Neuroprotection in ischemic stroke--combination drug therapy and mild hypothermia in a rat model of permanent focal cerebral ischemia.
We have recently demonstrated marked neuroprotective efficacy of a combination therapy with magnesium (calcium- and glutamate-antagonist), tirilazad (antioxidant) and mild hypothermia (MTH) in a rat model of transient focal cerebral ischemia. In the present study, we investigated MTH under conditions of permanent focal cerebral ischemia. In part I, 20 Sprague-Dawley rats were subjected to 6 h of permanent, laser-Doppler flowmetry (LDF) controlled middle cerebral artery occlusion (MCAO). Drugs were administered 30 min before and 1 h after MCAO. Hypothermia (33 degrees C) was maintained for 2 h. Infarct size was planimetrically determined after 6 h. In part II, 29 rats were assigned to the same treatment arms and subjected to 7 days of permanent MCAO. Neurological deficits and body weight were assessed daily. Infarct size was determined on day 7. In part I, MTH significantly reduced infarct formation by 52% after 6 h. In part II, high mortality within the first 3 days was observed in both groups. Treated animals showed a significantly better postoperative weight gain on day 7 and neurological recovery on days 6 and 7 compared to controls without significant differences in infarct volume. MTH seems to exert its neuroprotective properties even in a setting of permanent cerebral ischemia. High mortality and absence of infarct reduction after 7 days might be due to model limitations. Neurological recovery, the most important clinical outcome parameter, is significantly improved in 7-day survivors. Significant neuroprotection under conditions of permanent ischemia and former promising results in transient ischemia justify further investigations of MTH.
Schöller
Karsten
K
Department of Neurosurgery, Ludwig-Maximilians-Universität, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany. kschoell@nc.med.uni-muenchen.de
Zausinger
Stefan
S
Baethmann
Alexander
A
Schmid-Elsaesser
Robert
R
D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D001786:Blood Glucose / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007839:Functional Laterality / Q000502:physiology; D007035:Hypothermia / Q000209:etiology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
D001786:Blood Glucose