Cadmium Neurotoxicity Research Articles

Protective Role of Quercetin in Cadmium-Induced Cholinergic Dysfunctions in Rat Brain by Modulating Mitochondrial Integrity and MAP Kinase Signaling.

With the increasing evidences of cadmium-induced cognitive deficits associated with brain cholinergic dysfunctions, the present study aimed to decipher molecular mechanisms involved in the neuroprotective efficacy of quercetin in rats. A decrease in the binding of cholinergic-muscarinic receptors and mRNA expression of cholinergic receptor genes (M1, M2, and M4) was observed in the frontal cortex and hippocampus on exposure of rats to cadmium (5.0mg/kg body weight, p.o.) for 28days compared to controls. Cadmium exposure resulted to decrease mRNA and protein expressions of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) andenhance reactive oxygen species (ROS) generation associated with mitochondrial dysfunctions, ultrastructural changes, and learning deficits. Enhanced apoptosis, as evidenced by alterations in key proteins involved in the pro- and anti-apoptotic pathway and mitogen-activated protein (MAP) kinase signaling, was evident on cadmium exposure. Simultaneous treatment with quercetin (25mg/kg body weight, p.o.) resulted toprotect cadmium-induced alterations in cholinergic-muscarinic receptors, mRNA expression of genes (M1, M2, and M4), and expression of ChAT and AChE. The protective effect on brain cholinergic targets was attributed to the antioxidant potential of quercetin, which reduced ROS generation and protected mitochondrial integrity by modulating proteins involved in apoptosis and MAP kinase signaling. The results exhibit that quercetin may modulate molecular targets involved in brain cholinergic signaling and attenuate cadmium neurotoxicity.

Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria.

Cadmium (Cd) is a persistent environmental toxin and occupational pollutant that is considered to be a potential risk factor in the development of neurodegenerative diseases. Abnormal mitochondrial dynamics are increasingly implicated in mitochondrial damage in various neurological pathologies. The aim of this study was to investigate whether the disturbance of mitochondrial dynamics contributed to Cd-induced neurotoxicity and whether melatonin has any neuroprotective properties. After cortical neurons were exposed to 10 μM cadmium chloride (CdCl2 ) for various periods (0, 3, 6, 12, and 24 hr), the morphology of their mitochondria significantly changed from the normal tubular networks into punctuated structures within 3 hr. Following this pronounced mitochondrial fragmentation, Cd treatment led to signs of mitochondrial dysfunction, including excess reactive oxygen species (ROS) production, decreased ATP content, and mitochondrial membrane potential (▵Ψm) loss. However, 1 mM melatonin pretreatment efficiently attenuated the Cd-induced mitochondrial fragmentation, which improved the turnover of mitochondrial function. In the brain tissues of rats that were intraperitoneally given 1 mg/kg CdCl2 for 7 days, melatonin also ameliorated excessive mitochondrial fragmentation and mitochondrial damage in vivo. Melatonin's protective effects were attributed to its roles in preventing cytosolic calcium ([Ca(2+) ]i ) overload, which blocked the recruitment of Drp1 from the cytoplasm to the mitochondria. Taken together, our results are the first to demonstrate that abnormal mitochondrial dynamics is involved in cadmium-induced neurotoxicity. Melatonin has significant pharmacological potential in protecting against the neurotoxicity of Cd by blocking the disbalance of mitochondrial fusion and fission.

Protective effect of selenium and zinc against cadmium toxicity in SHSY-5Y neurons

