Inflammatory Response Following Hemorrhagic Stroke: The Role of Cytokines

Hemorrhagic stroke is a dangerous form of stroke resulting from the rupturing of weakened blood vessels, releasing blood that increases intracranial pressure and causes the death of surrounding tissue. Treatment options are improving but remain limited, as evidenced by this condition being characterized by high rates of mortality as well as long-term morbidity. Unregulated inflammatory responses that occur following injury may be partially to blame for these poor outcomes. In response to any injury, the immune system releases cytokines to recruit immune cell activation and promote inflammation. But after hemorrhagic stroke, whether aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH), the rapid increase in inflammation and an imbalance of inflammatory cytokines can lead to the development of secondary ischemic injury. Several animal models have been developed to investigate these forms of stroke, and despite their shortcomings, these models have been crudely applied for the study of neuroinflammation post-stroke. There is an imperative need to establish a clear and robust animal model that accurately represents the condition taking place in human patients. This dissertation work began with a systematic review of the literature to more clearly understand the work that has been done in this area. Next, the endovascular puncture model of aSAH was utilized in rats. Tissue samples were collected and compared to human blood and cerebrospinal fluid samples to assess for cytokine changes. Lastly, collagenase mouse models for ICH were utilized to understand the changes that take place in the TXNIP-NLRP3 inflammasome following stroke and the therapeutic effects of verapamil on inflammatory, functional, and behavioral outcomes. This dissertation work adds to the body of literature on the relationship between inflammation, cytokine release, and outcomes, which will ultimately allow for the development of improved treatment protocols