Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels.
We investigated the involvement of endocannabinoids in the control of neuronal damage and memory retention loss in rodents treated with the beta-amyloid peptide (1-42) (BAP). Twelve days after stereotaxic injection of BAP into the rat cortex, and concomitant with the appearance in the hippocampus of markers of neuronal damage, 2-arachidonoyl glycerol, but not anandamide, levels were enhanced in the hippocampus. VDM-11 (5 mg/kg, i.p.), an inhibitor of endocannabinoid cellular reuptake, significantly enhanced rat hippocampal and mouse brain endocannabinoid levels when administered sub-chronically starting either 3 or 7 days after BAP injection and until the 12-14th day. VDM-11 concomitantly reversed hippocampal damage in rats, and loss of memory retention in the passive avoidance test in mice, but only when administered from the 3rd day after BAP injection. We suggest that early, as opposed to late, pharmacological enhancement of brain endocannabinoid levels might protect against beta-amyloid neurotoxicity and its consequences.
van der Stelt
M
M
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R. Pozzuoli, Naples, Italy.
Mazzola
C
C
Esposito
G
G
Matias
I
I
Petrosino
S
S
De Filippis
D
D
Micale
V
V
Steardo
L
L
Drago
F
F
Iuvone
T
T
Di Marzo
V
V
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007276:Injections, Intraventricular; D008568:Memory / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity*; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013238:Stereotaxic Techniques; D013997:Time Factors
D016229:Amyloid beta-Peptides; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); C094503:glyceryl 2-arachidonate; C078814:anandamide