title: Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway.
abstract: We tested the hypothesis that the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway mediates some of the neuroprotective effects of progesterone (PROG) after ischemic stroke. We examined whether PROG acting through the PI3K/Akt pathway could affect the expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Rats underwent permanent focal cerebral ischemia by electrocoagulation and received intraperitoneal injections of PROG (8 mg/kg) or vehicle at 1 h post-occlusion and subcutaneous injections at 6, 24, and 48 h. PAkt/Akt levels, apoptosis and apoptosis-related proteins (phosphorylated Bcl-2-associated death promoter (pBAD), BAD, caspase-3, and cleaved caspase-3) were analyzed by TUNEL assays, Western blotting and immunohistochemistry at 24 h post-pMCAO. VEGF and BDNF were analyzed at 24, 72 h and 14 days post-pMCAO with Western blots. Following pMCAO, PROG treatment significantly (P<0.05) reduced ischemic lesion size and edema. Treatment with PROG significantly (P<0.05) decreased VEGF at 24 and 72 h but increased VEGF expression 14 days after injury. The treatment also increased BDNF, and attenuated apoptosis by increasing Akt phosphorylation compared with vehicle alone. The selective PI3K inhibitor wortmannin compromised PROG-induced neuroprotective effects and reduced the elevation of pAkt levels in the ischemic penumbra. Our findings lead us to suggest that the PI3K/Akt pathway can play a role in mediating the neuroprotective effects of PROG after stroke by altering the expression of trophic factors in the brain.
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, 1365 B Clifton Road, Suite 5100, Atlanta, GA 30322, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ishrat
authors.forename: I
authors.initials: I
authors.lastname: Sayeed
authors.forename: F
authors.initials: F
authors.lastname: Atif
authors.forename: F
authors.initials: F
authors.lastname: Hua
authors.forename: D G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D011374:Progesterone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt