Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation.
Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has led to the possible involvement of CBr in the control of brain inflammation. In the present study we examined the effect of the CBr agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate (WIN-55212-2), on microglial activation and spatial memory performance, using a well-characterized animal model of chronic brain inflammation produced by the infusion of lipopolysaccharide (LPS, 250 ng/h for 3 weeks) into the fourth ventricle of young rats. WIN-55212-2 (0.5 or 1.0 mg/kg/day, i.p.) was administered for 3 weeks. During the third week of treatment, spatial memory ability was examined using the Morris water-maze task. We found that 0.5 and 1 mg/kg WIN-55212-2 reduced the number of LPS-activated microglia, while 1 mg/kg WIN-55212-2 potentiated the LPS-induced impairment of performance in the water maze task. Cannabinoid receptors 1 were not expressed by microglia and astrocytes, suggesting an indirect effect of WIN-55212-2 on microglia activation and memory impairment. Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.
Marchalant
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Arizona Research Laboratories, Division of Neural Systems Memory and Aging, University of Arizona, Tucson, AZ, USA.
Rosi
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Wenk
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D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D002908:Chronic Disease; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005911:Gliosis / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000494:pharmacology; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone