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
Objective To study the influence of progesterone (PROG) on infarct volume and functional outcome and to evaluate the therapeutic value of PROG on cerebral infarction in rats.Methods Health adult male Sprague-Dawley rats were randomly divided into sham-operated (control) group,ischemic group,vehicle-treated group and PROG-treated group.Permanent cerebral ischemia was induced by occlusion of the left middle cerebral artery (MCA) using an intraluminal filament technique.Sham-operated rats were subjected to the same surgical procedure,except that the filament was not advanced to occlude the MCA.Progesterone or 2-hydroxypropyl-β-cyclodextrin was injected intraperitoneally following permanent middle cerebral artery occlusion (PMCAO) of rats.Zea Longa test was used to evaluate their functional outcome at 1d,2d,3d after stroke.TTC staining was used to detect the infarct volume at 3d after stroke.Results The results of Zea Longa test showed that there were no functional deficits in all animals prior to ischemia.There were no significant changes in motor function in sham-operated animals across the 3 days assessment period.Both PROG and vehicle-treated rats experienced significant decline in scores following occlusion.However,PROG-treated rats (3.00 ± 0.63,2.83 ± 0.75,2.00 ± 0.89 )demonstrated a gradual improvement in scores compared with ischemic (4.00 ± 0.89,3.83 ± 0.75,3.16 ± 0.75 )and vehicle-treated rats ( 3.67 ± 1.21,3.50 ± 1.05,2.83 ± 0.76) at different times (P ＜ 0.05 ).TTC staining revealed that PROG administration significantly reduced the total infarct volume in the PROG-treated rats ( ( 15.03± 3.75) ％ ) compared with ischemic ( (23.74 ± 4.48 ) ％ ) and vehicle-treated rats ( ( 24.42 ± 7.07 ) ％,P ＜0.05).Conclusions PROG significantly reduces infarct volume and promotes the recovery of neurological functions after pMCAO,which has good therapeutic value for the rat model of cerebral infarction.