Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia.
OBJECTIVE
Cell death after cerebral ischemia is mediated by release of excitatory amino acids, calcium influx into cells, and generation of free radicals. We examined the hypothesis that concurrent administration of tirilazad, a well-known antioxidant, and magnesium, an antagonist of calcium and excitatory amino acids, would result in a synergistic neuroprotective effect.


METHODS
Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and assigned to one of four treatment arms (n = 10 in each): 1) vehicle, 2) tirilazad, 3) MgCl2, or 4) tirilazad and MgCl2. Cortical blood flow was recorded using laser Doppler flowmetry. Functional deficits were quantified by performing daily neurological examinations. Infarct volume was assessed after 7 days.


RESULTS
There was no difference in cortical blood flow among groups. Animals that received tirilazad or MgCl2 monotherapy had significantly better neurological function compared with control animals only on postoperative Days 3 and 4, whereas animals treated with both drugs had significantly better neurological function than did control animals from postoperative Days 2 through 7. Magnesium reduced total infarct volume by 25% (nonsignificant), tirilazad by 48% (P<0.05), and combination therapy by 59% (P<0.05) compared with control data.


CONCLUSIONS
Combined therapy with antagonists of excitatory amino acids and free radicals provides better neuroprotection from the effects of transient focal ischemia than does therapy with either antagonist alone. In contrast to many experimental agents, tirilazad and magnesium offer the advantage of being licensed for clinical use. This drug combination could be of great benefit when administered before temporary artery occlusion in patients undergoing cerebrovascular surgery.
Schmid-Elsaesser
R
R
Department of Neurosurgery, Ludwig-Maximilians-Universität, Klinikum Grosshadern, Munich, Germany.
Zausinger
S
S
Hungerhuber
E
E
Baethmann
A
A
Reulen
H J
HJ
D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply; D002544:Cerebral Infarction / Q000473:pathology / Q000503:physiopathology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D015636:Magnesium Chloride / Q000494:pharmacology*; D008297:Male; D009460:Neurologic Examination / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D011281:Pregnatrienes; D015636:Magnesium Chloride; C053355:tirilazad