The "Dark Side" of Endocannabinoids: A Neurotoxic Role for Anandamide

Ibolja Cernak, Robert Vink, JoAnne E Natale, Bogdan Stoica, Paul M. Lea IV, Vilen Movsesyan, Farid Ahmed, Susan M. Knoblach, Stanley T. Fricke, Alan I. Faden

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Endocannabinoids, including 2-arachidonoylglycerol and anandamide (N-arachidonoylethanolamine; AEA), have neuroprotective effects in the brain through actions at CB1 receptors. However, AEA also binds to vanilloid (VR1) receptors and induces cell death in several cell lines. Here we show that anandamide causes neuronal cell death in vitro and exacerbates cell loss caused by stretch-induced axonal injury or trophic withdrawal in rat primary neuronal cultures. Administered intracerebroventricularly, AEA causes sustained cerebral edema, as reflected by diffusion-weighted magnetic resonance imaging, regional cell loss, and impairment in long-term cognitive function. These effects are mediated, in part, through VR1 as well as through calpain-dependent mechanisms, but not through CBI receptors or caspases. Central administration of AEA also significantly upregulates genes involved in proinflammatory/microglial-related responses. Thus, anandamide produces neurotoxic effects both in vitro and in vivo through multiple mechanisms independent of the CB1 receptor.

Original languageEnglish (US)
Pages (from-to)564-578
Number of pages15
JournalJournal of Cerebral Blood Flow and Metabolism
Volume24
Issue number5
StatePublished - May 2004
Externally publishedYes

Keywords

  • Anandamide
  • Cell death
  • Cognitive deficit
  • Endocannabinoids
  • Magnetic resonance imaging
  • Microarray

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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    Cernak, I., Vink, R., Natale, J. E., Stoica, B., Lea IV, P. M., Movsesyan, V., Ahmed, F., Knoblach, S. M., Fricke, S. T., & Faden, A. I. (2004). The "Dark Side" of Endocannabinoids: A Neurotoxic Role for Anandamide. Journal of Cerebral Blood Flow and Metabolism, 24(5), 564-578.