Journal of the Neurological Sciences 178 (2000) 107–113 www.elsevier.com / locate / jns Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat a,b, c,d b c b * Turgut Tatlisumak , Richard A.D. Carano , Kentaro Takano , Michael R. Meiler , Fuhai Li , c e f b Christopher H. Sotak , Dietrich Arndts , Uwe Pschorn , Marc Fisher a Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland b Departments of Neurology, UMass Memorial Health Care and University of Massachusetts Medical Center, Worcester, MA, USA c Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA d Synarc Inc., San Francisco, CA, USA e Department of CNS Research, Boehringer Ingelheim Pharma KG, Ingelheim am Rhein, Germany f Corporate Pharma-Research, Development and Medicine Division, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany Received 7 February 2000; received in revised form 14 June 2000; accepted 11 July 2000 Abstract 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 ( P50.03), 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 ( P50.0001) 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.  2000 Elsevier Science B.V. All rights reserved. Keywords: Calcium; Cerebral infarction; Cerebral ischemia, focal; Magnetic resonance imaging; Neuroprotection; Perfusion; Rats 1. Introduction Abbreviations: ADC, apparent diffusion coefficient; ADC , average av Focal brain ischemia is associated with cell membrane apparent diffusion coefficient; AMPA, a-amino-3-hydroxy-5-methyl-4- depolarization and a massive increase of extracellular 21 isoxazolepropionate; ANOVA, analysis of variance; Ca , calcium; CBF , i excitatory amino acids, glutamate and aspartate [1]. This cerebral blood flow index; DWI, diffusion-weighted magnetic resonance 21 leads to an excessive influx of calcium (Ca ), sodium imaging; i.v., intravenous; MCAO, middle cerebral artery occlusion; 1 1 MRI, magnetic resonance imaging; Na , sodium; NMDA, N-methyl-D- (Na ), chloride, and water into the neurons and an efflux 1 1 aspartate; K , potassium; %HLV, percent hemispheric lesion volume; PI, of potassium (K ) into the extracellular space, a process perfusion imaging; SOC, store-operated calcium channel; TTC, 2,3,5- involving several distinct membrane channels [1–3]. triphenyltetrazolium chloride; VOC, voltage-operated calcium channel 21 Among these ion changes, the massive influx of Ca is *Corresponding author. Tel.: 1358-9-4719-51616, fax: 1358-9-4717- detrimental and in part responsible for neuronal death 4009. E-mail address: turgut.tatlisumak@hus.fi (T. Tatlisumak). [3,4]. 0022-510X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0022-510X(00)00380-4