Upregulation of the cannabinoid CB 2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease

Abstract

In recent years, it has become evident that Parkinson's disease is associated with a self-sustaining cycle of neuroinflammation and neurodegeneration, with dying neurons activating microglia, which, once activated, can release several factors that kill further neurons. One emerging pharmacological target that has the potential to break this cycle is the microglial CB 2 receptor which, when activated, can suppress microglial activity and reduce their neurotoxicity. However, very little is known about CB 2 receptor expression in animal models of Parkinson's disease which is essential for valid preclinical assessment of the anti-Parkinsonian efficacy of drugs targeting the CB 2 receptor. Therefore, the aim of this study was to investigate and compare the changes that occur in CB 2 receptor expression in environmental and inflammation-driven models of Parkinson's disease. To do so, male Sprague Dawley rats were given unilateral, intra-striatal injections of the Parkinson's disease-associated agricultural pesticide, rotenone, or the viral-like inflammagen, polyinosinic:polycytidylic acid (Poly (I:C)). Animals underwent behavioural testing for motor dysfunction on days 7, 14 and 28 post-surgery, and were sacrificed on days 1, 4, 14 and 28. Changes in the endocannabinoid system and neuroinflamamtion were investigated by qRT-PCR, liquid chromatography-mass spectrometry and immunohistochemistry. After injection of rotenone or Poly (I:C) into the rat striatum, we found that expression of the CB 2 receptor was significantly elevated in both models, and that this increase correlated significantly with an increase in microglial activation in the rotenone model. Interestingly, the increase in CB 2 receptor expression in the inflammation-driven Poly (I:C) model was significantly more pronounced than that in the neurotoxic rotenone model. Thus, this study has shown that CB 2 receptor expression is dysregulated in animal models of Parkinson's disease, and has also revealed significant differences in the level of dysregulation between the models themselves. This study indicates that these models may be useful for further investigation of the CB 2 receptor as a target for anti-inflammatory disease modification in Parkinson's disease.