Injectable VEGF Hydrogels Produce Near Complete Neurological and Anatomical Protection following Cerebral Ischemia in Rats

Abstract

Vascular endothelial growth factor (VEGF) is a potent proangiogenic peptide and its administration has been considered as a potential neuroprotective strategy following cerebral stroke. Because VEGF has a short half-life and limited access to the brain parenchyma following systemic administration, approaches are being developed to deliver it directly to the site of infarction. In the present study, VEGF was incorporated into a sustained release hydrogel delivery system to examine its potential benefits in a rat model of cerebral ischemia. The hydrogel loaded with VEGF (1 μg) was stereotaxically injected into the striatum of adult rats 15 min prior to a 1-h occlusion of the middle cerebral artery. Two days after surgery, animals were tested for motor function using the elevated bias swing test (EBST) and Bederson neurological battery. Control animals received either stroke alone, stroke plus injections of a blank gel, or a single bolus injection of VEGF (1 μg). Behavioral testing confirmed that the MCA occlusion resulted in significant deficits in the the EBST and Bederson tests. In contrast, the performance of animals receiving VEGF gels was significantly improved relative to controls, with only modest impairments observed. Cerebral infarction analyzed using 2,3,5-triphenyl-tetrazolium chloride staining confirmed that the VEGF gels significantly and potently reduced the lesion volume. No neurological or histological benefits were conferred by either blank gel or bolus VEGF injections. These data demonstrate that VEGF, delivered from a hydrogel directly to the brain, can induce significant functional and structural protection from ischemic damage in a rat model of stroke.