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Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferator-activated receptor gamma-mediated suppression of nuclear factor-κB signaling pathway.
Neuroscience. 2011 Mar 10; 176:381-95.N

Abstract

Previous studies have demonstrated that pioglitazone (Piog), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. Piog has also been shown to exert anti-inflammatory effects by attenuation of nuclear factor-κB (NF-κB) activation after myocardial ischemia/reperfusion injury. Because NF-κB is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to elucidate whether pioglitazone attenuates ischemic neuronal damage through PPARγ-mediated suppression of NF-κB apoptotic signaling pathway. Permanent middle cerebral artery occlusion (pMCAO) model was induced by using an intraluminal filament technique in rats. Piog was administrated i.p. twice (24 h before and at the time of ischemia insult) or once (10 min after ischemia). The neuroprotection of Piog was analyzed by assessing neurological deficits, infarction volume and morphological changes. The inhibition of NF-κB signaling pathway by Piog was evaluated by detecting the nuclear translocation of NF-κB p65 with immunohistochemistry and its target gene p53 by real-time PCR, and the expression of phospholated NF-κB p65 (p- NF-κB p65) in primary cultured neurons and the protein levels of IκBα and p-ERK in the ischemic cortex or striatum with Western blotting analysis. The contribution of a PPARγ mechanism to Piog's inhibitory effects on NF-κB and neuroprotection was evaluated by pretreatment with the PPARγ irreversible antagonist GW9662. In vitro ischemia in cultured primary neurons was induced by the oxygen-glucose deprivation (OGD) and the protective effect of Piog on cultured neurons was measured by lactate dehydrogenase (LDH) assay. Piog (0.5, 1, 2 mg/kg) reduced infarction volume, and improved morphological changes and motor deficits. Piog markedly up-regulated the protein levels of IκBα or p-ERK 6 h or 12 h after ischemia. Piog reduced the nuclear translocation of NF-κB p65 in the ischemic cortical cells and repressed the expression of p53 12 h after ischemia. Pre-treatment with GW9662 blocked Piog-elicited reduction in infarction volume, the increase in protein levels of IκBα and p-ERK, the reduction in the nuclear translocation of NF-κB subunit p65 and the repression of p53 mRNA expression. In addition, Piog attenuated the OGD-induced neuronal damage and inhibited the OGD-induced increases in p- NF-κB p65 in neurons. The present findings suggest that Piog's neuroprotection appears to be associated with PPARγ-mediated suppression of NF-κB signaling pathway.

Authors+Show Affiliations

Department of Pharmacology and Laboratory of Aging and Nervous Diseases, College of Pharmaceutical Science, Soochow University School of Medicine, Suzhou 215123, Jiangsu, PR China. huilingzhang07@hotmail.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21185913

Citation

Zhang, H-L, et al. "Neuroprotective Effects of Pioglitazone in a Rat Model of Permanent Focal Cerebral Ischemia Are Associated With Peroxisome Proliferator-activated Receptor Gamma-mediated Suppression of Nuclear factor-κB Signaling Pathway." Neuroscience, vol. 176, 2011, pp. 381-95.
Zhang HL, Xu M, Wei C, et al. Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferator-activated receptor gamma-mediated suppression of nuclear factor-κB signaling pathway. Neuroscience. 2011;176:381-95.
Zhang, H. L., Xu, M., Wei, C., Qin, A. P., Liu, C. F., Hong, L. Z., Zhao, X. Y., Liu, J., & Qin, Z. H. (2011). Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferator-activated receptor gamma-mediated suppression of nuclear factor-κB signaling pathway. Neuroscience, 176, 381-95. https://doi.org/10.1016/j.neuroscience.2010.12.029
Zhang HL, et al. Neuroprotective Effects of Pioglitazone in a Rat Model of Permanent Focal Cerebral Ischemia Are Associated With Peroxisome Proliferator-activated Receptor Gamma-mediated Suppression of Nuclear factor-κB Signaling Pathway. Neuroscience. 2011 Mar 10;176:381-95. PubMed PMID: 21185913.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferator-activated receptor gamma-mediated suppression of nuclear factor-κB signaling pathway. AU - Zhang,H-L, AU - Xu,M, AU - Wei,C, AU - Qin,A-P, AU - Liu,C-F, AU - Hong,L-Z, AU - Zhao,X-Y, AU - Liu,J, AU - Qin,Z-H, Y1 - 2010/12/24/ PY - 2010/08/25/received PY - 2010/12/12/revised PY - 2010/12/19/accepted PY - 2010/12/28/entrez PY - 2010/12/28/pubmed PY - 2011/6/2/medline SP - 381 EP - 95 JF - Neuroscience JO - Neuroscience VL - 176 N2 - Previous studies have demonstrated that pioglitazone (Piog), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. Piog has also been shown to exert anti-inflammatory effects by attenuation of nuclear factor-κB (NF-κB) activation after myocardial ischemia/reperfusion injury. Because NF-κB is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to elucidate whether pioglitazone attenuates ischemic neuronal damage through PPARγ-mediated suppression of NF-κB apoptotic signaling pathway. Permanent middle cerebral artery occlusion (pMCAO) model was induced by using an intraluminal filament technique in rats. Piog was administrated i.p. twice (24 h before and at the time of ischemia insult) or once (10 min after ischemia). The neuroprotection of Piog was analyzed by assessing neurological deficits, infarction volume and morphological changes. The inhibition of NF-κB signaling pathway by Piog was evaluated by detecting the nuclear translocation of NF-κB p65 with immunohistochemistry and its target gene p53 by real-time PCR, and the expression of phospholated NF-κB p65 (p- NF-κB p65) in primary cultured neurons and the protein levels of IκBα and p-ERK in the ischemic cortex or striatum with Western blotting analysis. The contribution of a PPARγ mechanism to Piog's inhibitory effects on NF-κB and neuroprotection was evaluated by pretreatment with the PPARγ irreversible antagonist GW9662. In vitro ischemia in cultured primary neurons was induced by the oxygen-glucose deprivation (OGD) and the protective effect of Piog on cultured neurons was measured by lactate dehydrogenase (LDH) assay. Piog (0.5, 1, 2 mg/kg) reduced infarction volume, and improved morphological changes and motor deficits. Piog markedly up-regulated the protein levels of IκBα or p-ERK 6 h or 12 h after ischemia. Piog reduced the nuclear translocation of NF-κB p65 in the ischemic cortical cells and repressed the expression of p53 12 h after ischemia. Pre-treatment with GW9662 blocked Piog-elicited reduction in infarction volume, the increase in protein levels of IκBα and p-ERK, the reduction in the nuclear translocation of NF-κB subunit p65 and the repression of p53 mRNA expression. In addition, Piog attenuated the OGD-induced neuronal damage and inhibited the OGD-induced increases in p- NF-κB p65 in neurons. The present findings suggest that Piog's neuroprotection appears to be associated with PPARγ-mediated suppression of NF-κB signaling pathway. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/21185913/Neuroprotective_effects_of_pioglitazone_in_a_rat_model_of_permanent_focal_cerebral_ischemia_are_associated_with_peroxisome_proliferator_activated_receptor_gamma_mediated_suppression_of_nuclear_factor_κB_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(10)01634-9 DB - PRIME DP - Unbound Medicine ER -