Distinct regulation of nNOS and iNOS by CB 2 receptor in remote delayed neurodegeneration

S. Oddi, L. Latini, M. T. Viscomi, E. Bisicchia, M. Molinari, M. Maccarrone

Research output: Contribution to journalArticlepeer-review


Hemicerebellectomy results in remote delayed degeneration of precerebellar neurons. We have reported that such a lesion induces type 2 cannabinoid receptor (CB2) expression in precerebellar neurons and that stimulation of CB2, but not CB1, has neuroprotective effects. In this study, we found that in the same model, the CB 2 agonist JWH-015 enhances neuronal nitric oxide synthase (nNOS) expression in axotomized neurons and that CB2-mediated neuroprotection is abrogated by pharmacological inhibition of nNOS. JWH-015 prevented the axotomy-induced upregulation of inducible NOS (iNOS) in astrocytes but had no effect on endothelial NOS (eNOS). In addition, we observed that JWH-015 significantly reduces hemicerebellectomyinduced neuroinflammatory responses and oxidative/nitrative stress. With regard to the signaling pathways of CB2/nNOSmediated neuroprotection, we noted nNOS-dependent modulation of the expression of anti-oxidative (Hsp70) and anti-apoptotic (Bcl-2) proteins. These findings shed light on the interactions between the endocannabinoid and nitrergic systems after focal brain injury, implicating distinct functions of nNOS activation and iNOS inhibition in CB 2 signaling, which protect neurons from axotomy-induced cell death.

Original languageEnglish
Pages (from-to)371-387
Number of pages17
JournalJournal of Molecular Medicine
Issue number4
Publication statusPublished - Apr 2012


  • Cannabinoids
  • Neurodegeneration
  • Nitric oxide
  • Oxidative stress

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)


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