title: Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke.
abstract: Recent studies have uncovered that accumulation of glutamate after ischaemic stroke is closely associated with the down-regulation of glutamate transporter-1 (GLT-1) expression, suggesting that GLT-1 expression critically controls glutamate accumulation and the abnormal glutamate transport-elicited neuronal cell excitotoxicity in patients with ischaemic stroke. However, it remains unknown how GLT-1 expression is regulated under ischaemic stroke conditions. In the present study, we screened the expression of nine brain-specific or brain-enriched miRNAs in a focal cerebral ischaemia/reperfusion (I/R) injury rat model, which showed glutamate accumulation and down-regulated GLT-1 expression as expected, and revealed that the miR-107 level was elevated in both brain tissue and plasma in the model. Next, we examined the functional relationship of miR-107 with GLT-1 expression in a nerve cell hypoxia/reoxygenation (H/R) injury model. H/R treatment increased apoptosis of the nerve cells concomitant with glutamate accumulation, miR-107 elevation and suppressed GLT-1 expression, mimicking our in vivo findings in the cerebral I/R injury rat model in vitro. Co-treating the cells with an miR-107 inhibitor blocked all of the effects, demonstrating that miR-107 functions to inhibit GLT-1 expression and elevate glutamate accumulation. To extend these animal and cell-based studies to clinical patients, we measured the plasma levels of miR-107 and glutamate, and observed that both miR-107 and glutamate were elevated in patients with ischaemic stroke. On the basis of these observations, we conclude that elevated miR-107 expression after ischaemic stroke accounts, at least partially, for glutamate accumulation through suppression of GLT-1 expression. Our findings also highlight that the plasma level of miR-107 may serve as a novel biomarker for monitoring excitotoxicity in patients with ischaemic stroke.
authors.affiliation: *Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Zhong-Bao
authors.initials: ZB
authors.lastname: Yang
authors.affiliation: †Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: *Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Ting-Bo
authors.initials: TB
authors.lastname: Li
authors.affiliation: *Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Lou
authors.affiliation: †Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Li
authors.affiliation: †Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: †Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Xiu-Ju
authors.initials: XJ
authors.lastname: Luo
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D015536:Down-Regulation; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D034622:RNA Interference; D016372:RNA, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C549045:MIRN107 microRNA, human; C579315:MIRN107 microRNA, rat; D035683:MicroRNAs; D016372:RNA, Antisense; D018698:Glutamic Acid