Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat

Autor: Michael R. Meiler, Kentaro Takano, Christopher H. Sotak, Richard A. D. Carano, Turgut Tatlisumak, Uwe Pschorn, Fuhai Li, Dietrich Arndts, Marc Fisher
Rok vydání: 2000
Předmět:
Zdroj: Journal of the neurological sciences. 178(2)
ISSN: 0022-510X
Popis: 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 iv 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.
Databáze: OpenAIRE
Externí odkaz: