Edaravone Antagonizes Cadmium Chloride-induced Subacute Neurotoxicity And Its Mechanism

In recent years,cadmium pollution has caused a serious impact on human health,which has contributed to widespread concern in society.Cadmium can cross the blood-brain barrier and cause damage to the brain,and it’s known as one of the most neurotoxic heavy metals.Cadmium induces severe diseases of the nervous system,such as neurode’generative diseases and mental diseases,by inducing oxidative stress,down-regulation of brain-derived neurotrophic factors,and neuroinflammation.Therefore,the research and development of medicine for the treatment and prevention of cadmium neurotoxicity have important theoretical and practical significance.Edaravone(EDA)is an oxygen-free radical scavenger,which has good antioxidant and anti-inflammatory effects and has a conspicuous repair effect on the nerve damage.In this study,by establishing cadmium chloride(CdCl2)cell injury and cadmium chloride mouse injury models,in vitro and in vivo levels systematically and deeply explored the recovery effect of EDA on cadmium-induced nerve injury and its molecular mechanism.This article draws the following conclusions by analyzing the experimental data:(1)This article explored the protective effect of different concentrations of EDA on cadmium-infected cells.And the results demonstrated that EDA can significantly increase the survival rate of cadmium-infected cells(P<0.001),restore damaged cell morphology,and reduce cytotoxicity.It was found that 200 μM EDA has the most protective effect.Meanwhile,we found that BDNF/P-TrkB and PI3K/Akt signal pathways are involved in protecting nerve cells by EDA.In cadmium-infected cells,the expression of brain-derived neurotrophic factor(BDNF),phosphorylated tyrosine kinase B(P-TrkB),and phosphorylated protein kinase B(P-Akt)decreased,and protein expression levels after EDA treatment significantly increased.Interestingly,after adding the BDNF signal pathway blocker and PI3K/Akt signal pathway blocker,the protective effect of EDA decreased significantly(P<0.001).(2)This article explored the effect of EDA on the learning and memory ability and mental state of mice with cadmium poisoning.And the results showed cadmium-exposed mice had more worse mental status,less weight,higher urine protein,and poorer learning and memory;after EDA treatment,cadmium-intoxicated mice improved their mental status,increased their body weight,decreased urine protein,and ameliorated learned and memory.It illustrated that 40 mg/kg EDA has the best protective effect.(3)This article explored the protective mechanism of EDA on cadmium-injured mice.In oxidative stress-related experiments,we found that the superoxide dismutase(SOD)and catalase(CAT)activities decreased,and malondialdehyde(MDA)content increased in the brain tissue and serum of mice exposed to cadmium;EDA intervention can increase the activity of SOD and CAT,and decrease the content of MDA,which proves that EDA could antagonize the neurotoxicity of cadmium by inhibiting oxidative stress.EDA inhibits neuroinflammation by down-regulating the expression of Notch/NF-kB signaling pathway-related proteins in the brains of cadmium-injured mice.ELISA results showed that EDA down-regulated the expression of pro-inflammatory factors tumor necrosis factor(TNF-α),interleukin 1β(IL-1β),and interleukin 6(IL-6)in the brain tissue of mice injured by cadmium,and up-regulated the anti-inflammatory factor interleukin 10(IL-10)expression;morphological observations further confirmed that EDA can alleviate the inflammatory response in the cerebral cortex and hippocampus of mice and reduce neuronal apoptosis.The study found that the BDNF/P-TrkB and PI3K/Akt signaling pathways are also involved in the protective process of EDA on cadmium-injured mouse brains.The results of this study provide a new basis for EDA to antagonize cadmium-induced neurotoxicity and molecular mechanisms,and provide a new target for solving environmental health problems caused by cadmium pollution.