Gene therapy for neurovascular unit

Abstract

Gene transfer technique may be applicable to the treatment of serious types of brain infarction. Recently the neurovascular unit is proposed as an important target for brain infarction. Therefore, we examined usefulness of gene transfer approach for neurovascular protection in brain ischemia. Focal brain ischemia was produced by photothrombotic occlusion of the distal middle cerebral artery in spontaneously hypertensive rats. Candidate genes, such as midkine, dominant negative MCP-1, interleukin 10 or soluble Flt-1 (sFlt-1) were transferred using adenoviral vectors into the lateral ventricle 90 minutes after induction of ischemia. Marked expression of transgene was detected at the periventricular area from 6 hours to 7 days after gene transfer and ischemia. Postischemic gene transfer of midkine reduced infarct volume with marked attenuation of apoptosis. Overexpression of anti-inflammatory genes attenuated leukocytes and microglia/macrophages infiltrations with marked reduction of infarct volume. Gene transfer of sFlt-1 provided prominent reduction of blood brain barrier permeability that lead to reduction of brain edema and infarction. Postischemic gene transfer approach was useful for neurovascular protection, and the novel molecular approaches may have potentials for treatment of brain nfarction.