Date of Award
Ph.D. in Pharmaceutical Sciences
University of Mississippi
Strokes are a leading cause of mortality and disability worldwide; thus, there is a dire need for new, effective pharmacotherapeutics that can be administered to reduce the burden of disease post-insult. Clinical findings have shown that insulin-like growth factor-1 (IGF-1) levels and post-stroke functional outcomes exhibit a positive relationship. Importantly, the administration of exogenous IGF-1 in rodent models of ischemic stroke attenuates neurological damage and functional deficits following stroke. Ongoing stroke damage after the initial insult is primarily induced by increased extracellular glutamate causing substantial neuronal death, increased neuro-inflammation, and leading to greater tissue loss. Evidence from our laboratory has shown that reductions of the IGF-1 receptor (IGF-1R) in astrocytes reduces their ability to buffer excitotoxic levels of glutamate and a reduction in glutamate transporters and receptors. Based on this, we proposed that loss of astrocytic IGF-1 signaling could modulate the extent of stroke damage. Considering neurons also express the IGF-1R, it is likely that IGF-1 protects neurons by directly modulating the neurons. Our hypothesis is that the functional regulation of both neurons and astrocytes by IGF-1 is critical to minimize damage in ischemic stroke. To address this (Chapter 2), we first conducted in vitro experiments to determine if the inhibition of IGF-1R in astrocytes altered neuroprotection from glutamate-induced toxicity. Moreover, we utilized novel inducible astrocyte-specific or neuron-specific transgenic mouse models to reduce IGF-1R in specific cell populations in the adult brain and subjected them to stroke to assess immediate (3 hour) and longer term (3 days) post-stroke changes (Chapter 3). One to three months following knockout, mice were subjected to photothrombosis to induce ischemic stroke, and we subsequently analyzed the extent of tissue damage and sensorimotor dysfunction. Our central findings were that astrocyte and neuronal knockouts had reduced blood brain barrier permeability, increased microglial number, and altered biochemical profile within the infarct tissue. In addition, astrocyte knockouts exhibited a neuroprotective phenotype shown by a reduced infarct size in the days following stroke. Overall, our findings provide a foundation for the development of pharmacological interventions that can target astrocyte mechanisms of protection to combat stroke damage.
Hayes, Cellas A., "Cellular Mechanisms of IGF-1 Neuroprotection after Ischemic Stroke" (2022). Electronic Theses and Dissertations. 2435.