Cadmium is a widespread heavy metal environmental toxicant and pollutant. Cadmium toxicity affects many tissues and organs including the central nervous system and cadmium exposure has been related to many neurodegenerative diseases (1). Cadmium-induced toxic effects include oxidative damage, apoptosis, interference with calcium/zinc-dependent mechanisms, inhibition of cellular respiratory processes and others, but the underlying mechanisms of cadmium neurotoxicity are not completely understood (2). On the other hand heavy metal toxicity can be counteracted by bioelements such as zinc, selenium and others mainly through the induction of metallothionein expression levels and other antioxidant pro-teins (3). Human neuroblastoma SHSY-5Y cell line, in both the undifferentiated and neuronal-like differentiated state, were used in this study to better elucidate the mechanisms un-derlying the protective effect of zinc and selenium against the cadmium neurotoxicity. Toxic effects of cadmium chloride (10 mM, 24h) observed by cell viability assay, western blot anal-ysis of Bax and Gap-43, and immunostaining of b3 tubulin and cytochrome c proteins, were reverted to control values by a 24h-pretreatment with zinc chloride (50 mM) both in undiffer-entiated and differentiated neurons. Interestingly, the reverting effect of a 24h-pretreatment with sodium selenite (100 nM) against cadmium toxicity, was observed only in undifferentiat-ed neurons. In conclusion we can hypothesize that in undifferentiated and differentiated SHSY-5Y neurons, the protective effects of zinc and selenium compounds against cadmium toxicity depend on the activation of partially common signalling pathways. Moreover sodium selenite dont exert a significant protective effect in differentiated SHSY-5Y demonstrating that the differentiated and undifferentiated phenotypes show different responses.

Effect of cadmium exposure on the histopathology of cerebral cortex in juvenile mice.

Cadmium, a heavy metal, is a toxic environmental and industrial pollutant. Exposure to cadmium can lead to the toxic effects in a variety of tissues, also including the brain. The present study investigated the effect of cadmium exposure on the histopathology of cerebral cortex in juvenile mice. Juvenile mice were randomly divided into control, low (1.87mg/kg), medium (3.74mg/kg), and high (7.48mg/kg) dose groups. After cadmium exposure by drinking water for 10days, the cerebral cortex was obtained for histopathology studies. The medium and high dose of cadmium, rather than low dose, could induce the histopathology alterations of cerebral cortex in a dose-dependent manner. In the high-dose group, microstructure significantly showed pia mater encephali divorcing from cerebral cortex layer, serious hyperemia of blood capillary in pia mater encephali and cerebral cortex, broadening vessel peripheral clearance, a large number of eosinophil leukocyte infiltrating around blood vessel, vacuolar degeneration in part granule cells, and obviously increasing apoptotic cells. Ultrastructure obviously displayed marginalized heterochromatin, incomplete or fused nuclear membranes, broadened perinuclear space, ambiguous mitochondria cristae, decreased synaptic cleft, and fused presynaptic and postsynaptic membrane. Our results revealed that cadmium at the middle and high dose could induce obvious microstructure and ultrastructure alterations of cerebral cortex in juvenile mice, which may be one important mechanism of cadmium neurotoxicity.

Protective effects of selenium on cadmium neurotoxicity

Prolonged exposure to Cadmium may cause serious toxic effects due to its accu- mulation on both central and peripheral nervous systems. Cadmium could be uptak- en from the nasal mucosa via the olfactory pathways and gain direct access into the nervous system circumventing the blood-brain barrier. However, mechanisms under- lying the cadmium uptake and neurotoxicity remain not completely understood. Oxidative damage, interference with calcium-, copper- and zinc-dependent processes, dysregulation of cell repair mechanisms, estrogen-like effects, and epigenetic modifi- cations may be considered mechanisms for cadmium-induced neurotoxicity [1]. Our previous data demonstrated that zinc chloride counteracts the toxic effects of cadmium chloride (CdCl2) on human neurons in vitro [2]. Thus, in this study we evaluate the efficacy of Sodium Selenite (Na2SeO3) in preventing and/or counteracting the damages induced by exposure to cadmium chloride on a human neuronal cell line. In this study we treated SH-SY5Y human neurons with different sub-toxic concentrations of CdCl2 for 24 h with and without a 24 h pre-treatment with Na2SeO3. Cell viability, morphological modifications, and protein expression of specific neuronal plasticity and apoptosis (Gap43 and caspase 3) markers were evaluated. Our results suggest that toxic effects of CdCl2 can be prevented and reverted by Na2SeO3 suggesting a role for selenium compounds in protecting neuronal cells and rebuilding the complex network connections.

Cadmium neurotoxicity to a freshwater planarian.

