Recent Advances in Molecular Mechanism of Stroke Injury: Possibility of New Therapy

Stroke is one of the leading causes of death and disability worldwide. About 80% of cases of stroke are ischemic stroke caused by blood clots which cut off the supply of blood to the brain. For ischemic stroke thrombolysis is treatment but for effective treatment it must be done in less than three hours. Following ischemic stroke, levels of glutamate increase rapidly, leading to over-activation of N-methyl-D-aspartic acid receptors (NMDARs). This pathway is believed to be a major contributor to neuronal injury after ischemic stroke, NMDA receptor antagonists have not proved effective in reducing brain injury after stroke due to limitations like interference with the normal physiological functions of NMDARs and a narrow therapeutic window. Hence a need to look for new pathway. Recently one such pathway has been identified. Over-activation of NMDARs by glutamate has been found to activate sterol regulatory element binding protein-1 (SREBP-1), a transcription factor that regulates genes involved in lipid biosynthesis. Activation of SREBP-1 requires cleavage of an inactive  embranebound precursor protein by two dedicated proteases in the golgi apparatus. Under basal, unstimulated conditions, immature SREBPs form a stable complex with SREBP cleavage–activating protein (SCAP) and are retained in the endoplasmic reticulum (ER) by the interaction between SCAP and the ER membrane–resident protein, Insulin Inducing Gene-1 (Insig-1). Insig-1 is degraded by the proteasome after ubiquitination. Insig-1–derived interference peptide (Indip) is a synthesized product that competes for ubiquitination and has been found to block NMDA-induced degradation of Insig-1 and reduce neuronal cell death. This review will highlight the role of SREBP-1 in neuronal cell death after Ischemic stroke and agents that reduce SREBP-1 activation may be a new class of neuroprotective therapeutics against stroke.