IGF-1-Mediated Reinforcement of the Blood Brain Barrier During Ischemia-Reperfusion in Middle-Aged Female Rats
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Nearly three quarters of all strokes occur in people over 65, and within this older group, strokes are more common and more severe in women than men. Added to this disease burden, is the lack of suitable therapies for stroke patients. My research focused on identifying a stroke therapy that is effective for older female stroke patients. Middle-aged female rats were used as a model system to understand disparities in stroke outcomes in middle-aged postmenopausal women. Our laboratory has shown previously that post-stroke Insulin like growth factor (IGF)-I treatment reduces blood brain barrier permeability and decreases infarct volumes in middle aged female rats. In three major experiments, this dissertation tested the hypothesis that IGF-1 acts on the endothelium to reduce neuroinflammation and improve recovery. Through Experiment 1, we found that IGF-1 treatment provided by intracerebroventricular injection, decreased extravasation of CD4+ cells into the ischemic hemisphere. Similarly, IGF-1 reduced protein transfer across a monolayer of brain microvessel endothelial cells derived from middle aged females, further implicating this cell type as the locus of IGF-1 action. Experiment 2 showed that IGF-1 stabilized the actin cytoskeleleton and adhesion of endothelial cells exposed to OGD and preserved microvessel diameter and length in vivo after stroke. Both in vivo and in vitro, IGF-1’s effects were reversed with concurrent exposure to the IGFR antagonist JB-1. Additionally, while IGF-1 treatment improved microvessel morphology in early acute phase of stroke, sensory-motor behavior was improved during both the early and late acute phase of stroke. Experiment 3 tested the novel hypothesis that IGF-1 secreted by astrocytes is neuroprotective. With age, astrocyte derived IGF-1 decreases, and by using IGF-1 gene transfer targeted to astrocytes, we found reduced stroke-induced sensory motor impairment and decreased blood brain barrier permeability, without affecting infarct volumes. Collectively, these data support and suggest that the aging endothelium and astrocyte interaction may be critical for post stroke recovery.
Johnson, Andre (2019). IGF-1-Mediated Reinforcement of the Blood Brain Barrier During Ischemia-Reperfusion in Middle-Aged Female Rats. Doctoral dissertation, Texas A&M University. Available electronically from