| Objective: Glutamate is one of the most important excitatory neurotransmitters in the central nervous system and is involved in the regulation of many nervous functions, such as nourishing the nervous system, promoting the growth and development of neurons and the axons. On the other hand, it is also one kind of neurotoxins under certain conditions. Firstly, over amount of glutamate can cause excitatory neurotoxicity by activating glutamate receptor. Secondly, glutamate can induce neurons injury by inhibition of glutamate/cystine transporters. Glutamate toxicity plays an important role in the development of some neurodegenerative diseases, such as stroke, Parkinson's disease (PD), Alzheimer's disease (AD), and so on.Statins, 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are the most widely prescribed class of cholesterol-lowering drugs for the prevention of cardiovascular disease. In addition to their vascular effects, increasing evidence suggests that statins may have potential therapeutic implications in neurological diseases, such as stroke, Alzheimer disease, Parkinson disease. However, the mechanisms by which statins on the protective effects against neurological injuries, in particular, glutamate induced injury are still unclear.The present study was designed to detect the effects of simvastatin against glutamate-induced hippocampus injury. The hippocampus damage of rat was induced by injection with glutamate through the lateral ventricle. By detection of the MDA content, the activity of SOD and GSH-Px, the hydroxyl radical generation capacity in the homogenate of hippocampus, AMPA receptor subunit 2(GluR2) mRNA and protein expression levels, our results indicated that simvastatin has beneficial effects to prevent nerve injury and central nervous system retrogression sickness caused by massive releases of glutamate, which are associated with the regulation of AMPA expression and decrease in oxidative stress.Method: 88 Wistar rats were randomly divided into 4 groups: sham-operation group, glutamate-induced injury group, simvastatin 10 mg·kg-1 and 20 mg·kg-1 dose group. Normal saline or simvastatin solution were administered by intra-gastric administration for 10 days; Under the anesthesia state, rats in the sham-operation group were given 4μl normal saline and those from other three groups were given 4μl glutamate solution (1 mg·kg-1) through the lateral ventricle. In 2 h after injection of glutamate solution, the hippocampuses were separated and the homogenates of hippocampus were prepared. Then the content of MDA, the activity of SOD and GSH-Px and the hydroxyl radical generation capacity were measured; the pathologic changes in hippocampus of rats were observed by HE staining. The mRNA expression and protein levels of GluR2 were detected by RT-PCR and immunohistochemical assays.Results: Rats treated with simvastatin (20 mg·kg-1) had a significant decrease in MDA content and hydroxyl radical generation capacity (P<0.05, P<0.01 respectively). And the activity of SOD and GSH-Px were markedly increased (P<0.05) by simvastatin treatment. Morphological examinations by HE staining showed that the neuron death and denaturation in hippocampus were significantly decreased in rats of simvastatin group. Furthermore, it was found that both mRNA expression and protein levels of GluR2 were decreased in the hippocampus of glutamate-induced injury group (P<0.01). However, simvastatin (both 10 mg·kg-1 and 20 mg·kg-1) significantly increased the expression of GluR2 in hippocampus compared with those in glutamate-induced injury group (P<0.05, P<0.01 respectively).Conclusion: Our results showed that simvastatin can reduce glutamate-induced hippocampus injury by injection of glutamate injected through the lateral ventricle . These beneficial effects are associated with decreasing the content of MDA and the hydroxyl radical generation capability, and increasing the activity of anti-oxidant enzyme (SOD and GSH-Px ) in hippocampus. Glutamate can also decrease the expression of GluR2 hippocampus injury, which can be recovered by simvastatin treatment. In summary, our results indicated that simvastatin has beneficial effects to prevent nerve injury, which are associated with the regulation of AMPA expression and decrease in oxidative stress.
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