Nanodrug delivery systems for regulating microglial polarization in ischemic stroke treatment: A review.

The incidence of ischemic stroke (IS) is rising in tandem with the global aging population. There is an urgent need to delve deeper into the pathological mechanisms and develop new neuroprotective strategies. In the present review, we discuss the latest advancements and research on various nanodrug delivery systems (NDDSs) for targeting microglial polarization in IS treatment. Furthermore, we critically discuss the different strategies. NDDSs have demonstrated exceptional qualities to effectively permeate the blood-brain barrier, aggregate at the site of ischemic injury, and target specific cell types within the brain when appropriately modified. Consequently, NDDSs have considerable potential for reshaping the polarization phenotype of microglia and could be a prospective therapeutic strategy for IS. The treatment of IS remains a challenge. However, this review provides a new perspective on neuro-nanomedicine for IS therapies centered on microglial polarization, thereby inspiring new research ideas and directions.

Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.

Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.

Role of lipocalin 2 in stroke.

Stroke is the second leading cause of death worldwide; however, the treatment choices available to neurologists are limited in clinical practice. Lipocalin 2 (LCN2) is a secreted protein, belonging to the lipocalin superfamily, with multiple biological functions in mediating innate immune response, inflammatory response, iron-homeostasis, cell migration and differentiation, energy metabolism, and other processes in the body. LCN2 is expressed at low levels in the brain under normal physiological conditions, but its expression is significantly up-regulated in multiple acute stimulations and chronic pathologies. An up-regulation of LCN2 has been found in the blood/cerebrospinal fluid of patients with ischemic/hemorrhagic stroke, and could serve as a potential biomarker for the prediction of the severity of acute stroke. LCN2 activates reactive astrocytes and microglia, promotes neutrophil infiltration, amplifies post-stroke inflammation, promotes blood-brain barrier disruption, white matter injury, and neuronal death. Moreover, LCN2 is involved in brain injury induced by thrombin and erythrocyte lysates, as well as microvascular thrombosis after hemorrhage. In this paper, we review the role of LCN2 in the pathological processes of ischemic stroke; intracerebral hemorrhage; subarachnoid hemorrhage; and stroke-related brain diseases, such as vascular dementia and post-stroke depression, and their underlying mechanisms. We hope that this review will help elucidate the value of LCN2 as a therapeutic target in stroke.

Remote ischemic conditioning attenuates blood-brain barrier disruption after recombinant tissue plasminogen activator treatment via reducing PDGF-CC.

Treatment of acute ischemic stroke with the recombinant tissue plasminogen activator (rtPA) is associated with increased blood-brain barrier (BBB) disruption and hemorrhagic transformation. Remote ischemic conditioning (RIC) has demonstrated neuroprotective effects against acute ischemic stroke. However, whether and how RIC regulates rtPA-associated BBB disruption remains unclear. Here, a rodent model of thromboembolic stroke followed by rtPA thrombolysis at different time points was performed with or without RIC. Brain infarction, neurological outcomes, BBB permeability, and intracerebral hemorrhage were assessed. The platelet-derived growth factor CC (PDGF-CC)/PDGFRα pathway in the brain tissue, PDGF-CC levels in the skeletal muscle and peripheral blood were also measured. Furthermore, impact of RIC on serum PDGF-CC levels were measured in healthy subjects and AIS patients. Our results showed that RIC substantially reduced BBB injury, intracerebral hemorrhage, cerebral infarction, and neurological deficits after stroke, even when rtPA was administrated in a delayed therapeutic time window. Mechanistically, RIC significantly decreased PDGFRα activation in ischemic brain tissue and reduced blood PDGF-CC levels, which partially resulted from PDGF-CC reduction in the skeletal muscle of RIC-applied hindlimbs and platelets. Intravenous or intraventricular recombinant PDGF-CC supplementation abolished RIC protective effects on BBB integrity. Moreover, similar changes of PDGF-CC in serum by RIC were also observed in healthy humans and acute ischemic stroke patients. Together, our study demonstrates that RIC can attenuate rtPA-aggravated BBB disruption after ischemic stroke via reducing the PDGF-CC/PDGFRα pathway and thus supports RIC as a potential approach for BBB disruption prevention or treatment following thrombolysis.

The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets.

