PMID- 22450229 OWN - NLM STAT- MEDLINE DCOM- 20120921 LR - 20211021 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 210 DP - 2012 May 17 TI - Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway. PG - 442-50 LID - 10.1016/j.neuroscience.2012.03.008 [doi] AB - 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. CI - Copyright (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Ishrat, T AU - Ishrat T AD - Department of Emergency Medicine, Emory University School of Medicine, 1365 B Clifton Road, Suite 5100, Atlanta, GA 30322, USA. FAU - Sayeed, I AU - Sayeed I FAU - Atif, F AU - Atif F FAU - Hua, F AU - Hua F FAU - Stein, D G AU - Stein DG LA - eng GR - R01 HD061971/HD/NICHD NIH HHS/United States GR - U01 NS062676/NS/NINDS NIH HHS/United States GR - U01 NSO 62676/PHS HHS/United States GR - 5R01HD61971/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120316 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Neuroprotective Agents) RN - 4G7DS2Q64Y (Progesterone) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Blotting, Western MH - Brain/*drug effects/metabolism MH - Brain Injuries/drug therapy/metabolism MH - Brain Ischemia/drug therapy/*metabolism MH - Immunohistochemistry MH - In Situ Nick-End Labeling MH - Male MH - Neuroprotective Agents/*pharmacology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Progesterone/*pharmacology MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects PMC - PMC3358507 MID - NIHMS368929 COIS- DISCLOSURE/CONFLICT OF INTEREST DGS is entitled to royalty payment (~6.5%) from BHR Pharmaceuticals related to research on progesterone and brain injury. His future financial interests may be affected by the outcome of this research. The terms of this arrangement have been reviewed and approved by Emory University, which receives the largest share of any benefits (~60.0%) in accordance with its conflict of interest policies. The abstract was presented at the AHA/ASA International Stroke Conference, February 9-11, 2011, Los Angeles, CA. EDAT- 2012/03/28 06:00 MHDA- 2012/09/22 06:00 PMCR- 2013/05/17 CRDT- 2012/03/28 06:00 PHST- 2011/06/03 00:00 [received] PHST- 2012/02/20 00:00 [revised] PHST- 2012/03/07 00:00 [accepted] PHST- 2012/03/28 06:00 [entrez] PHST- 2012/03/28 06:00 [pubmed] PHST- 2012/09/22 06:00 [medline] PHST- 2013/05/17 00:00 [pmc-release] AID - S0306-4522(12)00220-5 [pii] AID - 10.1016/j.neuroscience.2012.03.008 [doi] PST - ppublish SO - Neuroscience. 2012 May 17;210:442-50. doi: 10.1016/j.neuroscience.2012.03.008. Epub 2012 Mar 16.