Progesterone in transient ischemic stroke: a dose-response study

• Type of Material: Article
• Authors: Seema Yousuf, Emory University; Fahim Atif, Emory University; Iqbal Sayeed, Emory University; Huiling Tang, Emory University; DONALD STEIN, Emory University
• Language: English
• Date: 2014-09-01
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Springer-Verlag.
• Final Published Version (URL): http://dx.doi.org/10.1007/s00213-014-3556-8
• Title of Journal or Parent Work: Psychopharmacology
• ISSN: 0033-3158
• Volume: 231
• Issue: 17
• Start Page: 3313
• End Page: 3323
• Grant/Funding Information: search was supported by a NIH award U01 NS062676, BHR Pharma, and Allen and Company.
• Keywords: BEHAVIORAL-ASSESSMENT; FUNCTIONAL RECOVERY; Life Sciences & Biomedicine; Stroke; Neurosciences & Neurology; MICE; INTRACEREBRAL HEMORRHAGE; Functional outcomes; Progesterone; OUTCOMES; Infarct; Science & Technology; RATS; Pharmacology & Pharmacy; Dose response; DAMAGE; CEREBRAL-ARTERY OCCLUSION; Neurosciences; NEUROPROTECTION; TRAUMATIC BRAIN-INJURY; Psychiatry
• Research Categories: Health Sciences, Epidemiology; Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

Rationale: Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose-response study in a transient ischemic stroke model is lacking. Objectives: We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats. Methods: Cerebral ischemia was induced in 13-month-old male Sprague-Dawley rats by right middle cerebral artery occlusion for 2 h followed by reperfusion. Rats received intraperitoneal injections of 8, 16, or 32 mg/kg of progesterone (P8, P16, P32) or vehicle at 2 h post-occlusion followed by subcutaneous injections at 6 h and every 24 h post-injury for 7 days. Functional recovery was evaluated at intervals over 22 days using motor, sensory, and cognitive tests. Infarct size was evaluated at 22 days post-stroke. Results: Repeated-measures ANOVA showed significant group effects on grip strength, rotarod, and sensory neglect. All progesterone-treated groups had improved (p < 0.05) spatial memory performance. The P8 and P16 groups showed maximum improvement in long-term memory compared to vehicle. Significant (p < 0.05) gait impairments were observed in the vehicle group compared to shams. Animals receiving the P8 dose showed maximum gait improvement compared to vehicle. Post hoc analysis revealed that the P8 and P16 groups showed significant attenuation in infarct volume compared to vehicle. Animals receiving the P32 dose did not show any effect on infarct volume. Conclusions: Although all doses were somewhat effective, progesterone given at 8 mg/kg led to the most consistent improvements across a panel of behavioral/functional tests and reduced the severity of ischemic infarct injury.