Neuroprotective Effects of Combination Therapy with Tirilazad and Magnesium in Rats Subjected to Reversible Focal Cerebral Ischemia

Neuroprotective Effects of Combination Therapy with Tirilazad and Magnesium in Rats Subjected to... AbstractOBJECTIVE: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 MgCI_> 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.CONCLUSION: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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Neuroprotective Effects of Combination Therapy with Tirilazad and Magnesium in Rats Subjected to Reversible Focal Cerebral Ischemia

Neuroprotective Effects of Combination Therapy with Tirilazad and Magnesium in Rats Subjected to Reversible Focal Cerebral Ischemia

Neuroprotective Effects of Combination Therapy with Tirilazad and Magnesium in Rats Subjected to Reversible Focal Cerebral Ischemia Robert Schmid-Elsaesser, M .D ., Stefan Zausinger, M .D ., Edwin Hungerhuber, Alexander Baethmann, M .D ., Ph.D., Hans-Juergen Reulen, M .D ., Ph.D. Department of Neurosurgery (RS-E, SZ, H-JR) and Institute for Surgical Research (EH, AB), Ludwig-M axim ilians-Universitat, Klinikum Grosshadern, M unich, G erm an y OBJECTIVE: Cell death after cerebral ischemia is mediated by release of excitatory amino acids, calcium influx into cells, and generation of free radicals. W e 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 neuropro­ tective 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) M gCl2, or 4) tirilazad and M gCl2. 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 MgCI_> 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 2 5 % (nonsignificant), tirilazad by 4 8 % (P < 0.05), and combination therapy by 5 9 % (P < 0.05) compared with control data. CONCLUSION: 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...
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Publisher
Oxford University Press
Copyright
© Published by Oxford University Press.
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1097/00006123-199901000-00100
Publisher site
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Abstract

AbstractOBJECTIVE: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 MgCI_> 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.CONCLUSION: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.

Journal

NeurosurgeryOxford University Press

Published: Jan 1, 1999

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