prostaglandin-a1 and Infarction--Middle-Cerebral-Artery

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.

Topics: Active Transport, Cell Nucleus; Anilides; Animals; Brain Infarction; Brain Ischemia; Corpus Striatum; Cytoprotection; Disease Models, Animal; I-kappa B Proteins; Infarction, Middle Cerebral Artery; Male; Nerve Degeneration; Neuroprotective Agents; NF-kappa B; PPAR gamma; Prostaglandins A; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription Factor RelA; Up-Regulation

Both prostaglandin A(1) (PGA(1)) and lithium have been reported to protect neurons against excitotoxic and ischemic injury. The present study was undertaken to examine the effects of lithium and PGA1 on heat shock proteins (HSP) and the growth arrest and DNA-damage-inducible gene (GADD153) and to evaluate if lithium could potentiate PGA(1)'s neuroprotective effects against cerebral ischemia. Rats were pretreated with a subcutaneous injection of lithium for 2 days and a single intracerebral ventricle administration of PGA(1) 15 min before ischemic insult. Brain ischemia was induced by a permanent middle cerebral artery occlusion. The infarct volume, motor behavior deficits and brain edema were analyzed 24 h after ischemic insult. The result showed that PGA(1) significantly reduced infarct volume, neurological deficits and brain edema. Except for neurological deficit, lithium enhanced PGA(1)'s neuroprotection. The neuroprotective effects of PGA(1) were associated with an up-regulation of cytoprotective heat shock proteins HSP70 and GRP78 in the ischemic brain hemisphere as determined by immunoblotting and immunofluorescence. The induction of HSP70 and GRP78 was enhanced by lithium. However, although the expression of GADD153 was enhanced significantly after pMCAO, it was not influenced by either PGA(1) or lithium or their combination. These studies suggest that lithium can potentiate PGA(1)'s neuroprotective effects and thus may have potential clinical value for the treatment of stroke in combination with other neuroprotective agents.

Topics: Analysis of Variance; Animals; Blotting, Western; Brain Edema; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Immunohistochemistry; Infarction, Middle Cerebral Artery; Lithium; Male; Molecular Chaperones; Neurologic Examination; Neuroprotective Agents; Prostaglandins A; Rats; Rats, Sprague-Dawley; Time Factors; Transcription Factor CHOP

The present study evaluated the neuroprotective potential of prostaglandin A1 (PGA1) in rodent models of focal cerebral ischemia. PGA1 33 nmol reduced infarction volume by about 43% (P < 0.05) when administered intracerebroventricularly before and after transient ischemia in mice. PGA1 16.5-66 nmol diminished infarction volume by 18% to 27% (P < 0.01) when administered immediately following permanent ischemia in rats. PGA1 treatment also significantly ameliorated motor dysfunction after brain ischemia. These results suggest that PGA1 protects neurons from ischemic injury.

Topics: Analysis of Variance; Animals; Brain Ischemia; Disease Models, Animal; Infarction, Middle Cerebral Artery; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Motor Activity; Neurons; Neuroprotective Agents; Prostaglandins A; Rats; Rats, Sprague-Dawley