Although freshwater planarians are evolutionarily primitive, they are some of the simplest bilateral animals possessing integrated neural networks similar to those in vertebrates. We attempted to develop planarian Dugesia japonica as a model for investigating the neurotoxicity of environmental pollutants such as cadmium (Cd). This study was therefore designed to study the effects of Cd on the locomotor activity, neurobehavior, and neurological enzymes of D. japonica. After planarians were exposed to Cd at high concentrations, altered neurobehavior was observed that exhibited concentration-dependent patterns. Morphological alterations in Cd-treated planarians included irregular shape, body elongation, screw-like hyperkinesia, and bridge-like position. To study the direct effects of Cd on neurological enzymes, tissue homogenates of planarians were incubated in vitro with Cd before their activity was measured. Results showed that acetylcholinesterase (AChE), adenosine triphosphatase (ATPase), and monoamine oxidase A (MAO-A) activities were inhibited in a concentration-dependent manner. MAO-B activity was significantly induced by Cd at low concentrations and inhibited at high concentrations. Changes in the in vivo activity of AChE and ATPase were also found after planarians were treated with Cd at a sublethal concentration (5.56 μM). These observations indicate that neurotransmission systems in planarians are disturbed after Cd exposure.

Celastrol prevents cadmium‐induced neuronal cell death via targeting JNK and PTEN‐Akt/mTOR network

Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant-derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd-induced neurotoxicity. Here, we show that celastrol protected against Cd-induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd-induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase-3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd-induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over-expression of dominant negative c-Jun potentiated celastrol protection against Cd-induced cell death. Furthermore, pre-treatment with celastrol prevented Cd down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3'-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd-activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders. Celastrol, a plant-derived triterpene, has shown neuroprotective effects. However, little is known regarding the effect of celastrol on cadmium (Cd) neurotoxicity. This study underscores that celastrol prevents Cd-induced neuronal apoptosis via inhibiting activation of JNK (c-Jun N-terminal kinase) and Akt/mTOR network. Celastrol suppresses Cd-activated Akt/mTOR pathway by elevating PTEN (phosphatase and tensin homolog). The findings suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.

Developmental neurotoxicity of cadmium on enzyme activities of crucial offspring rat brain regions

Cadmium (Cd) is an environmental contaminant known to exert significant neurotoxic effects on both humans and experimental animals. The aim of this study was to shed more light on the effects of gestational (in utero) and lactational maternal exposure to Cd (50 ppm of Cd as Cd-chloride in the drinking water) on crucial brain enzyme activities in important rat offspring brain regions (frontal cortex, hippocampus, hypothalamus, pons and cerebellum). Our study provides a brain region-specific view of the changes in the activities of three crucial brain enzymes as a result of the developmental neurotoxicity of Cd. Maternal exposure to Cd during both gestation and lactation results into significant changes in the activities of acetylcholinesterase and Na(+),K(+)-ATPase in the frontal cortex and the cerebellum of the offspring rats, as well as in a significant increase in the hippocampal Mg(2+)-ATPase activity. These brain-region-specific findings underline the need for further research in the field of Cd-induced developmental neurotoxicity. Deeper understanding of the mechanisms underlying the neurodevelopmental deficits taking place due to in utero and early age exposure to Cd could shed more light on the causes of its well-established cognitive implications.

Neurotoxicity of cadmium on immature hippocampus and a neuroprotective role for p38 MAPK

The developing brain is very sensitive to damage by toxic agents, many of which only manifest in adulthood. Cadmium [Cd(II)] is an environmental pollutant which is widely used in industry and is a constituent of tobacco smoke. Exposure to Cd(II) has been linked to detrimental effects on mammalian cells including neural cells. We have investigated the action of Cd(II) on immature hippocampus by assessing cell viability and modulation of AKT/PKB and mitogen-activated protein kinase (MAPK) family members including extracellular signal-regulated kinase (ERK)-1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). Hippocampal slices from immature rats (postnatal day 14; PN14) were incubated with Cd(II) (5–200 μM) for 3 h and the effects on protein phosphorylation were analyzed by western blotting. Phosphorylation of p38 MAPK was enhanced by Cd(II) at all doses tested. Cd(II) also stimulated the phosphorylation of ERK1/2 in a concentration-dependent manner. However, the phosphorylation of JNK and AKT was not altered by the metal. Moreover, Cd(II) reduced cell viability, as measured by MTT reduction. Inhibition of p38 MAPK by SB203580 aggravated the acute Cd(II)-induced impairment of cell viability, whereas inhibition of MEK by PD98059 did not alter the effects of Cd(II). The present data suggest that in immature hippocampal cells p38 MAPK may be a part of signaling pathway that counteracts acute Cd(II) neurotoxicity. In conclusion, our results showed that Cd(II) impairs cell viability and disturbs MAPKs pathways in an important developmental stage for synaptic organization.

