Senescence and SASP Are Potential Therapeutic Targets for Ischemic Stroke.

Aging is a known co-morbidity of ischemic stroke with its risk and severity increasing every year past 55+. While many of the current stroke therapies have shown success in reducing mortality, post-stroke morbidity has not seen the same substantial reduction. Recently, the involvement of cellular senescence and SASP in brain injury and neurological degeneration has been recognized. Ischemic injury causes oxidative stress and mitochondrial damage that induces senescence through the activation of p21 and p16 pathways, ultimately leading to synthesis and release of senescence-associated secretory phenotype (SASP). This ischemic event causes stress-induced premature senescence (SIPS), aging the brain decades beyond the standard biological age due to an increase in senescent cells in the ischemic core and ipsilateral hemisphere. Therefore, therapies that target the senescent cells and SASP, including senolytics, senomorphic drugs, stem cell therapies, and other cell-specific interventions, may be a new path for stroke treatment.

VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases.

Therapeutic angiogenesis has long been considered a viable treatment for vasculature disruptions, including cerebral vasculature diseases. One widely-discussed treatment method to increase angiogenesis is vascular endothelial growth factor (VEGF) A. In animal models, treatment with VEGFA proved beneficial, resulting in increased angiogenesis, increased neuronal density, and improved outcome. However, VEGFA administration in clinical trials has thus far failed to replicate the promising results seen in animal models. The lack of beneficial effects in humans and the difficulty in medicinal translation may be due in part to administration methods and VEGFA's ability to increase vascular permeability. One solution to mitigate the side effects of VEGFA may be found in the VEGFA isoforms. VEGFA is able to produce several different isoforms through alternative splicing. Each VEGFA isoform interacts differently with both the cellular components and the VEGF receptors. Because of the different biological effects elicited, VEGFA isoforms may hold promise as a tangible potential therapeutic for cerebrovascular diseases.

The Potential Role of Integrin Signaling in Memory and Cognitive Impairment.

Dementia currently has no cure and, due to the increased prevalence and associated economic and personal burden of this condition, current research efforts for the development of potential therapies have intensified. Recently, targeting integrins as a strategy to ameliorate dementia and other forms of cognitive impairment has begun to gain traction. Integrins are major bidirectional signaling receptors in mammalian cells, mediating various physiological processes such as cell-cell interaction and cell adhesion, and are also known to bind to the extracellular matrix. In particular, integrins play a critical role in the synaptic transmission of signals, hence their potential contribution to memory formation and significance in cognitive impairment. In this review, we describe the physiological roles that integrins play in the blood-brain barrier (BBB) and in the formation of memories. We also provide a clear overview of how integrins are implicated in BBB disruption following cerebral pathology. Given that vascular contributions to cognitive impairment and dementia and Alzheimer's' disease are prominent forms of dementia that involve BBB disruption, as well as chronic inflammation, we present current approaches shown to improve dementia-like conditions with integrins as a central focus. We conclude that integrins are vital in memory formation and that their disruption could lead to various forms of cognitive impairment. While further research to understand the relationships between integrins and memory is needed, we propose that the translational relevance of research efforts in this area could be improved through the use of appropriately aged, comorbid, male and female animals.

Bilateral Carotid Artery Stenosis and Cerebral Blood Flow Outcomes.

Bilateral carotid artery stenosis (BCAS) is a valid approach for modeling vascular dementia (VaD) in mice as it induces cerebral hypoperfusion and produces white matter degeneration and cognitive impairment. VaD is one of the major causes of cognitive impairment and currently has no approved therapy; hence its preclinical modeling is warranted for investigating potential therapeutic compounds. BCAS enables the characterization of brain pathology and associated cognitive phenotype of VaD. In this chapter, we describe the surgical method of inducing BCAS in mice, using titanium micro-coils, and we report cerebral blood flow changes before and after surgical induction as well as some histological findings in the corpus callosum of diabetic mice subjected to long-term BCAS.

Promising Cerebral Blood Flow Enhancers in Acute Ischemic Stroke.

Ischemic stroke presents a major global economic and public health burden. Although recent advances in available endovascular therapies show improved functional outcome, a good number of stroke patients are either ineligible or do not have access to these treatments. Also, robust collateral flow during acute ischemic stroke independently predicts the success of endovascular therapies and the outcome of stroke. Hence, adjunctive therapies for cerebral blood flow (CBF) enhancement are urgently needed. A very clear overview of the pial collaterals and the role of genetics are presented in this review. We review available evidence and advancement for potential therapies aimed at improving CBF during acute ischemic stroke. We identified heme-free soluble guanylate cyclase activators; Sanguinate, remote ischemic perconditioning; Fasudil, S1P agonists; and stimulation of the sphenopalatine ganglion as promising potential CBF-enhancing therapeutics requiring further investigation. Additionally, we outline and discuss the critical steps required to advance research strategies for clinically translatable CBF-enhancing agents in the context of acute ischemic stroke models.