The Protective Effects Of ?-lipoid-acid On Toxic Damage Of Cadmium And Lead Exposure In Cerebral Cortex Of Rats

Lead(Pb)and cadmium(Cd),as the common heavy metal pollutant in the environment,often damage the organisms in the form of complex.The brain is an important target organ for toxic damage of Pb and Cd.The experiments in vitro had shown that oxidative damage and the Fas/FasL pathway,mitochondrial pathway and endoplasmic reticulum stress-medicated apoptosis are important mechanisms of the damage induced by Pb and Cd in neuronal cells.At present,systemic studies of toxic damage on combination of Pb and Cd are seldom seen,and the conclusions are different.The previous experiments showed that alpha lipoic acid(a-LA)can improve the antioxidant ability,inhibit the activation of mitochondrial signaling pathway and endoplasmic reticulum stress,decrease apoptosis of PC 12 cells and cerebral cortical neurons in rats induced by Cd.However,the systemic studies of toxic damage on combination of Pb and Cd in developing rats and the protective effect of a-LA have not been elucidated.In current study,the model of SD rats exposed to Pb and/or Cd in drinking water and ?-LA by gavage concurrently were used to explore the protective effects of a-LA on damage of Pb and Cd exposure in cerebral cortex of rats,which will offer some theoretic evidences for further exploring the mechanism of neurotoxicity,prevention and control of Pb and Cd.Forty-eight 21-day-old SD rats were randomly divided into 8 groups:control group,a-LA group,Cd-treated group,Cd and a-LA co-treated group,Pb-treated group,Pb and a-LA co-treated group,Pb and Cd co-treated group,and finally Pb and Cd and a-LA co-treated group.The rats were exposed to Cd(50 mg/L)and/or Pb(300 mg/L)in drinking water.a-LA(50 mg/kg)was given to rats by gavage concurrently in the co-treated group over 12 weeks.After concluding the treatments,the following experiments were conducted:?The weight of rats was measured over 12 weeks.After sacrificing,isolating,and weighing whole brain tissue,the brain index was calculated.The cerebral cortex was stripped and the contents of Cd and Pb in cerebral cortex were measured by Atomic Absorption Spectrophotometry.?The enzymatic activities of GSH-Px,SOD and CAT and the contents of GSH and MDA in cerebral cortex were determined by colorimetry,and the levels of trace elements(Mn,Fe,Cu,Zn,Se)were measured by Atomic Absorption Spectrophotometry.? The changes of histopathology and ultrastructure in cerebral cortex were observed using light microscopy and Transmission Electron Microscopy.?The expressions of Fas/FasL apoptosis pathway,mitochondrial apoptosis pathway and endoplasmic reticulum stress-related proteins were measured by Western blot.The results are as follows:?Compared to controls,the body weights of the Cd and/or Pb-treated groups was decreased but the difference was not significant(p>0.05).The brain index was decreased significantly(p<0.05)and the cortical Cd content in the Cd-treated group and the Pb and Cd co-treated group increased significantly(p<0.01).Cortical Pb content in the Pb-treated group and the Pb and Cd co-treated group also increased significantly(p<0.01).Compared to the corresponding poisoning group,animals treated with ?-LA had increased body weights and brain indices(p<0.05 or p>0.05),and the cortical Pb or Cd contents were significantly reduced(p<0.05 or p<0.01).?Compared to the control group,the GSH and MDA levels and the GSH-Px,SOD and CAT activities in the cerebral cortex were increased(p<0.05 or p>0.05),and the Mn,Fe,Cu,Zn and Se contents in the cerebral cortex decreased(p<0.05 or p>0.05)after Cd and/or Pb exposure.The Cu content showed no significant changes in the Pb treatment group(p>0.05).Compared to the corresponding poisoning groups,GSH and MDA levels and GSH-Px,SOD and CAT activities had no significant difference(p>0.05),the Mn,Fe,Cu,Zn and Se contents in the a-LA protection groups increased(p>0.05,p<0.05 or p<0.01).?Compared to the control group,there were no obvious histopathological changes in the cerebral cortex of Cd and/or Pb groups under light microscope,but there were obvious ultrastructural changes detectable via Transmission Electron Miscroscopy including pyknosis of cell nucleus,unevenness of chromatin,and disruption and partial disappearance of mitochondrial cristae.Furthermore,nuclear and mitochondrial damage in the Cd and Pb co-treated group was more severe.Compared to the corresponding poisoning group,the nuclear and mitochondrial damage in the cerebral cortex was alleviated in the a-LA treatment groups.?Compared to the control group,protein expression of the Fas/FasL apoptosis pathway-related proteins Fas,FasL,FADD,and cleaved caspsase-8 were significantly increased(p<0.05 or p<0.01).The protein expressions of the mitochondrial apoptosis pathway-related proteins cleaved caspase-9 and-3 were increased and the ratio of Bcl-2/Bax was decreased significantly(p<0.05 or p<0.01).The protein expressions of the endoplasmic reticulum stress-related proteins BIP,PERK,p-eIF2?,ATF4,CHOP,ATF6,and cleaved caspase-12 were increased significantly(p<0.05 or p<0.01).Furthermore,FasL,PERK and ATF4 protein expression in the Cd and Pb co-treated group was significantly higher than that in either the Cd or Pb group(p<0.05 or p<0.01).Compared to the corresponding poisoning group,protein expression changes in the Fas/FasL apoptosis pathway,mitochondrial apoptosis pathway,and the endoplasmic reticulum stress of the a-LA treatment groups were alleviated(p>0.05,p<0.05 or p<0.01).Conclusions:? Rat body weight and brain growth are affected by Cd and/or Pb exposure.Cd and Pb can accumulate in cerebral cortex.?-LA can increase the body and brain weight of rats and reduce the accumulation of Cd and/or Pb caused by Cd and/or Pb exposure.? Cd and/or Pb may cause oxidative damage in the cerebral cortex of rats,and a-LA can increase the antioxidant capacity of the cerebral cortex.? Cd and/or Pb can cause ultrastructural damage in the cerebral cortex.a-LA can relieve the ultrastructural damages caused by Cd and/or Pb.?Cd and/or Pb can activate the Fas/FasL pathway,mitochondrial apoptosis pathway,and stimulate endoplasmic reticulum stress.a-LA can protect the cerebral cortex of rats by inhibiting the activation of the Fas/FasL pathway,mitochondrial apoptosis pathway,and the endoplasmic reticulum stress caused by Cd and/or Pb.