LOE 908 hydrochloride

The broad-spectrum cation channel blocker pinokalant (LOE 908 MS) reduces brain infarct volume in rats: a temperature-controlled histological study.[Pubmed:15755315]

Basic Clin Pharmacol Toxicol. 2005 Apr;96(4):316-24.

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).

Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat.[Pubmed:11018702]

J Neurol Sci. 2000 Sep 15;178(2):107-13.

Cation channels conduct calcium, sodium and potassium, cations that are likely deleterious in the evolution of focal ischemic injury. We studied the effects of a novel, broad-spectrum inhibitor of several cation channels, LOE 908 MS, on acute ischemic lesion development with diffusion-weighted magnetic resonance imaging (DWI) and on cerebral perfusion with perfusion imaging (PI) in vivo and on cerebral infarct size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem. A total of 18 male Sprague-Dawley rats underwent 90 min of middle cerebral artery occlusion (MCAO) and were randomly and blindly assigned to either LOE 908 MS or vehicle starting 30 min after inducing focal ischemia and continuing for 4 h. Whole-brain DWI and multislice PI were done before initiation of treatment and repeated frequently for the next 3.5 h. DWI-derived lesion volume at 4 h showed a significant difference in favor of the drug treated group (P=0.03), whereas PI-derived perfusion deficit volumes did not significantly differ between the groups. The postmortem infarct volume at 24 h was significantly attenuated in the treated group in comparison to controls (P=0.0001) and neurological score was significantly better in the treated group (P<0.02). Blocking several distinct cation channels with LOE 908 MS significantly reduced infarct size and improved neurological outcome without observable adverse effects in this focal ischemia model.

LOE 908 blocks delayed rectifier type potassium channels in PC12 cells and cortical neurons in culture.[Pubmed:9535721]

Biochem Biophys Res Commun. 1998 Mar 27;244(3):659-64.

The effects of (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2- phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908) were studied on K+ currents in undifferentiated cells from a phaeochromocytoma cell line (PC12), in cortical neurons from rat in primary culture, in a rat blood lymphoma cell line (RBL-1) and in a kidney cell line (BHK21). In PC12 cells delayed rectifier K+ currents measured in the whole-cell mode of the patch clamp technique were almost completely blocked by 10 microM LOE 908. The IC50 value was 0.7 microM and the Hill coefficient 0.8. After washout of the inhibitor about 80% of the current recovered. In rat cortical neurons in primary culture LOE 908 inhibited tetraethylammonium (TEA, 10 mM)-sensitive delayed rectifying K+ currents (LOE 908: 1 microM, 61 +/- 25% inhibition; 10 microM 103 +/- 19% inhibition). In contrast to the inhibitory action of LOE 908 on delayed rectifying K+ currents, Ca(2+)-activated potassium currents in BHK21 cells were only inhibited by 25 +/- 5% (10 microM LOE 908, n = 5) and no effect of LOE 908 was found on inward-rectifying K+ currents in RBL-1 cells. We conclude that LOE 908 is a K+ channel blocker with selectivity for delayed outward rectifying K+ channels.