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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039912-07
Application #
6986703
Study Section
Special Emphasis Panel (ZRG1-BDCN-D (01))
Program Officer
Golanov, Eugene V
Project Start
2000-04-15
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
7
Fiscal Year
2006
Total Cost
$394,416
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
Muccioli, Giulio G; Stella, Nephi (2008) An optimized GC-MS method detects nanomolar amounts of anandamide in mouse brain. Anal Biochem 373:220-8
Wang, Jiou; Caruano-Yzermans, Amy; Rodriguez, Angela et al. (2007) Disease-associated mutations at copper ligand histidine residues of superoxide dismutase 1 diminish the binding of copper and compromise dimer stability. J Biol Chem 282:345-52
Greenberg, David A (2007) Neurogenesis and stroke. CNS Neurol Disord Drug Targets 6:321-5
Greenberg, David A; Jin, Kunlin (2007) Regenerating the brain. Int Rev Neurobiol 77:1-29
Kim, Sun Hee; Won, Seok Joon; Mao, Xiao Ou et al. (2006) Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis. J Pharmacol Exp Ther 319:150-4
Kim, Sun Hee; Won, Seok Joon; Mao, Xiao Ou et al. (2005) Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. J Pharmacol Exp Ther 313:88-94
Jin, Kunlin; Xie, Lin; Kim, Sun Hee et al. (2004) Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol 66:204-8
Franklin, Allyn; Parmentier-Batteur, Sophie; Walter, Lisa et al. (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 23:7767-75
Parmentier-Batteur, Sophie; Jin, Kunlin; Mao, Xiao Ou et al. (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22:9771-5
Parmentier-Batteur, Sophie; Jin, Kunlin; Xie, Lin et al. (2002) DNA microarray analysis of cannabinoid signaling in mouse brain in vivo. Mol Pharmacol 62:828-35

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