REVIEW ARTICLE The interplay of microRNAs and post-ischemic glutamate excitotoxicity: an emergent research field in stroke medicine Alireza Majdi 1 • Javad Mahmoudi 1 • Saeed Sadigh-Eteghad 1 • Mehdi Farhoudi 1 • Siamak Sandoghchian Shotorbani 2 Received: 6 March 2016 / Accepted: 20 June 2016 Ó Springer-Verlag Italia 2016 Abstract Stroke is the second leading cause of death and the most common cause of adult disabilities among elder- lies. It involves a complex series of mechanisms among which, excitotoxicity is of great importance. Also, miRNAs appear to play role in post-stroke excitotoxicity, and changes in their transcriptome occur right after cerebral ischemia. Recent data indicate that specific miRNAs such as miRNA-223, miRNA-181, miRNA-125a, miRNA-125b, miRNA-1000, miRNA-132 and miRNA-124a regulate glutamate neurotransmission and excitotoxicity during stroke. However, limitations such as poor in vivo stability, side effects and inappropriate biodistribution in miRNA- based therapies still exist and should be overcome before clinical application. Thence, investigation of the effect of application of these miRNAs after the onset of ischemia is a pivotal step for manipulating these miRNAs in clinical use. Given this, present review concentrates on miRNAs roles in post-ischemic stroke excitotoxicity. Keywords Ischemic stroke  Glutamate excitotoxicity  MicroRNA  NMDA receptors  AMPA receptors Introduction Stroke is the second leading cause of death, the second most common cause of dementia and the most common cause of adult disabilities among elderlies [1–3]. Globally, it is responsible for nearly 5.5 million deaths every year, with 44 million disability-adjusted life-years lost which will increase up to 61 million in 2020 [2, 4]. Of this, ischemic stroke accounts for approximately 73 to 86 %, whereas hemorrhagic stroke is responsible for 8 to 18 % of the cases [5]. Brain ischemia initiates a cascade of pathological events that finally lead to irreversible neuronal damage [6]. It involves a complex series of biological and molecular mechanisms such as excitotoxicity, oxidative stress, inflammation, ionic imbalance, blood–brain barrier dis- ruption and apoptosis [7, 8]. Among these mechanisms, excitotoxicity is notable. It is mainly a glutamate-mediated specific type of neurotoxicity and is the overlooked link between ischemic stroke and neuronal damage and cell death [9]. It stems from excessive accumulation of exci- tatory amino acids such as glutamate and leads to toxic increases in intracellular calcium [7, 10] which mediates neuronal damage in stroke [11]. miRNAs are small (*19 to 23 nucleotides) noncoding endogenous molecules that bind messenger RNAs (mRNA) and promote their degradation or repression of translation [12]. They have been found to be responsible for neuronal differentiation and development [6] and their role as mediators of silencing of post-transcriptional gene in pathological aspects of ischemic stroke has been proved [13]. Changes in the microRNAs (miRNA) transcriptome occur right after focal cerebral ischemia which indicates miRNAs role in the pathological cascades of ischemic stroke [13–15]. Alteration in miRNAs level after brain ischemic injury was first noticed in focal brain and fore- brain ischemia and recent studies have assessed the sig- nificance of local changes in miRNA expression level [12, 16]. Furthermore, microRNAs aberrant, both up and down, regulation has been reported during cerebral & Javad Mahmoudi javadmahmoudi1992@yahoo.com 1 Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, P.O. Box: 5166614756, Tabriz, Iran 2 Department of Immunology, Tabriz Branch, Islamic Azad University, Tabriz, Iran 123 Neurol Sci DOI 10.1007/s10072-016-2643-5