Effects of cadmium on memory processes in mice exposed to transient cerebral oligemia

The purpose of the present study was to examine whether the effects of chronic or acute exposure to cadmium on memory processes in mice could be exacerbated by transiently reducing cerebral oxygen supply. Adult mice were subjected to bilateral clamping of the carotid artery (BCCA) for 30 min under anesthesia. Cadmium chloride was administered intraperitoneally after surgery at single doses of: 0.7 mg/kg (low dose), 1.4 mg/kg (high dose), or at a prolonged dose of 0.7 mg/kg for up to 10 days. Long-term memory was evaluated in a step-through passive avoidance task while spatial working memory was evaluated using a Y-maze spontaneous alternation task. BCCA mice injected with the 1.4 mg/kg dose of cadmium exhibited recall deficits in the step-through passive avoidance task. Combined treatment at either dose had no effect on the acquisition of passive avoidance. In the Y-maze task, spontaneous alternation behavior was only impaired in BCCA mice treated with the prolonged cadmium dose. These results indicate that cerebral oligemic hypoxia may alter cadmium neurotoxicity and potentiate the tendency for cadmium-induced memory impairments in the passive avoidance task and spontaneous alternation deficits.

RESISTANCE OF DELAYED-RECTIFIER K+ CURRENT TO CADMIUM IN DROSOPHILA NEURONS

The delayed-rectifier potassium current (IKDR) is important in repolarizing the membrane potential and determining the level of neuronal excitability. We investigated the effect of cadmium on this potassium current. The whole-cell patch-clamp technique was used to measure IKDR from cultured Drosophila neurons derived from embryonic neuroblasts. The current was measured from neurons before and after the application of 0.1 mM cadmium to the external saline. IKDR was similar in the cadmium-containing saline (383 ± 47 pA) and the control saline (401 ± 60 pA). These results indicate that cadmium neurotoxicity does not specifically affect IKDR in Drosophila neurons

Cholinergic and Behavioral Neurotoxicity of Carbaryl and Cadmium to Larval Rainbow Trout (Oncorhynchus mykiss)

Pesticides and heavy metals are common environmental contaminants that can cause neurotoxicity to aquatic organisms, impairing reproduction and survival. Neurotoxic effects of cadmium and carbaryl exposures were estimated in larval rainbow trout (RBT; Oncorhynchus mykiss) using changes in physiological endpoints and correlations with behavioral responses. Following exposures, RBT were videotaped to assess swimming speed. Brain tissue was used to measure cholinesterase (ChE) activity, muscarinic cholinergic receptor (MChR) number, and MChR affinity. ChE activity decreased with increasing concentrations of carbaryl but not of cadmium. MChR were not affected by exposure to either carbaryl or cadmium. Swimming speed correlated with ChE activity in carbaryl-exposed RBT, but no correlation occurred in cadmium-exposed fish. Thus, carbaryl exposure resulted in neurotoxicity reflected by changes in physiological and behavioral parameters measured, while cadmium exposure did not. Correlations between behavior and physiology provide a useful assessment of neurotoxicity.

Effects of Cadmium Chloride on Neurite Outgrowth and Gene Expression in Human Neuroblastoma NB-1 Cells.

