Targeting cannabinoid Type 2 receptors to modulate inflammation and protect against Asyn-induced PD-like pathologies
Valerie Joers1, Benjamin Murray1, Danielle Oliver1, Lori Blanchfield1, Sean Kelly1, Fredric P Manfredsson2, Bob M Moore II3, Malú G. Tansey1
1Department of Physiology, Emory University, Atlanta, GA; 2Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MN; 3Department Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN
Numerous studies have demonstrated that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic degeneration as found in Parkinson's disease (PD). Modulating the activation state of microglia or infiltrating immune cells can largely alter the local environment via cytokine signaling, and in turn impact neuronal survival. The cannabionoid type 2 receptor (CB2) is highly expressed on activated microglia and circulating monocytes, upregulated in the nigra of PD patients and when modulated protects against rotenone-induced nigral degeneration. Studies conducted using a novel CB2 inverse agonist SMM-189 demonstrated immunomodulatory effects that improve acute neuronal injury and behavioral outcomes. Here we report the peripheral and central immunomodulatory effect of SMM-189 treatment in an AAV2/5-hAsyn rat model of PD. We hypothesize that targeting CB2 will benefit the central inflammatory environment by inhibiting activation of central and peripheral immune cells and promoting phagocytosis and clearance of Asyn to protect against PD-like pathology. Spraque-Dawley rats (n=28) were unilaterally injected in the nigra with AAV2/5-hAsyn and followed for 8 weeks. One week later, animals were randomly selected to receive daily systemic SMM-189 (6 mg/kg, n=14) or vehicle (n=14). Our preliminary results indicate SMM-189 decreased gene expression of pro-inflammatory marker TNF (p=0.0084) while promoting anti-inflammatory behavior with increased TGFβ (p=0.0204) in peripheral blood mononuclear cells. Similar altered gene expression was found in the frontal cortex with increased CD206 (p=0.0107) and YMI (p=0.0291) after CB2 treatment. Additionally, nigral IBA1+ cell size was significantly decreased in SMM-189-treated (p<0.0001) compared to vehicle-treated, suggesting that targeting CB2 ameliorates persistent microgliosis from Asyn overexpression. CD68-immunoreactivity trends to increase in SMM-189-treated rats (p=0.0651). Functionally, CD68+ cells may be responsible for decreasing the amount of phosphorylated Asyn (pSer129 Asyn) as determined by histological analysis. CSF levels of SMM-189 were not significantly different from vehicle treated rats, suggesting that central effects may be in part influenced by peripheral infiltrates. We are currently completing analysis of cell surface markers by flow cytometry to elucidate changes in circulating immune populations following SMM-189 treatment.