Endogenous cannabinoid (endocannabinoid) signaling pathways have been implicated in normal brain function, as well as in neuroprotection following cerebral ischemia. We have shown that cannabinoid receptor agonists reduce neuronal loss from global and focal cerebral ischemia in rats, that the size of cerebral infarcts after middle cerebral artery occlusion (MCAO) is increased in CB1 cannabinoid receptor (CB1R)-knockout (KO) mice, and that the brain's response to ischemia involves up-regulation of neuronal CB1R and increased production of endogenous anti-inflammatory endocannabinoid-related compounds. Recovery from cerebral ischemia may involve not only neuroprotective mechanisms that promote cell survival, but also the replacement of lethally injured neurons by the generation of new cells (neurogenesis). Recent evidence suggests that endocannabinoids may regulate neurogenesis. We found that in CB1R-KO compared to age- and strain-matched wild-type mice, basal neurogenesis was reduced by 50% in the two principal neuroproliferative zones of the adult brain, the subgranular zone (SGZ) of the hippocampal dentate gyrus and the rostral subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. Thus, we hypothesize that the endocannabinoid signaling system has an important role in regulating both neuroprotection and neurogenesis after focal cerebral ischemia. The long term objective of our work is to identify new treatments for stroke. In furtherance of this objective, we propose to pursue the following Specific Aims: (1) Determine the effect of deleting the gene for fatty acid amide hydrolase (FAAH), which inactivates the endocannabinoid anandamide (AEA), on histological and functional outcome from focal cerebral ischemia; (2) Investigate the role of nitric oxide synthase isoforms (nNOS, eNOS and iNOS) in the neuroprotective effect of cannabinoids against focal cerebral ischemia; (3) Characterize the effects of cannabinoids on neuronal proliferation, death, migration, differentiation and function associated with adult neurogenesis, under normal conditions and after MCAO; and (4) Evaluate the role of growth factors (BDNF, TGFalpha, VEGF and FGF2) in cannabinoid-stimulated adult neurogenesis.
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