title: Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat.
abstract: Cation channels conduct calcium, sodium, and potassium, cations that are likely deleterious in the evolution of focal ischemic injury. Diffusion-weighted magnetic resonance imaging (DWI) is a powerful tool for evaluation of acute cerebral ischemia. We studied the effects of a novel, broad-spectrum inhibitor of several cation channels, LOE 908 MS, on acute ischemic lesion development with DWI and on cerebral infarct size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem. Eighteen male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) and were randomly and blindly assigned to either LOE 908 MS (1 mg/kg bolus 30 min after MCAO and continuous i.v. infusion of 10 mg/kg for 4 h thereafter) or vehicle. Whole-brain DWI was done before initiation of treatment and repeated every 30 min for the next 3.5 h. The animals were reperfused in the magnetic resonance imaging (MRI) scanner 90 min after MCAO. At 24 h, the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal. Physiological parameters, body weight, and premature mortality (3 in the placebo group and 1 in the treated group) did not differ between the groups. No hypotension, abnormal behavior, or other adverse effects were seen. Pretreatment, the DWI-derived %HLV did not differ between the groups (19.8 +/- 6.2 in the control group and 17.9 +/- 7.9 in the treated group), whereas at 4 h after MCAO, it was significantly smaller in the treated group (21.8 +/- 15.4 vs 40.4 +/- 15.5, p = 0.03). Postmortem, TTC-derived %HLV was significantly attenuated in the LOE 908 MS group (21.3 +/- 11.9 vs 50.1 +/- 10.7, p = 0.0001) and the neurological scores at 24 h were significantly better among the treated rats (2.1 +/- 1.5 vs 4.0 +/- 1.0, p < 0.02). LOE 908 MS significantly improved neurological outcome and reduced infarct size without observable effects in rats as demonstrated in vivo by DWI and confirmed postmortem by TTC staining. Blocking several distinct cation channels by LOE 908 MS showed significant neuroprotection.
authors.affiliation: Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Tatlisumak
authors.forename: R A
authors.initials: RA
authors.lastname: Carano
authors.forename: K
authors.initials: K
authors.lastname: Takano
authors.forename: M R
authors.initials: MR
authors.lastname: Meiler
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.forename: C H
authors.initials: CH
authors.lastname: Sotak
authors.forename: U
authors.initials: U
authors.lastname: Pschorn
authors.forename: M
authors.initials: M
authors.lastname: Fisher
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000503:physiopathology*; D004058:Diffusion; D007089:Image Enhancement; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D007546:Isoquinolines / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology
chemical_list: D000081:Acetamides; D007546:Isoquinolines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C081356:LOE 908