Role of Steroid Therapy after Ischemic Stroke by N-Methyl-D-Aspartate Receptor Gene Regulation

Background: Stroke is the main cause of cerebrovascular disease mortality. Prolonged stimulation of N-methyl-D-aspartate (NMDA) receptor subtypes by the accumulation of glutamate neurotransmitter in the extracellular space after a stroke could activate cell death pathways. It is reported that progesterone provides different mechanisms of neuroprotection and could be considered as a candidate for stroke treatment. This study aimed to investigate progesterone impact on the expression of NMDA receptor subunits NR1, NR2(A and B), NR3 (A and B) after an experimental model of ischemic stroke which is followed by an in silico analysis. Methods: Progesterone was introduced subcutaneously after transient middle cerebral artery occlusion in male rats. After a period of reperfusion, a set of behavioral tests was performed to evaluate the postischemic neurological deficits. The 2,3,5-triphenyltetrazolium chloride staining method was done for quantification of infarct volume and gene expression analysis was performed in the penumbra region using reverse transcription polymerase chain reaction for NMDA receptor subunits. An AutoDock tool was employed to perform molecular docking analyses for evaluation of progesterone interaction with NMDA receptor. Results: Cerebral ischemia caused a significant downregulation in NR1, NR2A, NR2B and a profound upregulation of NR3B in cortical penumbraregion. Treatment with progesterone resu lted in upregulation of NR1, NR2A, and NR3B which could explain a possible the neuroprotection of steroids via binding to NMDA glutamate receptor. In addition, in silico analysis revealed that progesterone could strongly interact with NR1/NR2B and NR2A. Conclusion: The findings elucidate a new aspect of the neuroprotective mechanism of progesterone via NMDA receptors gene regulation. Keywords: Stroke NMDA receptor Progesterone Gene expressio