Central CB2 receptors in inflammation-driven neurodegeneration: dysregulation and therapeutic potential

Abstract

In recent times there has been an intensification of interest in the pathological role of neuroinflammation in neurodegenerative disease. Neuroprotective strategies to slow, halt or reverse neurodegeneration have not proven fruitful clinically, and the notion of a multi-hit hypothesis in the progression of neurodegenerative disease has steered focus towards other contributory pathological factors, particularly neuroinflammation. Neuroinflammation is believed to sustain the neurodegenerative pathology, forming a cyclical and self-sustaining pathological process, with dying neurons activating microglia, which, once activated, can release several factors that kill further neurons (reviewed in Blandini, 2013). Indeed, evidence of neuroinflammation has been observed around sites of neuropathological lesions in many neurodegenerative conditions including Parkinson's disease (Gómez-Gálvez et al., 2015). Furthermore, epidemiological evidence suggests that chronic administration of drugs with anti-inflammatory action, including non-steroidal anti-inflammatory drugs (NSAIDs), may reduce the risk of developing neurodegenerative conditions. With this in mind, the concept of anti-inflammatory therapy for disease-modification in neurodegenerative disease has emerged, with a view to identifying specific, novel targets to reduce inflammation in neurodegeneration. One such anti-inflammatory target that has garnered particular attention in the context of Parkinson's disease is the anti-inflammatory and immunosuppressant cannabinoid type-2 (CB2 ) receptor. The endocannabinoid system has been the focus of much interest in Parkinson's disease research, initially due to the role of the CB1 receptor in the basal ganglia neurocircuitry. Indeed, in Parkinson's disease patients, elevated levels of the endogenous cannabinoid, anandamide, and dysregulation of the central CB1 receptor have been reported, and preclinically, targeting the CB1 receptor has shown therapeutic benefit in treating both symptomatic and drug-induced motoric features (reviewed in Concannon et al., 2015a). In contrast, preclinical studies targeting the CB1 receptor have been less successful as a neuroprotective strategy, and this has led to increased interest in the CB2 receptor for disease-modification. The CB2 receptor has emerged as an exciting target for modulation of neuroinflammation because it is expressed on microglial cells, and when activated, has profound anti-inflammatory and immunosuppressant effects on these neuroimmune cells (Mecha et al., 2016). This perspective will draw together some of the recent evidence indicating that CB2 receptor expression is profoundly increased at sites of injury in the brain, thus supporting the concept that specific targeting of this receptor may have the potential to break the pathological cycle of neuroinflammation and neurodegeneration in neurodegenerative disease.