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.
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.
Zhang
Hui-Ling
HL
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.
Gu
Zhen-Lun
ZL
Savitz
Sean I
SI
Han
Feng
F
Fukunaga
Kohji
K
Qin
Zheng-Hong
ZH
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011454:Prostaglandins A / Q000378:metabolism / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D047495:PPAR gamma; D011454:Prostaglandins A; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051996:Transcription Factor RelA; C100573:prostaglandin A1