X-linked methyl-CpG binding protein 2 mutations can induce symptoms similar to those of Parkin-son’s disease and dopamine metabolism disorders, but the specific role of X-linked methyl-CpG binding protein 2 in the pathogenesis of Parkinson’s disease remains unknown. In the present study, we used 6-hydroxydopamine-induced human neuroblastoma cel (SH-SY5Y cel s) injury as a cel model of Parkinson’s disease. The 6-hydroxydopamine (50 μmol/L) treatment decreased protein levels for both X-linked methyl-CpG binding protein 2 and tyrosine hydroxylase in these cel s, and led to cel death. However, overexpression of X-linked methyl-CpG binding protein 2 was able to ameliorate the effects of 6-hydroxydopamine, it reduced 6-hydroxydopamine-induced apoptosis, and increased the levels of tyrosine hydroxylase in SH-SY5Y cel s. These findings suggesting that X-linked methyl-CpG binding protein 2 may be a potential therapeutic target for the treatment of Parkinson’s disease.

Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson’s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before expo-sure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death pro-cess of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range (5–30 μM) elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Par-kinson’s disease.

Effect of Resveratrol on Motor Dysfunction in Unilateral 6-hydroxydopamine Parkinson's Model Rats and its Underlying Mechanisms

Objective:The present study was designed to investigate the effect of resveratrol (Res)on the motor function of Parkinson's model rats induced by 6-hydroxydopamine(6-OHDA)and to explore its underlying mechanism. Methods:After a week of adaptive feeding,50 male Sprague-Dawley(SD)rats were randomly divided into five groups:sham-operated group,normal group(Res, 30 mg·kg-1),model group(6-OHDA,8μg),6-OHDA+Res low-dose group(15 mg·kg-1,6-OHDA+Res high-dose group(30 mg·kg-1). 6-OHDA 8 μg(2 μg·μL-1)were injected into the substantia nigra of the rats to establish the model of dopaminergic neuronal damage,while the rats of sham group were injected with volume-matched saline with 0.2％ Vitamin C.Rats were pretreated with Res for 1 day before 6-OHDA treatment. Model and sham groups were administered with volume-matched vehicle for 36 days.Rotarod test was applied to evaluate motor function of rats on 7 th,14 th and 21 th day after surgery,open field experiment and grid-walking test applied on 33 th and 35 th day,respectively. Then the rats were sacrificed.Immunohistochemistry was used to detect the number of TH-positive cells in substantia nigra pars compacta(SNc);the protein expression of TH,Bax,Bcl-2,pro-caspase-3, active-caspase-3,p-PDK1 and p-Akt in midbrain were detected by Western blot. Results:The body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of model group were significantly decreased compared with sham group;the protein of Akt phosphorylation levels were decreased while it showed no effect on PDK1,and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly increased,pro-caspase-3 decreased. However,compared with model,the body weight,motor function,number of dopaminergic neurons in SNc and the protein expression of TH in midbrain of Res high-dose group were markedly increased;the protein of Akt phosphorylation levels were increased while it showed no effect on PDK1, the protein level of BDNF and TrkB were significantly decreased and the expression of apoptosis-related proteins Bax/Bcl-2,active-caspase-3 were significantly decreased,and pro-caspase-3 were increased.Conclusion:Under the experimental conditions,6-OHDA-induced motor dysfunction and apoptosis in dopaminergic neuronal cells of rats is significantly attenuated by Res,and its potential mechanism may be related to up-regulation of Akt phosphorylation at Ser473 and inhibit the expression of apoptosis-related proteins.