Background and Purpose: Our previous work shows that middle aged female rats sustain larger strokes as compared to younger female rats. With age, circulating and brain parenchymal levels of IGF-1 are reduced. Exogenous IGF-1 treatment improves infarct volume in aging females. Our recent studies show that astrocytes from aging females synthesize less IGF-1. Here we tested the hypothesis that elevation of astrocyte derived IGF-1 would improve stroke impairment in older female rats.
Methods: Middle-aged (10-12 month old; acyclic) female rats were injected with adeno-associated virus serotype 5 (rAAV5) into the cortex and striatum. rAAV5 was packaged with the coding sequence of the IGF-1 gene downstream of an astrocyte-specific gene (GFAP). The construct contained the mCherry reporter gene. Control rAAV consisted of an identical shuttle vector construct without the IGF-1 gene. In separate experiments, two titers of virus were injected: high dose (5 X 1012 VP/mL) or low dose (5 X 1011 VP/mL). Three to four weeks after injection, middle-cerebral artery occlusion via an intraluminal suture for ninety minutes was performed followed by reperfusion. Post-surgery survival was monitored as well as sensory motor function using the vibrissae evoked forelimb placement task.
Results: Specificity of IGF-1 expression was confirmed by visualization of the mCherry reporter under fluorescent illumination and immunohistochemistry. Post stroke survival was improved in animals that received the high dose rAAV-IGF-1 animals a 5-day period (p<0.001). Low dose rAAV-IGF-1 did not affect post stroke survival, however sensory motor performance was preserved in this group. In low dose control animals, ischemic stroke impaired performance on the vibrissae evoked forelimb placement task. Impairment was seen in the same-side and cross-midline task performance on the limb contralateral to the infarct and cross midline task on the limb ipsilateral to the infarcted side (p<0.05). No significant deficits were seen in the rAAV-IGF-1 low dose treated animals.
Conclusion: These data support the hypothesis that increasing astrocytic IGF-1 in aging females improves post stroke survival and behavior outcomes.