Premium
The Broad‐Spectrum Cation Channel Blocker Pinokalant (LOE 908 MS) Reduces Brain Infarct Volume in Rats: A Temperature‐Controlled Histological Study
Author(s) -
Christensen Thomas,
Wienrich Marion,
Ensinger Helmut A.,
Diemer Nils Henrik
Publication year - 2005
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2005.pto960407.x
Subject(s) - medicine , middle cerebral artery , penumbra , anesthesia , occlusion , blood pressure , ischemia , cardiology , infarction , myocardial infarction
Activation of cation channels conducting Ca 2+ , 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 mm 3 to 24.5±13.1 mm 3 (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 mm 3 (P<0.005).