Ischemic brain damage: reduction by sodium-calcium ion channel modulator RS-87476.
A novel sodium-calcium ion channel modulator, RS-87476, reduced cerebral infarct size in cats subjected to permanent unilateral occlusion of the middle cerebral artery. Cerebral injury was assessed in vivo with a combination of magnetic resonance (MR) imaging and spectroscopy for 5-12 hours after occlusion and was compared with the area of histochemically ischemic brain tissue. Compared with infarcts in placebo-treated animals, infarcts in cats given RS-87476 were reduced by an average of 70% at the lowest dose, 75% at the intermediate dose, and 88% at the highest dose. Tissue edema, observed as areas of signal hyperintensity on diffusion- and T2-weighted spin-echo images, was confined to small regions of the parietal cortex and basal ganglia in drug-treated animals. Mean plasma levels of RS-87476 at the lowest dose were 13 ng/mL initially, falling to maintenance levels of 3-5 ng/mL; at the intermediate and highest doses, plasma levels of drug were approximately five- and 20-fold greater. The drug was only slightly hypotensive. At least part of the potent cerebroprotective effects of RS-87476 result from its ability to stabilize metabolic energy reserves, reduce lactate formation in ischemic tissues, and attenuate intracerebral edema.
Kucharczyk
J
J
Department of Radiology, University of California, San Francisco, School of Medicine 94143.
Mintorovitch
J
J
Moseley
M E
ME
Asgari
H S
HS
Sevick
R J
RJ
Derugin
N
N
Norman
D
D
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002415:Cats; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D007093:Imidazoles; D010879:Piperazines; C067927:lifarizine