Effects of hCG on DA neuronal death of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, with the incidence in men being about twice as compared to women. Gender differences may provide clues for finding key targets that mediate the death of dopaminergic (DA) neurons in PD. Luteinizing hormone (LH), analog of human chorionic gonadotropin (hCG), and their receptor, luteinizing hormone/choriogonadotropin receptor (LHCGR), are associated with the pathogenesis of PD. Movement-related symptoms are partially improved by hCG in PD patients. However, the relationship between hCG and PD, as well as its roles in mediating DA neuronal death, has not been elucidated. In this study, we investigated the potential of hCG as a treatment during PD progression. After establishment of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models, we found that hCG restored the decrease of LHCGR activity caused by down-regulation of LH in the substantia nigra. Furthermore, the reduction of LHCGR activity led to DA neuronal death through knocking down the LHCGR in DA neurons by AAV-mTH-shRNA. Treatment with hCG alleviated the DA neuronal death induced by MPTP. Finally, hCG exerted neuroprotective effects by inhibiting the activation of glycogen synthase kinase 3 beta (GSK3β) in our MPTP-induced PD mouse and MPP⁺-treated SH-SY5Y cell models. Together, these results demonstrate that hCG exerts neuroprotective effects for PD through LHCGR, and the inhibition of GSK3β activation is involved in this protective effect, suggesting that hCG can be taken as a potential therapeutic for the treatment of PD.