title: A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury.
abstract: Cannabinoid CB2 receptor activation has been shown to have many pharmacological but not psychotropic effects. The aim of this study was to investigate the potential protection of brain tissues afforded by the novel substituted 4-quinolone-3-carboxylic acid derivative COR167, a selective CB2 agonist, toward ischemia and reperfusion-induced injury, as well as the mechanism of this potential effect. Rat brain cortical slices subjected to oxygen and glucose deprivation (OGD) followed by re-oxygenation were used. Cell damage was quantified by measuring at the end of the reperfusion phase the release into the artificial cerebrospinal fluid (ACSF) of lactate dehydrogenase (LDH), glutamate, IL-6 and TNF-α and by evaluating in tissue the lipid-peroxides (thiobarbituric acid-reactive substances, TBARS), the free, reduced glutathione content (GSH) and the water gain (TWG), taken as an index of cell swelling. COR167 (10nM or 100 nM), added to ACSF during the entire reperfusion phase, markedly reduced LDH and glutamate release, as well as TWG. Lower (0.1-1 nM) or higher concentrations (1,000 nM) were ineffective, suggesting thereby an hormetic behavior. COR167 at 10nM concentration markedly reverted in tissues TBARS increase and GSH decrease, while reducing IL-6 and TNF-α release into ACSF. COR167 effects on glutamate and LDH release were abrogated by the selective CB2 inverse-agonists COR170 (1 nM) and AM630 (1μM) but not by the CB1 antagonist AM251 (1 μM). COR170 as well as AM630 per se were able to revert TWG. The CB2 receptor agonist COR167 potently protected rat brain cortical slices against OGD and reperfusion injury, partly through CB2 receptors activation.
authors.affiliation: Dipartimento di Neuroscienze, Sezione di Farmacologia, Università di Siena, viale A. Moro 2, 53100 Siena, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Contartese
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Federica
authors.initials: F
authors.lastname: Pessina
authors.forename: Carlo
authors.initials: C
authors.lastname: Aldinucci
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D005947:Glucose / Q000172:deficiency*; D018698:Glutamic Acid / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D010100:Oxygen / Q000378:metabolism*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: D063386:Cannabinoid Receptor Agonists; C469526:Cnr2 protein, rat; D015850:Interleukin-6; C580859:N-(adamantan-1-yl)-4-oxo-1-pentyl-6-phenyl-1,4-dihydroquinoline-3-carboxamide; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D014867:Water; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D000218:Adamantane; D010100:Oxygen