Cadmium is a well-studied environmental toxicant. The neurotoxicity of cadmium is a concern, especially in the developing human brain, because it is thought that cadmium exerts long-term and irreversible effects. In the present study cadmium toxicity using human neuroblastoma NB-1 cells was investigated in relation to gene expression and subsequent neurite extension using cDNA macroarray and image analysis techniques. The neurite outgrowth in NB-1 cells was stimulated significantly by the presence of dibutyryl-cyclicAMP (db-cAMP) and by cadmium chloride at sublethal concentrations. Db-cAMP-stimulated neurite outgrowth was associated with a three-fold increased expression of axonal membrane protein growth-associated protein-43 (GAP-43), but cadmium chloride did not affect GAP-43 expression. Db-cAMP also increased dopamine β-hydroxylase gene expression eight-fold and down-regulated muscle/brain cAMP-dependent protein kinase inhibitor gene expression. However, cadmium chloride had no effect on gene expression except for that of metallothionein II (mtII) gene among 1764 genes analyzed. The results demonstrate that the increased neurite outgrowth with cadmium chloride is not associated with the same gene expression profile of that with db-cAMP.

Oxidative stress-mediated neurotoxicity of cadmium

Young albino rats were administered cadmium i.p. (0.4 mg/kg body weight) for a period of 30 days and membrane fluidity, intracellular calcium level, MDA level, phospholipids, (phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylserine and sphingomyelin) and reduced glutathione were studied in olfactory bulb, cerebellum and rest of brain. A decrease in membrane fluidity was observed in all the brain regions studied, maximum being in olfactory bulb (21%). Intracellular calcium (Ca ++) 1 level was increased significantly in olfactory bulb (150%) followed by rest of brain (98%) and cerebellum (71%) in Cd-exposed rats in comparison with controls. A significant decrease in phosphatidylcholine (27%) and phosphatidylethanolamine (22%) was observed in olfactory bulb, while other phospholipids remained unaffected. TBA reactivity was increased in olfactory bulb (77%), cerebellum (35%) and rest of brain (27%). Reduced glutathione level was also decreased in different brain regions. The results suggest that the effect of cadmium in brain is region-specific and most pronounced in olfactory bulb.

Effect of central acute administration of cadmium on drinking behavior

The effect of acute third ventricle cadmium administration on the drinking behavior of adult male rats under different situations was studied. Injections of cadmium chloride (0.07, 0.7, and 7.0 ng/rat) significantly attenuated water intake in dehydrated rats. Drinking behavior induced by acute intracerebroventricular injections of carbachol (2 μg/rat) or angiotensin II (5 ng/rat) was also inhibited by central cadmium injections. Cadmium-induced blockade in water intake in dehydrated animals was reverted by the previous administration of a S-HT 2 antagonist (RP62203) in different doses (5 and 10 μg/rat). The data clearly reveal that cadmium elicits very fast actions on the central nervous system. It is suggested that cadmium-induced attenuation of water intake may rely on at least three different mechanisms: impairment of cholinergic and angiotensinergic systems in the brain and stimulation of a central serotonergic drive acting on 5-HT 2 receptors. The study of cadmium neurotoxicity by observation of drinking behavior, a behavioral parameter easy to be recorded and measured, is proposed.

Influence of ethanol on cadmium accumulation and its impact on lipid peroxidation and membrane bound functional enzymes (Na+, K(+)-ATPase and acetylcholinesterase) in various regions of adult rat brain.

Influence of ethanol on cadmium accumulation and its effect on metallothionein induction, binding of cadmium to metallothionein, lipid peroxidation and membrane bound functional enzymes such as (Na(+)-K+)-ATPase and acetylcholinesterase in various regions of adult rat brain was investigated. Ethanol (2 g/kg body wt) and cadmium (1 mg/kg body wt) were administered alone as well as in combination to different groups of rats, i.p., for a period of 1 week. It was observed that cadmium when co-administered with ethanol led to pronounced increase in cadmium accumulation in various regions of the brain. This ethanol induced accumulation of cadmium did not induce the synthesis of metallothionein and also did not bind to this protein in brain and mainly was present as non-metallothionein bound cadmium. It lead to a significant increase in lipid peroxidation and inhibition of membrane bound functional enzymes; (Na(+)-K+)-ATPase and acetylcholinesterase in various regions of the brain indicating functional impairment. The results of the present study imply that ethanol renders the adult brain more susceptible to cadmium neurotoxicity. Corpus striatum and cerebral cortex are more vulnerable regions than other areas of the brain.

