Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia.
OBJECTIVE
Hypothermia has been suggested to be the most potent therapeutic approach to reduce experimental ischemic brain injury identified to date, and mild hypothermia is increasingly used for neuroprotection during neurovascular surgery. We have recently demonstrated that combined administration of tirilazad mesylate and magnesium provides for an overall enhanced neuroprotective effect. The present study was designed to determine whether the efficacy of mild hypothermia (33 degrees C) can be increased by combination pharmacotherapy with tirilazad and magnesium (MgCl(2)).


METHODS
Forty Sprague-Dawley rats were subjected to transient, middle cerebral artery occlusion and were randomly assigned to 1 of 4 treatment arms (n=10 each): (1) normothermia+vehicle, (2) normothermia+tirilazad+MgCl(2), (3) hypothermia+vehicle, or (4) hypothermia+tirilazad+MgCl(2). Cortical blood flow was monitored by a bilateral laser-Doppler flowmeter, and the electroencephalogram was continuously recorded. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed after 7 days.


RESULTS
Tirilazad+MgCl(2), hypothermia, and hypothermia+tirilazad+MgCl(2) reduced total infarct volume by 56%, 63%, and 77%, respectively, relative to controls. In animals treated with both hypothermia and combination pharmacotherapy, cortical infarction was almost completely abolished (-99%), and infarct volume in the basal ganglia was significantly reduced by 55%. In addition, this treatment provided for the best electrophysiological recovery and functional outcome.


CONCLUSIONS
The neuroprotective efficacy of hypothermia can be increased by pharmacological antagonism of excitatory amino acids and free radicals by using clinically available drugs. This treatment strategy could be of great benefit when applied during temporary artery occlusion in cerebrovascular surgery.
Schmid-Elsaesser
R
R
Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany. schmid-elsaesser@nc.med.uni-muenchen.de
Hungerhuber
E
E
Zausinger
S
S
Baethmann
A
A
Reulen
H J
HJ
D000818:Animals; D001479:Basal Ganglia / Q000473:pathology; D002545:Brain Ischemia / Q000503:physiopathology / Q000628:therapy*; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D007036:Hypothermia, Induced; D017078:Laser-Doppler Flowmetry; D015636:Magnesium Chloride / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011281:Pregnatrienes / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain
D018696:Neuroprotective Agents; D011281:Pregnatrienes; D015636:Magnesium Chloride; C053355:tirilazad