that Cd impairs autophagy leading to apoptosis by Ca2+-dependent activation of JNK signaling pathway in neuronal cells. Our findings highlight that manipulation of intracellular Ca2+ level and/or JNK activity to ameliorate autophagy may be a promising intervention against Cd-induced neurotoxicity and neurodegeneration.