siRNA mediated down-regulation of Sprouty2/4 diminishes ischemic brain injury

Abstract

Down-regulation of Sprouty proteins promotes axon regeneration in lesioned nerves and prevents neurodegeneration following excitotoxic brain injury. In this study, siRNAs directed against Sprouty2 and -4 were stereotactically injected along with the vasoconstrictive peptide endothelin-1 to create cortical infarcts in the adult rat brain. A single injection of Sprouty2/4 siRNAs (25μM each) significantly decreased Spry2 and Spry4 mRNA levels two days later and diminished the size of the injury area in the subchronic phase following vasoconstriction. Reducing Spry2/4 genetically in mice is neuroprotective and stimulates injury-induced astrogliosis which limits neuronal cell death and lesion size. The present results are consistent with the established functions of negative feedback inhibitors of receptor tyrosine kinase signaling pathways in neuronal survival and glial proliferation and suggest a novel role for Spry2/4 as possible pharmacological targets in stroke patients.

Keywords: Cortex; Endothelin; Gene silencing; Gliosis; Stroke; Vasoconstriction.