The broad-spectrum cation channel blocker pinokalant (LOE 908 MS) reduces brain infarct volume in rats: a temperature-controlled histological study.
Activation of cation channels conducting Ca2+, Na+ and K+ is involved in the pathogenesis of infarction in experimental focal cerebral ischaemia. Pinokalant (LOE 908 MS) is a novel broad-spectrum inhibitor of several subtypes of such channels and has previously been shown to improve the metabolic and electrophysiologic status of the ischemic penumbra and to reduce lesion size on magnetic resonance images in the acute phase following middle cerebral artery occlusion in rats. The purpose of the present study was to investigate whether these beneficial effects of pinokalant are translated into permanent neuroprotection in terms of a reduction in infarct size one week after middle cerebral artery occlusion in rats. Halothane-anaesthetized male Wistar rats subjected to permanent distal middle cerebral artery occlusion were randomly assigned to one of two treatment groups: 1) Control (vehicle intravenous loading dose followed by infusion); 2) Pinokalant (0.5 mg/kg intravenous loading dose followed by infusion of 1.25 mg/kg/hr). Infusions started 30 min. after middle cerebral artery occlusion and were continued for 24 hr. Body temperature and mean arterial blood pressure were monitored by telemetry during this period and the spontaneous temperature after course in control rats established in other experiments was imitated. Seven days later histological brain sections were prepared and the infarct volumes measured. Body temperature did not differ between the groups. Mean arterial blood pressure was slightly higher in the pinokalant group. Pinokalant treatment significantly reduced cortical infarct volume from 33.8+/-15.8 mm3 to 24.5+/-13.1 mm3 (control group versus pinokalant group, P=0.017, t-test). Taking the effective drug plasma concentration established in other experiments into account revealed that in rats with plasma concentrations within the therapeutic interval, infarct volumes were further reduced to 17.9+/-7.5 mm3 (P<0.005).
Christensen
Thomas
T
Laboratory of Molecular Neuropathology, Institute of Molecular Pathology, University of Copenhagen, Denmark. tc@dadlnet.dk
Wienrich
Marion
M
Ensinger
Helmut A
HA
Diemer
Nils Henrik
NH
D000081:Acetamides / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology*; D020520:Brain Infarction / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D006416:Hematoxylin; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013534:Survival / Q000502:physiology
D000081:Acetamides; D007546:Isoquinolines; C081356:LOE 908; D006416:Hematoxylin