Commentary Cell Science Reviews Vol 6 No 3 ISSN 1742-8130

Neuroprotection against stroke-induced damage by transcriptional inhibition
of pathways controlling lipid metabolism

The N-methyl-D-aspartate type of glutamate receptors (NMDARs) plays fundamental roles in normal and pathological functioning of the CNS. Delayed neuronal death occurring in cerebrovascular and neurodegenerative diseases is mainly due to excitotoxicity induced by overstimulation of the NMDARs. Therapies currently available to treat these pathologies are not satisfactory and, therefore, it is a priority to identify new targets for therapeutic intervention. To this aim, we need a better understanding of the molecular and cellular mechanisms underlying the excitotoxic type of neuronal death and, particularly, those regulating the expression of proteins involved in survival or death pathways. A recent study in Nature Medicine is an important contribution to our knowledge on how gene transcription can be modified after ischemic stroke and contribute to neuronal death. They have demonstrated that activation of the sterol regulatory element binding protein-1 (SREBP-1) transcription factor is a novel NMDAR downstream signaling mechanism leading to excitotoxic neuronal death in both in vitro and in vivo models of stroke. The activation of SREBP-1 is a consequence of insulin-induced gene-1 (Insig-1) degradation, which can be prevented by an Insig-1-derived interference peptide (Indip). Using a model of focal ischemia, they show that systemic administration of this peptide prevents SREBP-1 activation and, more importantly, significantly reduces ischemia-induced neuronal damage and behavioral deficits. Their findings disclose Indip as a novel type of neuroprotective molecule against stroke, which might also have important implications for acute trauma and chronic neurodegenerative disorders.

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