The "dark side" of endocannabinoids: a neurotoxic role for anandamide.
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 CB1 receptors or caspases. Central administration of AEA also significantly upregulates genes involved in pro-inflammatory/microglial-related responses. Thus, anandamide produces neurotoxic effects both in vitro and in vivo through multiple mechanisms independent of the CB1 receptor.
Cernak
Ibolja
I
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. ifc@georgetown.edu
Vink
Robert
R
Natale
JoAnne
J
Stoica
Bogdan
B
Lea
Paul M
PM
Movsesyan
Vilen
V
Ahmed
Farid
F
Knoblach
Susan M
SM
Fricke
Stanley T
ST
Faden
Alan I
AI
D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D002154:Calpain / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D063388:Endocannabinoids; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000033:anatomy & histology / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D018782:Maze Learning; D008569:Memory Disorders; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D051381:Rats
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D002154:Calpain; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C078814:anandamide