title: Allopregnanolone and its precursor progesterone do not reduce injury after experimental stroke in hypertensive rats - role of postoperative temperature regulation?
abstract: Allopregnanolone is a neurosteroid synthesized from progesterone in brain. It increases inhibition through modulation of the gamma-aminobutyric acid type A (GABA-A) receptor. Both agents are putative neuroprotectants after ischemic stroke. We sought to confirm their effectiveness in a hypertensive rat stroke model, with intra- and post-operative temperature regulation. The primary study compared allopregnanolone, progesterone or vehicle control treatments, administered 105 minutes after induction of temporary middle cerebral artery occlusion in spontaneously hypertensive rats. Temperature was controlled intraoperatively and a heat mat used in the 6 hours postoperatively to permit animal temperature self-regulation. The primary outcome was infarct volume and secondary outcomes were tests of sensory and motor function. There was no significant effect of treatment on any outcome measure. Given prior reports of GABA-A receptor agonists causing hypothermia, follow-up experiments were conducted to examine postoperative temperature regulation. These did not reveal a difference in postoperative temperature in neurosteroid-treated animals compared to control. However, in all rats maintained postoperatively in ambient temperature, moderate hypothermia was observed. This was in contrast to rats maintained over a heat mat. The lowest mean postoperative temperature was between 34.4-34.9°C in all 3 groups. These data do not support a neuroprotective effect of allopregnanolone or progesterone in ischemic stroke in hypertensives in the setting of normothermia. Given previous evidence of synergy between neuroprotective agents and hypothermia, demonstration of neuroprotective effect of these agents in the absence of postoperative hypothermia would be prudent before consideration of these agents for further clinical investigation.
authors.affiliation: School of Biomedical Sciences, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia; Hunter New England Local Health District, Newcastle, Australia.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Spratt
authors.affiliation: School of Biomedical Sciences, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tomkins
authors.affiliation: School of Biomedical Sciences, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Debbie
authors.initials: D
authors.lastname: Pepperall
authors.affiliation: School of Biomedical Sciences, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Damian D
authors.initials: DD
authors.lastname: McLeod
authors.affiliation: School of Biomedical Sciences, University of Newcastle, and Hunter Medical Research Institute, Newcastle, Australia; School of Medicine, The University of Tasmania, Hobart, Australia.
authors.forename: Mike B
authors.initials: MB
authors.lastname: Calford
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011184:Postoperative Period; D011280:Pregnanolone / Q000008:administration & dosage*; D011374:Progesterone / Q000008:administration & dosage*; D051381:Rats; D011918:Rats, Inbred SHR; D013696:Temperature
chemical_list: D018696:Neuroprotective Agents; D011374:Progesterone; D011280:Pregnanolone