Delayed cerebral ischemia is a major predictor of poor outcomes in patients who suffer subarachnoid hemorrhage. Treatment options are limited and often ineffective despite many years of investigation and clinical trials. Modern advances in basic science have produced a much more complex, multifactorial framework in which delayed cerebral ischemia is better understood and novel treatments can be developed. Leveraging this knowledge to improve outcomes, however, depends on a holistic understanding of the disease process. We conducted a review of the literature to analyze the current state of investigation into delayed cerebral ischemia with emphasis on the major themes that have emerged over the past decades. Specifically, we discuss microcirculatory dysfunction, glymphatic impairment, inflammation, and neuroelectric disruption as pathological factors in addition to the canonical focus on cerebral vasospasm. This review intends to give clinicians and researchers a summary of the foundations of delayed cerebral ischemia pathophysiology while also underscoring the interactions and interdependencies between pathological factors. Through this overview, we also highlight the advances in translational studies and potential future therapeutic opportunities.

Background: The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. Methods: We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. Results: NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. Conclusions: We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health of the gut microbiome plays a vital role in regulating the overall function and well-being of the individual. Microbes release short-chain fatty acids (SCFAs) that regulate G-protein-coupled receptors to mediate hormone release, neurotransmitter release (i.e., serotonin, dopamine, noradrenaline, γ-aminobutyric acid (GABA), acetylcholine, and histamine), and regulate inflammation and mood. Further gaseous factors (i.e., nitric oxide) are important in regulating inflammation and have a response in injury. Neurologic injuries such as ischemic stroke, spinal cord injury, traumatic brain injury, and hemorrhagic cerebrovascular lesions can all lead to gut dysbiosis. Additionally, unfavorable alterations in the composition of the microbiota may be associated with increased risk for these neurologic injuries due to increased proinflammatory molecules and clotting factors. Interventions such as probiotics, fecal microbiota transplantation, and oral SCFAs have been shown to stabilize and improve the composition of the microbiome. However, the effect this has on neurologic injury prevention and recovery has not been studied extensively. The purpose of this review is to elaborate on the complex relationship between the nervous system and the microbiome and to report how neurologic injury modulates the status of the microbiome. Finally, we will propose various interventions that may be beneficial in the recovery from neurologic injury.

Traumatic brain injury (TBI) is a devastating event with severe long-term complications. TBI and its sequelae are one of the leading causes of death and disability in those under 50 years old. The full extent of secondary brain injury is still being intensely investigated; however, it is now clear that neurotrauma can incite chronic neurodegenerative processes. Chronic traumatic encephalopathy, Parkinson’s disease, and many other neurodegenerative syndromes have all been associated with a history of traumatic brain injury. The complex nature of these pathologies can make clinical assessment, diagnosis, and treatment challenging. The goal of this review is to provide a concise appraisal of the literature with focus on emerging strategies to improve clinical outcomes. First, we review the pathways involved in the pathogenesis of neurotrauma-related neurodegeneration and discuss the clinical implications of this rapidly evolving field. Next, because clinical evaluation and neuroimaging are essential to the diagnosis and management of neurodegenerative diseases, we analyze the clinical investigations that are transforming these areas of research. Finally, we briefly review some of the preclinical therapies that have shown the most promise in improving outcomes after neurotrauma.