Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

Abstract

There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson’s disease (PD). From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of PD patients and in mice models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration, however CB2 has not been pharmacologically and selectively targeted in an alpha-synuclein focused model of PD. We find that 7 weeks of peripheral SMM-189 treatment reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 altered brain immune cell phenotypes with increased CD68 and decreased CD163 protein expression, elevated wound healing immune mediator gene expression and modified leukocyte infiltration kinetics as determined by flow cytometry. Additionally, peripheral immune cells increased wound healing non-classical monocytes and decreased pro-inflammatory classical monocytes. Together, results suggest that targeting CB2 with SMM-189 biased immune cell function toward a phagocytic phenotype and reduced toxic species of alpha-synuclein aggregation. This study highlights that CB2 may be a target for proteinopathies with notable accompanying inflammation.