Objective: A promising and potential direction to treat PD is to develop new non-dopaminergic drugs without producing dyskinesia, as well as arresting and even reversing the degeneration of dopaminergic neurons. In this study, we investigated the role and mechanism of CB2R agonist AM1241 on MPTP-induced neurotoxicity and regeneration of DA neurons.

Background: PD is a kind of neurodegenerative movement disorder, which is characterized primarily by a massive loss and degeneration of DA neurons in the substantianigra compact and a significant reduction of striatal dopamine.Current pharmacotherapies relieve PD symptoms but fail to prevent or slow down the disease progression.

Methods: The research was studied on MPTP-induced PD mice. Behavioral tests were assessed the treatment function of AM1241, and using HPLC to detect the striatal DA and 5-HT levels. To explore the mechanism, the expressions of CB1, CB2, Parkin, PINK1, pPI3K and pAkt were determined by both western blot and immunofluorescence. And RT-PCR detected the mRNA levels of CB1, CB2, Parkin and PINK1. The neurogenesis of AM1241 on DA neurons through immunofluorescence with DA neurons,astrocytes and microglia markers.

Results: Upon treatment with AM1241, the behavior score markedly elevated and accompanied with the increase of DA and 5-HT. After administration MPTP, the experssion of CB2R in substantianigra was significantly down-regulated, meanwhile, treatment with AM1241 reversed the down-regulation. Besides, the western blot and immuno staining results both suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increase the expressions of Parkin and PINK1 both in substantianigra and hippo. The results of mRNA expressions further demonstrated that AM1241 activated CB2 receptor and Parkin/PINK1 signaling pathways. Furthermore, the increase of TH-positive cells and the co-localization of CB2R and DA neurons suggested that treatment of AM1241 induced the regeneration of DA neurons combined with the activation of CB2 receptor, which confirmed that AM1241 could be a non-dopaminergic potential candidate for PD treatment.

Conclusions: The selective CB2 agonists AM1241 has significant therapeutic effect on PD and can regenerate DA neurons which could alleviate the neurotoxicity of MPTP, and the one possible mechanism underlying the neurogenesis effect of AM1241 on DA neurons might be via modulating PI3K/AKT signaling pathways.

References:   

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cb2r-agonist-am1241-reverses-the-development-of-mptp-induced-pd-and-activates-the-regeneration-of-da-neurons/