Acute neuronal injury, excitotoxicity, and the endocannabinoid system.
The endocannabinoid system is a valuable target for drug discovery, because it is involved in the regulation of many cellular and physiological functions. The endocannabinoid system constitutes the endogenous lipids anandamide, 2-arachidonoylglycerol and noladin ether, and the cannabinoid CB1 and CB2 receptors as well as the proteins for their inactivation. It is thought that (endo)cannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. This paper reviews recent developments in the endocannabinoid system and its involvement in neuroprotection. Exogenous (endo)cannabinoids have been shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by CB1-mediated inhibition of glutamatergic transmission, reduction of calcium influx, and subsequent inhibition of deleterious cascades, TNF-alpha formation, and anti-oxidant activity. It has been suggested that the release of endogenous endocannabinoids during neuronal injury might be a protective response. However, several observations indicate that the role of the endocannabinoid system as a general endogenous protection system is questionable. The data are critically reviewed and possible explanations are given.
van der Stelt
Mario
M
Department of Bio-Organic Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, The Netherlands.
Veldhuis
Wouter B
WB
Maccarrone
Mauro
M
Bär
Peter R
PR
Nicolay
Klaas
K
Veldink
Gerrit A
GA
Di Marzo
Vincenzo
V
Vliegenthart
Johannes F G
JF
D000208:Acute Disease; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology / Q000502:physiology; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D005989:Glycerides / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D053284:Polyunsaturated Alkamides
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists; D005231:Fatty Acids, Unsaturated; D005989:Glycerides; D009498:Neurotoxins; D053284:Polyunsaturated Alkamides; C424442:noladin ether; C094503:glyceryl 2-arachidonate; C078814:anandamide