Ischemic stroke (IS) is a cerebrovascular disease causing high rates of disability and fatality. In recent years, the concept of the neurovascular unit (NVU) has been accepted by an increasing number of researchers and is expected to become a new paradigm for exploring the pathogenesis and treatment of IS. NVUs are composed of neurons, endothelial cells, pericytes, astrocytes, microglia, and the extracellular matrix. As an important part of the NVU, pericytes provide support for other cellular components and perform a variety of functions, including participating in the maintenance of the normal physiological function of the blood-brain barrier, regulating blood flow, and playing a role in inflammation, angiogenesis, and neurogenesis. Therefore, treatment strategies targeting pericyte functions, regulating pericyte epigenetics, and transplanting pericytes warrant exploration. In this review, we describe the reactions of pericytes after IS, summarize the potential therapeutic targets and strategies targeting pericytes for IS, and provide new treatment ideas for ischemic stroke.

Biological Functions and Regulatory Mechanisms of Hypoxia-Inducible Factor-1α in Ischemic Stroke.

Ischemic stroke is caused by insufficient cerebrovascular blood and oxygen supply. It is a major contributor to death or disability worldwide and has become a heavy societal and clinical burden. To date, effective treatments for ischemic stroke are limited, and innovative therapeutic methods are urgently needed. Hypoxia inducible factor-1α (HIF-1α) is a sensitive regulator of oxygen homeostasis, and its expression is rapidly induced after hypoxia/ischemia. It plays an extensive role in the pathophysiology of stroke, including neuronal survival, neuroinflammation, angiogenesis, glucose metabolism, and blood brain barrier regulation. In addition, the spatiotemporal expression profile of HIF-1α in the brain shifts with the progression of ischemic stroke; this has led to contradictory findings regarding its function in previous studies. Therefore, unveiling the Janus face of HIF-1α and its target genes in different type of cells and exploring the role of HIF-1α in inflammatory responses after ischemia is of great importance for revealing the pathogenesis and identifying new therapeutic targets for ischemic stroke. Herein, we provide a succinct overview of the current approaches targeting HIF-1α and summarize novel findings concerning HIF-1α regulation in different types of cells within neurovascular units, including neurons, endothelial cells, astrocytes, and microglia, during the different stages of ischemic stroke. The current representative translational approaches focused on neuroprotection by targeting HIF-1α are also discussed.

T Cell Response in Ischemic Stroke: From Mechanisms to Translational Insights.

Ischemic stroke, caused by a sudden disruption of blood flow to the brain, is a leading cause of death and exerts a heavy burden on both patients and public health systems. Currently available treatments for ischemic stroke are very limited and are not feasible in many patients due to strict time windows required for their administration. Thus, novel treatment strategies are keenly required. T cells, which are part of the adaptive immune system, have gained more attention for its effects in ischemic stroke. Both preclinical and clinical studies have revealed the conflicting roles for T cells in post-stroke inflammation and as potential therapeutic targets. This review summarizes the mediators of T cell recruitment, as well as the temporal course of its infiltration through the blood-brain-barrier, choroid plexus, and meningeal pathways. Furthermore, we describe the mechanisms behind the deleterious and beneficial effects of T cells in the brain, in both antigen-dependent and antigen-independent manners, and finally we specifically focus on clinical and preclinical studies that have investigated T cells as potential therapeutic targets for ischemic stroke.

The Role of Immune Cells in Post-Stroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown.

Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur due to ischemia-induced cerebral pathology. Mounting evidence indicates that the robust recruitment of immune cells plays a central role in the acute stage of stroke. Infiltrating peripheral immune cells and resident microglia mediate neuronal cell death and blood-brain barrier disruption by releasing inflammation-associated molecules. Nevertheless, profound immunological effects in the context of the subacute and chronic recovery phase of stroke have received little attention. Early attempts to curtail the infiltration of immune cells were effective in mitigating brain injury in experimental stroke studies but failed to exert beneficial effects in clinical trials. Neural tissue damage repair processes include angiogenesis, neurogenesis, and synaptic remodeling, etc. Post-stroke inflammatory cells can adopt divergent phenotypes that influence the aforementioned biological processes in both endothelial and neural stem cells by either alleviating acute inflammatory responses or secreting a variety of growth factors, which are substantially involved in the process of angiogenesis and neurogenesis. To better understand the multiple roles of immune cells in neural tissue repair processes post stroke, we review what is known and unknown regarding the role of immune cells in angiogenesis, neurogenesis, and neuronal remodeling. A comprehensive understanding of these inflammatory mechanisms may help identify potential targets for the development of novel immunoregulatory therapeutic strategies that ameliorate complications and improve functional rehabilitation after stroke.