AM1241 alleviates MPTP-induced Parkinson's disease and promotes the regeneration of DA neurons in PD mice

Abstract

The main pathological feature of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD. Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus. The mRNA expression analysis further demonstrated that AM1241 increased expression of the CB2R and activated Parkin/PINK1 signaling pathways. Furthermore, the increased number of TH-positive cells in the substantia nigra indicated that AM1241 regenerated DA neurons in PD mice, and could therefore be a potential candidate for PD treatment. The clear co-localization of CB2R and DA neurons suggested that AM1241 targeted CB2R, thus also identifying a novel target for PD treatment. In conclusion, the selective CB2 agonist AM1241 has a significant therapeutic effect on PD mice and resulted in regeneration of DA neurons following MPTP-induced neurotoxicity. The possible mechanisms underlying the neurogenesis effect of AM1241 might be the induction of CB2R expression and an increase in phosphorylation of the PI3K/AKT signaling pathway.

Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration?

“…Moreover, the expression of CB2, Parkin/PTEN-induced kinase 1 (PINK1) and PI3K/AKT in substantia nigra and hippocampus was restored. Probably, as for the previous evidence, P13K/AKT pathway is responsible for the regrowth of dopaminergic neurons, while Parkin/PINK1 plays a role in neuroprotection [ 111 ]. We had also shown that CBD, along with cannabigerol (CBG) both at doses of 1 or 5 μM, is able to upregulate the expression of dopaminergic receptors 2 and 4 in NSC-34 cells, inhibiting at the same time the expression of monoamine transporter 2, decreasing in such way dopamine uptake [ 112 ], and this may also have a role in synaptic plasticity.…”

Activation of CB2R with AM1241 ameliorates neurodegeneration via the Xist/miR‐133b‐3p/Pitx3 axis

“…An important advantage of AM1241 is that it does not induce any psychotropic effects associated with activation of CB1R, suggesting AM1241 is safe (Atwood & Mackie, 2010; Garcia‐Gutierrez, Garcia‐Bueno, Zoppi, Leza, & Manzanares, 2012). Our previous study showed that AM1241 exerted promising therapeutic effects on PD animals and may protect dopaminergic neurons (DA) after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) treatment (Shi et al, 2017). However, the underlying mechanisms have yet to be characterized.…”

Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice

“…In addition, the result demonstrated that administration of JWH133 alone or in combination with khat extract showed an anti-parkinsonian and likely a neuroprotective effect as evidenced by increased locomotor activity in MPTP lesioned mice after co-administration of khat extract and JWH133. Previous findings have shown that activation of the CB2Rs rescued nigrostriatal DA neurons from MPTP neurotoxicity [58,59,60,61], but the effect of co-administration of khat extract and JWH133 on locomotor activity in MPTP lesioned mice had not been investigated. The result suggests that khat extract alone or in combination with the CB2R agonist might have a neuroprotective effect and could probably have a significant role in reversing the motor deficits observed in PD patients.…”