Neuroprotective effect of rapamycin against Parkinson's disease in mice

Abstract

To investigate the effect of rapamycin on Parkinson's disease (PD) and its underlying mechanism in mice. Sixty SPF adult male C57BL/6 mice were randomly divided into control group, model group and treatment group. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(MPTP) was used to induce Parkinson's disease in model group and treatment group. All mice were trained to cross the runway and were subjected to computer-assisted CatWalk. The numbers of tyrosine hydroxylase positive (TH+) neurons in the substantia nigra (SN) were assessed by unbiased stereology using the optical fractionator method; protein expression was detected by Western blot analysis; and glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by spectrophotometry. In the model group, a decrease in stride rate and an increase in variation of stance and swing were noted by CatWalk system (P<0.05 or P<0.01); the numbers of TH+ neurons decreased (P<0.01); expression of p-Akt, p-S6K, p-S6 and p-ULK increased (all P<0.01); LC3-Ⅱ/Ⅰ ratio decreased (P<0.01); MDA level was elevated while the levels of SOD and GSH-PX were reduced (all P<0.01). Compared with the model group, after treated with rapamycin, the abnormal behavior including the stride length, variation of stance and swing and step patterns induced by MPTP were all improved (P<0.05 or P<0.01); the numbers of TH+ neurons increased (P<0.05); the expression of p-Akt, p-S6K, p-S6 and p-ULK was suppressed (all P<0.01); the LC3-Ⅱ/Ⅰ ratio was upregulated (P<0.05); MDA level decreased while the levels of GSH-Px and SOD increased (all P<0.01). Rapamycin inhibits the activation of mTOR pathway, which contributes to protect against the loss of dopaminergic neurons and provide behavioral improvements in mice with Parkinson's disease. These results are partially related to the ability of rapamycin in inducing autophagy and reducing oxidative stress.