WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway.
Cannabinoids have been shown to exert neuroprotective effects in a plethora of neurodegenerative conditions. Over the past decade, some studies demonstrate that cannabinoids can interact with nuclear peroxisome proliferator-activated receptors (PPARs). We investigated protective properties of WIN55212-2 (WIN, a non-selective cannabinoid receptor agonist) in beta-amyloid (Aβ)-induced neurodegeneration in rat hippocampus and possible involvement of PPAR-gamma (PPAR-γ). Aβ (1-42) was injected into the hippocampus of male rats. Animals were administered by intracerebroventricular rout the following treatments on days 1, 3, 5, 7: vehicle, WIN, GW9662 (selective PPAR-γ antagonist) plus WIN, AM251 (selective CB₁ receptor antagonist) plus WIN, SR144528 (selective CB₂ receptor antagonist) plus WIN, each of antagonists alone. Injection of Aβ-induced spatial memory impairment and a dramatic rise in hippocampal TNF-α, active caspase 3, nuclear NF-kB levels and TUNEL-positive neurons. WIN administration significantly improved memory function and diminished the elevated levels of these markers, while antagonizing either CB₁ or CB₂ receptor subtype partially attenuated the protective effects. Intriguingly, WIN significantly increased PPAR-γ level and transcriptional activity, the latter being partially inhibited with AM251 but not with SR144528. The enhancing effect on PPAR-γ pathway was crucial to WIN-induced neuroprotection since GW9662 partially reversed the beneficial actions of WIN. Co-administration of the three antagonists led to the complete abrogation of WIN effects. Our findings indicate that WIN exerts neuroprotective and anti-inflammatory actions against Aβ damage through both CB₁ and CB₂ receptors. Of great note, both direct and CB₁-mediated increase in PPAR-γ signaling also contributes to WIN-induced neuroprotection.
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, P.O. Box: 19615-1178, Tehran, Iran.
Gohar
G
Fakhfouri
Abolhasan
A
Ahmadiani
Reza
R
Rahimian
Ambra A
AA
Grolla
Fatemeh
F
Moradi
Ali
A
Haeri
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D009281:Naphthalenes / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018697:Nootropic Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; D009025:Morpholines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D047495:PPAR gamma; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; 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