ABSTRACT
Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.
ABSTRACT
The purpose of this study was to determine the effect of reperfusion about infarct size and infarct expansion by different duration of ischemic time. Temporary coronary ligation was performed in rats for 30min, 60min, 90min and 120min, followed by reflow. Rats with permanent ligation were used for comparison. After 7 days, transverse histologic heart sections were prepared for structual analysis. The results were as follows ; 1) Reperfusion after 30 min ischemic time 1.Infarct size of reperfusion (method 1 ; 16.5+/-8.3%, method 2 ; 20.9+/-8.0%) was smaller than that of permanent ligation (method 1 ; 29.8+/-8.9%, method 2 ; 33.5+/-12.1%)(p<0.01, p<0.05). 2. Expansion index of reperfusion (46.9+/-19.6) was smaller than that of permanent ligation (88.0+/-34.9)(p<0.01). 3. The infarct thickness of reperfusion (1.59+/-0.40mm) was larger than that of permanent ligation (1.10+/-0.21mm)(p<0.01). 4.The viable left ventricular tissue area of reperfusion (28.8+/-2.90mm2) was larger than that of permanent ligation (24.2+/-3.10mm2)(p<0.01). 2) Reperfusion after 60 min ischemic time 1. There was no difference in infarct size between reperfusion and permanent ligation. 2. Expansion ratio (27.2+/-5.9%) and expansion index (51.8+/-24.6) of reperfusion were smaller than those of peremanent ligation (35.7+/-7.4%, 88.0+/-34.9)(p<0.05, P<0.05). 3. The infarct thickness of reperfusion (1.48+/-0.32mm) was larger than that of permanent ligation (1.10+/-0.21mm)(p<0.01). 3) Reperfusion after 90~120 min ischemic time reduced neither infarct size nor infarct expansion. The results of this study in the rat preparation suggest a beneficial effect of reperfusion even in late on infarct expansion independent of myocardial salvage.