Blockade of cannabinoid CB(1) receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity.
The ability of cannabinoid CB(1) receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB(1) receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB(1) /CB(2) receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB(1) and SR144528 for CB(2) ) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA-induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB(1) receptor function. In contrast, blockade of CB(1), but not CB(2), receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest a critical involvement of CB(1) receptor tonus on neuronal survival following NMDA receptor-induced excitotoxicity in vivo.
Hansen
Henrik H
HH
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Avenida de Complutense s/n, 28040 Madrid, Spain.
Azcoitia
Iñigo
I
Pons
Sebastián
S
Romero
Julián
J
García-Segura
Luis Miguel
LM
Ramos
José Antonio
JA
Hansen
Harald S
HS
Fernández-Ruiz
Javier
J
D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate; D009281:Naphthalenes / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009498:Neurotoxins / Q000633:toxicity; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant
D048588:Benzoxazines; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D009025:Morpholines; D009281:Naphthalenes; D009498:Neurotoxins; D010880:Piperidines; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D016202:N-Methylaspartate; D000077285:Rimonabant