Improved therapeutic window for treatment of histotoxic hypoxia with a free radical spin trap.
The therapeutic time window for N-methyl-D-aspartate (NMDA) antagonists, non-NMDA antagonists, and glutamate release inhibitors in focal models of ischemia appears to be about 1-2 h. In contrast, a free radical spin trap was found to have an improved therapeutic window. We compared the therapeutic time windows of the NMDA antagonist dizolcilpine maleate (MK-801), the glutamate release inhibitor lamotrigine, and the free radical spin trap n-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) against striatal lesions produced by the mitochondrial toxin malonate, which produces histotoxic hypoxia. Lamotrigine exerted neuroprotective effects when administered at 1 h before malonate injections. MK-801 protected at 1 h before and 1 h after malonate injections, whereas S-PBN showed efficacy when administered up to 6 h after malonate injections. Striatal injections of malonate produced a rapid increase in lactate production and early changes in diffusion-weighted imaging as assessed by magnetic resonance imaging. Therefore, the time course to evolve a lesion in our model of histotoxic hypoxia is comparable with that of other models of focal ischemia. These findings provide direct evidence that a free radical spin trap has an improved therapeutic window compared to an NMDA antagonist and a glutamate release inhibitor. This could be a therapeutic advantage in the treatment of clinical stroke patients.
Schulz
J B
JB
Neurochemistry Laboratory, Massachusetts General Hospital, Boston, USA.
Matthews
R T
RT
Jenkins
B G
BG
Brar
P
P
Beal
M F
MF
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism* / Q000628:therapy*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D000077213:Lamotrigine; D008279:Magnetic Resonance Imaging; D008297:Male; D008314:Malonates / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019097:Spin Trapping; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology
D001557:Benzenesulfonates; D005609:Free Radicals; D008314:Malonates; D014227:Triazines; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; D016291:Dizocilpine Maleate; C030290:malonic acid; D010100:Oxygen; D000077213:Lamotrigine