Modulation of the cannabinoid CB1 and CB2 receptor activation in central nervous system disorders.

摘要

Central nervous system (CNS) disorders, such as stroke and multiple sclerosis, not only affect motor and/or sensation function, language and cognition ability but also alter lifestyle and reduce self-supportiveness of patients. Stroke is one of the leading causes of adult disability and remains the third leading cause of death in the United States. Unlike stroke, which mostly happens to older people, patients experience their first episode of multiple sclerosis (MS) during their young or middle age, and most of them continue to show relapsing-remitting symptoms.; It is widely reorganized that inflammatory reactions, especially leukocyte extravasations, is a primary contributor to the damage of the CNS during stroke and MS. It has been shown in various studies that interruptions of leukocytes extravasations could exert neuroprotection during both stroke and MS. Cannabinoids, the synthetic analogs of cannabis, have been found recently to have different neuromodulatory properties. There are two cloned cannabinoid receptors, designated CB1 and CB2. The CB1 receptor is primarily expressed in CNS, exhibiting a presynaptic location and playing a prominent role in synaptic neurotransmission. The CB2 receptor is expressed predominantly by cells of the immune system and has been shown to have immunomodulatory properties. The goal of this thesis to investigate if changing the pattern of CB1 and CB2 receptor activation could alter the outcomes resulting from stoke and multiple sclerosis.; The studies described in this thesis are based on mouse models of middle cerebral artery occlusion/reperfusion (MCAO/R) and experimental autoimmune encephalomyelitis (EAE). The results demonstrated that the CB1 receptor inhibition is protective while CB2 receptor inhibition is detrimental during cerebral ischemic injury in mouse; and selective stimulation of CB2 receptor decreased cerebral infarction which is possibly mediated by inhibition of leukocyte infiltration. The EAE study also showed that the selective CB2 activation attenuated disease progression and remission that is accompanied by decreased inflammatory responses. In conclusion, changing the pattern of CB1 and CB2 activation influenced the outcomes after cerebral ischemic injury; selective activation of CB2 receptors protected the CNS from ischemic and demyelination disorders which are mediated by the attenuation of inflammatory responses.