The endocannabinoid system: A new entry in remote cell death mechanisms

Functional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies. Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems. (C) 2010 Elsevier Inc. All rights reserved.