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Preclinical and Clinical Stroke - A Bidirectional Approach between Insult and Intervention

  • Author(s): Laiwalla, Azim
  • Advisor(s): Gonzalez, Nestor R
  • et al.
Abstract

Two interventions for the treatment and prevention of ischemic stroke are investigated. Remote ischemic conditioning (RIC) holds significant potential for the prevention of delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage (aSAH). Using a matched cohort analysis, lower-limb RIC demonstrated a positive effect on the functional outcomes of patients with aSAH. Differential expression and methylation analysis following RIC in aSAH patients identified genes enriched for cell cycle and inflammatory responses, potential biomarkers for the determination of an effective RIC dose. A reliable, minimally invasive rat model of SAH and vasospasm has been developed, allowing for the study of neuroprotective treatments without the confounding effects of invasive surgery.

Encephaloduroarteriosynangiosis (EDAS) for patients with intracranial atherosclerosis (IAS) also has great potential as a treatment for ischemic stroke. Patients with IAS are particularly susceptible to intraoperative variations in cerebral perfusion. The strict anesthesia protocol established for EDAS procedures was effective in reducing the intraoperative variability of targeted physiological parameters, while achieving established hemodynamic goals. Investigation into the perfusion profile following EDAS in IAS patients demonstrated a shift of the perfusion profile in the surgical site towards an increased probability of arterial components, with decreased postsurgical neurological events. A reliable mouse model of ischemic stroke and EDAS has been developed, allowing for the study of neovascularization following ischemic infarction and for therapies to enhance perfusion.

Differences in brain structure, including white matter, must be considered to achieve a model of ischemic stroke and maximize translational benefits. A minimally invasive endovascular canine model of ischemic stroke was developed, allowing visualization of the cerebrovasculature, and producing infarcts consistent with invasive models. The higher proportion of white matter in canine brain allows for the hyperacute detection of ischemic white matter changes by clinical MR imaging and its correlation to immunohistochemical changes. As early as four hours after insult, imaging shows extraaxonal edema of white fiber tracts, and immunohistochemistry studies demonstrate changes to oligodendroctyes. A direct link between the preclinical model and clinical state, with consideration for the therapeutic interventions of RIC and EDAS, disease state, and outcomes measured will maximize translational success.

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