TY - JOUR
T1 - Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis
AU - Sun, Hee Kim
AU - Seok, Joon Won
AU - Xiao, Ou Mao
AU - Ledent, Catherine
AU - Jin, Kunlin
AU - Greenberg, David A.
PY - 2006
Y1 - 2006
N2 - Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production. Accordingly, we measured neurogenesis in dentate gyrus (DG) and subventricular zone (SVZ) of CB1R-knockout (KO) and wild-type mice, some of whom were treated with the cannabinoid agonist R(+)-Win 55212-2 [(+)-[2,3-dihydro-5- methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl] -(1-naphthalenyl)methanone] or the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI). NOS activity was increased by ∼25%, whereas bromodeoxyuridine (BrdU) labeling of newborn cells in DG and SVZ was reduced by ∼50% in CB1R-KO compared with wild-type mice. 7-NI increased BrdU labeling in both DG and SVZ and to a greater extent in CB1R-KO than in wild-type mice. In addition, R(+)-Win 55212-2 and 7-NI enhanced BrdU incorporation into neuron-enriched cerebral cortical cultures to a similar maximal extent and in nonadditive fashion, consistent with a shared mechanism of action. Double-label confocal microscopy showed coexpression of BrdU and the neuronal lineage marker doublecortin (Dcx) in DG and SVZ of untreated and 7-NI-treated CB1R-KO mice, and 7-NI increased the number of Dcx- and BrdU/Dcx-immunoreactive cells in SVZ and DG. Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO.
AB - Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production. Accordingly, we measured neurogenesis in dentate gyrus (DG) and subventricular zone (SVZ) of CB1R-knockout (KO) and wild-type mice, some of whom were treated with the cannabinoid agonist R(+)-Win 55212-2 [(+)-[2,3-dihydro-5- methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl] -(1-naphthalenyl)methanone] or the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI). NOS activity was increased by ∼25%, whereas bromodeoxyuridine (BrdU) labeling of newborn cells in DG and SVZ was reduced by ∼50% in CB1R-KO compared with wild-type mice. 7-NI increased BrdU labeling in both DG and SVZ and to a greater extent in CB1R-KO than in wild-type mice. In addition, R(+)-Win 55212-2 and 7-NI enhanced BrdU incorporation into neuron-enriched cerebral cortical cultures to a similar maximal extent and in nonadditive fashion, consistent with a shared mechanism of action. Double-label confocal microscopy showed coexpression of BrdU and the neuronal lineage marker doublecortin (Dcx) in DG and SVZ of untreated and 7-NI-treated CB1R-KO mice, and 7-NI increased the number of Dcx- and BrdU/Dcx-immunoreactive cells in SVZ and DG. Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO.
UR - http://www.scopus.com/inward/record.url?scp=33749013040&partnerID=8YFLogxK
U2 - 10.1124/jpet.106.107698
DO - 10.1124/jpet.106.107698
M3 - Article
C2 - 16831955
AN - SCOPUS:33749013040
SN - 0022-3565
VL - 319
SP - 150
EP - 154
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -