Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen.
OBJECTIVE
A combined therapeutic approach has been advocated repeatedly for treatment of focal cerebral ischemia. A clinical example of combined therapy is administration of nimodipine, mannitol, dexamethasone, and barbiturates during temporary occlusion of a cerebral artery in neurovascular surgery. We have recently demonstrated outstanding neuroprotective properties of a combination therapy with magnesium (calcium antagonist and glutamate antagonist), tirilazad (antioxidant), and mild hypothermia (MTH). In this study we compared this treatment strategy with the customary treatment options in a rat model of transient focal cerebral ischemia.


METHODS
Sprague-Dawley rats (n=120) were subjected to 90 minutes of middle cerebral artery occlusion by an intraluminal filament (n=10 per group). In experiment 1, the customary treatment options (nimodipine, mannitol, dexamethasone, methohexital) were evaluated as monotherapy and in combination. In experiment 2, the customary and the new combination therapy (MTH) were compared. Mild hypothermia (33 degrees C) was maintained for 2 hours. Neurological examinations were performed daily. Infarct size was assessed histologically after 7 days.


RESULTS
In experiment 1, infarct volume was attenuated by 34% at maximum, with mannitol and methohexital being the most effective drugs given as monotherapy. In experiment 2, combined administration of the customary treatment options had no additive effect (infarct volume -36%). Combination therapy with MTH reduced total infarction by 73% and almost completely abolished cortical infarction (-91%). None of the animals of this group had any residual neurological deficit at the end of the observation period (P<0.05 versus all other groups).


CONCLUSIONS
The efficacy of drugs (monotherapy or in combination) most commonly used for neuroprotection during neurovascular surgery is limited. The newly proposed combination therapy (magnesium, tirilazad, and mild hypothermia), which is based on pathophysiological considerations, seems to be a promising alternative for neuroprotection in cerebrovascular surgery.
Department of Neurosurgery, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany. Stefan.Zausinger@nc.med.uni-muenchen.de
Stefan
S
Zausinger
Thomas
T
Westermaier
Nikolaus
N
Plesnila
Hans-Jakob
HJ
Steiger
Robert
R
Schmid-Elsaesser
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001783:Blood Flow Velocity / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007036:Hypothermia, Induced; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008274:Magnesium / Q000008:administration & dosage*; D008297:Male; D008353:Mannitol / Q000008:administration & dosage; D008723:Methohexital / Q000008:administration & dosage; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009553:Nimodipine / Q000008:administration & dosage; D011281:Pregnatrienes / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D000975:Antioxidants; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D011281:Pregnatrienes; D008353:Mannitol; D009553:Nimodipine; D003907:Dexamethasone; D008723:Methohexital; D008274:Magnesium; C053355:tirilazad