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WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway.
Neuropharmacology 2012; 63(4):653-66N

Abstract

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.

Authors+Show Affiliations

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, P.O. Box: 19615-1178, Tehran, Iran.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22634229

Citation

Fakhfouri, Gohar, et al. "WIN55212-2 Attenuates Amyloid-beta-induced Neuroinflammation in Rats Through Activation of Cannabinoid Receptors and PPAR-γ Pathway." Neuropharmacology, vol. 63, no. 4, 2012, pp. 653-66.
Fakhfouri G, Ahmadiani A, Rahimian R, et al. WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. Neuropharmacology. 2012;63(4):653-66.
Fakhfouri, G., Ahmadiani, A., Rahimian, R., Grolla, A. A., Moradi, F., & Haeri, A. (2012). WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. Neuropharmacology, 63(4), pp. 653-66. doi:10.1016/j.neuropharm.2012.05.013.
Fakhfouri G, et al. WIN55212-2 Attenuates Amyloid-beta-induced Neuroinflammation in Rats Through Activation of Cannabinoid Receptors and PPAR-γ Pathway. Neuropharmacology. 2012;63(4):653-66. PubMed PMID: 22634229.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. AU - Fakhfouri,Gohar, AU - Ahmadiani,Abolhasan, AU - Rahimian,Reza, AU - Grolla,Ambra A, AU - Moradi,Fatemeh, AU - Haeri,Ali, Y1 - 2012/05/23/ PY - 2011/12/14/received PY - 2012/04/27/revised PY - 2012/05/13/accepted PY - 2012/5/29/entrez PY - 2012/5/29/pubmed PY - 2012/12/10/medline SP - 653 EP - 66 JF - Neuropharmacology JO - Neuropharmacology VL - 63 IS - 4 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/22634229/WIN55212_2_attenuates_amyloid_beta_induced_neuroinflammation_in_rats_through_activation_of_cannabinoid_receptors_and_PPAR_γ_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(12)00198-0 DB - PRIME DP - Unbound Medicine ER -