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Neuroprotective effects of prostaglandin A(1) in rat models of permanent focal cerebral ischemia are associated with nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor-gamma up-regulation.
J Neurosci Res. 2008 Apr; 86(5):1132-41.JN

Abstract

We have previously reported that prostaglandin A(1) (PGA(1)) reduces infarct size in rodent models of focal ischemia. This study seeks to elucidate the possible molecular mechanisms underlying PGA(1)'s neuroprotective effects against ischemic injury. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. PGA(1) was injected intracerebroventricularly (icv) immediately after ischemic onset. Western blot analysis was employed to determine alterations in IkappaBalpha, pIKKalpha, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Immunohistochemistry was used to confirm the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65 and the expression of PPAR-gamma. RT-PCR was used to detect levels of c-Myc mRNA. The contribution of PPAR-gamma to PGA(1)'s neuroprotection was evaluated by pretreatment with the PPAR-gamma irreversible antagonist GW9662. A brief increase in pIKKalpha levels and rapid reduction in IkappaBalpha were observed after ischemia. PGA(1) blocked ischemia-induced increases in pIKKalpha levels and reversed the decline in IkappaBalpha levels. Ischemia-induced nuclear translocation of NF-kappaB p65 was attenuated by PGA(1). PGA(1) also repressed the ischemia-induced increase in expression of NF-kappaB target gene c-Myc mRNA. Immunohistochemistry demonstrated an increase in PPAR-gamma immunoreactivity in the nucleus of striatal cells at 3 hr after pMCAO. Western blot analysis revealed that the expression of PPAR-gamma protein significantly increased at 12 hr and peaked at 24 hr. PGA(1) enhanced the ischemia-triggered induction of PPAR-gamma protein. Pretreatment with the irreversible PPAR-gamma antagonist GW9662 attenuated PGA(1)'s neuroprotection against ischemia. These findings suggest that PGA(1)-mediated neuroprotective effect against ischemia appears to be associated with blocking NF-kappaB activation and likely with up-regulating PPAR-gamma expression.

Authors+Show Affiliations

Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.No 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

18074385

Citation

Zhang, Hui-Ling, et al. "Neuroprotective Effects of Prostaglandin A(1) in Rat Models of Permanent Focal Cerebral Ischemia Are Associated With Nuclear factor-kappaB Inhibition and Peroxisome Proliferator-activated Receptor-gamma Up-regulation." Journal of Neuroscience Research, vol. 86, no. 5, 2008, pp. 1132-41.
Zhang HL, Gu ZL, Savitz SI, et al. Neuroprotective effects of prostaglandin A(1) in rat models of permanent focal cerebral ischemia are associated with nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor-gamma up-regulation. J Neurosci Res. 2008;86(5):1132-41.
Zhang, H. L., Gu, Z. L., Savitz, S. I., Han, F., Fukunaga, K., & Qin, Z. H. (2008). Neuroprotective effects of prostaglandin A(1) in rat models of permanent focal cerebral ischemia are associated with nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor-gamma up-regulation. Journal of Neuroscience Research, 86(5), 1132-41.
Zhang HL, et al. Neuroprotective Effects of Prostaglandin A(1) in Rat Models of Permanent Focal Cerebral Ischemia Are Associated With Nuclear factor-kappaB Inhibition and Peroxisome Proliferator-activated Receptor-gamma Up-regulation. J Neurosci Res. 2008;86(5):1132-41. PubMed PMID: 18074385.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effects of prostaglandin A(1) in rat models of permanent focal cerebral ischemia are associated with nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor-gamma up-regulation. AU - Zhang,Hui-Ling, AU - Gu,Zhen-Lun, AU - Savitz,Sean I, AU - Han,Feng, AU - Fukunaga,Kohji, AU - Qin,Zheng-Hong, PY - 2007/12/13/pubmed PY - 2008/4/24/medline PY - 2007/12/13/entrez SP - 1132 EP - 41 JF - Journal of neuroscience research JO - J Neurosci Res VL - 86 IS - 5 N2 - We have previously reported that prostaglandin A(1) (PGA(1)) reduces infarct size in rodent models of focal ischemia. This study seeks to elucidate the possible molecular mechanisms underlying PGA(1)'s neuroprotective effects against ischemic injury. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. PGA(1) was injected intracerebroventricularly (icv) immediately after ischemic onset. Western blot analysis was employed to determine alterations in IkappaBalpha, pIKKalpha, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Immunohistochemistry was used to confirm the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65 and the expression of PPAR-gamma. RT-PCR was used to detect levels of c-Myc mRNA. The contribution of PPAR-gamma to PGA(1)'s neuroprotection was evaluated by pretreatment with the PPAR-gamma irreversible antagonist GW9662. A brief increase in pIKKalpha levels and rapid reduction in IkappaBalpha were observed after ischemia. PGA(1) blocked ischemia-induced increases in pIKKalpha levels and reversed the decline in IkappaBalpha levels. Ischemia-induced nuclear translocation of NF-kappaB p65 was attenuated by PGA(1). PGA(1) also repressed the ischemia-induced increase in expression of NF-kappaB target gene c-Myc mRNA. Immunohistochemistry demonstrated an increase in PPAR-gamma immunoreactivity in the nucleus of striatal cells at 3 hr after pMCAO. Western blot analysis revealed that the expression of PPAR-gamma protein significantly increased at 12 hr and peaked at 24 hr. PGA(1) enhanced the ischemia-triggered induction of PPAR-gamma protein. Pretreatment with the irreversible PPAR-gamma antagonist GW9662 attenuated PGA(1)'s neuroprotection against ischemia. These findings suggest that PGA(1)-mediated neuroprotective effect against ischemia appears to be associated with blocking NF-kappaB activation and likely with up-regulating PPAR-gamma expression. SN - 1097-4547 UR - https://www.unboundmedicine.com/medline/citation/18074385/Neuroprotective_effects_of_prostaglandin_A_1__in_rat_models_of_permanent_focal_cerebral_ischemia_are_associated_with_nuclear_factor_kappaB_inhibition_and_peroxisome_proliferator_activated_receptor_gamma_up_regulation_ L2 - https://doi.org/10.1002/jnr.21569 DB - PRIME DP - Unbound Medicine ER -