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Spatiotemporal Neuroprotection and Early Regeneration after Ischemic Stroke with Neuregulin-1 Treatment


Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability. Unfortunately, Tissue Plasminogen Activator is the only FDA approved stroke treatment but does not address acute injury or cerebral recovery. Neuregulin-1 (NRG-1) has demonstrated promise as an acute neuroprotective, anti-inflammatory, and neuroregenerative agent in animal stroke models. In this dissertation, we examined the spatial cellular and inflammatory mechanisms occurring early after ischemic stroke and with NRG-1 treatment. Exogenous NRG-1 treatment administered to C57bl/6 male and female mice via intra-arterial or intravenous routes significantly reduced cerebral cortical infarct volume, inhibited neuronal injury, and reduced apoptosis at 24-hours after MCAO. Neuroprotection by endogenous NRG-1 was also seen as male and female heterozygous NRG-1 (NRG-1 +/-) knockout mice demonstrated a sixfold increase in cortical infarct size compared to wild-type mice. Immunohistochemistry and Nanostring Digital Spatial Profiling (DSP) were then utilized to characterize the spatial mechanisms occurring early after ischemia and determine if NRG-1 plays a therapeutic role in a similar spatial manner. Male C57bl/6 mice were given a photothrombotic MCAO and sacrificed at three-days post-ischemia. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. DSP defined the core border profile as inducing neuronal death, apoptosis, immunoreactivity, and early degenerative proteins. The peri-infarct induced astrocytic immunoreactivity, autophagy, and neurodegenerative proteins, while the peri-infarct normal tissue demonstrated minimal changes. These profiles were then analyzed after daily NRG-1 treatment beginning at 24-hours after ischemic onset. We found no difference in FJB, Iba-1, or GFAP expression between treatment groups. However, delayed daily NRG-1 treatment induced proteomic changes indicating restoration of autophagy and mitophagy within neurons and myeloid cells within the ischemic core border and peri-infarct regions as early as three days post-ischemia, suggesting neuronal resistance to apoptosis and priming for an anti-inflammatory and neuroregenerative niche. Therefore, we identify NRG-1 as a potent ischemic therapeutic capable of inducing immediate and late neuroprotection, early neuroregeneration, and extending the therapeutic treatment window.

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