Differential effects of metal ions on type A and type B monoamine oxidase activities in rat brain and liver mitochondria.

To investigate the hypothesis that neurotoxic metals can exert their toxicity through the direct inhibition of monoamine oxidases (MAOs), the effects of several neurotoxic metal ions on type A (MAO-A) and type B (MAO-B) monoamine oxidase activities in rat forebrain nonsynaptic mitochondria and rat liver mitochondria were studied. At pathophysiological levels (10-100 microM), Cu2+ and Cd2+ are good inhibitors of brain mitochondrial MAO-A and, to a lesser extent, liver mitochondrial MAO-A. The inhibition of MAO-B activities in brain and liver mitochondria by Cu2+ and Cd2+ is only detected at the higher end of the concentration range (i.e., 50-100 microM). At the pathophysiological level of 0.5 mM, Al3+ only inhibits brain mitochondrial MAO-A but at the higher level of 2.5 mM, it inhibits both forms of MAO in brain as well as liver mitochondria. Even at toxic levels (e.g., 5 mM), neither Mn2+ nor Li+ inhibits the activities of MAO-A and MAO-B in brain and liver mitochondria. Our results are consistent with the hypothesis that some neurotoxic metals can exert their toxicity through the direct inhibition of the isoforms of MAO. Our data also suggest that the selective inhibition of brain MAO-A by Cu2+ and Cd2+ may assume pathophysiological importance in the neurotoxicity of copper and cadmium.

Peripheral Neurotoxicity of cadmium in growing rats: Preventive role of vitamin E

The effect of daily intraperitoneal administration of cadmium (0.4 mg/kg) to growing rats for 30 days on the peripheral neurotoxicity was investigated by using gastrocnemius sciatic nerve preparation and certain biochemical parameters. Further, the effect of vitamin E (5 mg/kg) administration on alternate days on the cadmium induced changes in the peripheral nervous system was also studied. Cadmium was found to markedly decrease the skeletal muscle contraction compared to controls while simultaneous administration of vitamin E completely antagonized cadmium induced inhibitory effect on muscular contraction. The activity of acetylcholine esterase, Na+, K+‐ATPase and 5'‐nucleotidase in sciatic nerve of cadmium treated rats was significantly increased while vitamin E had no effect on cadmium induced changes in the activity of these enzymes. Concurrent administration of vitamin E also did not influence the elevated levels of cadmium in the sciatic nerve due to metal exposure. It is suggested that the antagoni...

Glutathione status and cadmium neurotoxicity: Studies in discrete brain regions of growing rats

Intraperitoneal administration of cadmium (Cd 2+, 0.4 mg/kg) daily for 30 days to rats was found to decrease the contents of reduced glutathione (GSH) and increase oxidized glutathione (GSSG) in various brain regions. These changes resulted in a significant decline in the GSH/GSSG ratio in different brain regions, except for the hippocampus and midbrain. In addition, the activities of glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (GPDH) were also significantly inhibited in different brain regions. Measurement of regional Cd levels revealed that Cd administration significantly increased the levels in all brain regions except for the hippocampus, which could be the reason for not finding any change in any of the biochemical parameters studied in this region. The observed changes in the regional GSH/GSSG ratios could be the result of inhibition in GR activity, as this enzyme catalyzes an irreversible conversion of GSH to GSSG and is responsible for higher cellular GSH levels. GR uses NADPH in its reaction; therefore, the inhibition of GPDH may further aggravate the situation because of the short supply of NADPH. The alterations in the regional “glutathione status” may affect various related metabolic processes, including those required for detoxification of lipid peroxides which have recently been suggested to play a role in the mechanism of Cd neurotoxicity.

Glutathione Status and Cadmium Neurotoxicity: Studies in Discrete Brain Regions of Growing Rats

Glutathione Status and Cadmium Neurotoxicity: Studies in Discrete Brain Regions of Growing Rats