Obesity, a burgeoning global health issue, is increasingly recognized for its detrimental effects on the central nervous system, particularly concerning the integrity of the blood-brain barrier (BBB). This manuscript delves into the intricate relationship between obesity and BBB dysfunction, elucidating the underlying phenotypes and molecular mechanisms. We commence with an overview of the BBB’s critical role in maintaining cerebral homeostasis and the pathological alterations induced by obesity. By employing a comprehensive literature review, we examine the structural and functional modifications of the BBB in the context of obesity, including increased permeability, altered transport mechanisms, and inflammatory responses. The manuscript highlights how obesity-induced systemic inflammation and metabolic dysregulation contribute to BBB disruption, thereby predisposing individuals to various neurological disorders. We further explore the potential pathways, such as oxidative stress and endothelial cell dysfunction, that mediate these changes. Our discussion culminates in the summary of current findings and the identification of knowledge gaps, paving the way for future research directions. This review underscores the significance of understanding BBB dysfunction in obesity, not only for its implications in neurodegenerative diseases but also for developing targeted therapeutic strategies to mitigate these effects.

Stroke is one of the leading causes of mortality, and survivors experience serious neurological and motor behavioral deficiencies. Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur because of ischemia/reperfusion injury. Wnt signaling is an evolutionarily conserved signaling pathway that has been manifested to play a key role in embryo development and function maintenance in adults. Overactivation of Wnt signaling has previously been investigated in cancer-based research studies. Recently, abnormal Wnt signaling activity has been observed in ischemic stroke, which is accompanied by massive blood–brain barrier (BBB) disruption, neuronal apoptosis, and neuroinflammation within the central nervous system (CNS). Significant therapeutic effects were observed after reactivating the adynamic signaling activity of canonical Wnt signaling in different cell types. To better understand the therapeutic potential of Wnt as a novel target for stroke, we reviewed the role of Wnt signaling in the pathogenesis of stroke in different cell types, including endothelial cells, neurons, oligodendrocytes, and microglia. A comprehensive understanding of Wnt signaling among different cells may help to evaluate its potential value for the development of novel therapeutic strategies based on Wnt activation that can ameliorate complications and improve functional rehabilitation after ischemic stroke.

Ischemic stroke, accounting for the majority of stroke events, significantly contributes to global morbidity and mortality. Vascular recanalization therapies, namely intravenous thrombolysis and mechanical thrombectomy, have emerged as critical interventions, yet their success hinges on timely application and patient‐specific factors. This review focuses on the early phase pathophysiological mechanisms of ischemic stroke and the nuances of recanalization. It highlights the dual role of neutrophils in tissue damage and repair, and the critical involvement of the blood–brain barrier (BBB) in stroke outcomes. Special emphasis is placed on ischemia–reperfusion injury, characterized by oxidative stress, inflammation, and endothelial dysfunction, which paradoxically exacerbates cerebral damage post‐revascularization. The review also explores the potential of targeting molecular pathways involved in BBB integrity and inflammation to enhance the efficacy of recanalization therapies. By synthesizing current research, this paper aims to provide insights into optimizing treatment protocols and developing adjuvant neuroprotective strategies, thereby advancing stroke therapy and improving patient outcomes.

Background and Aims: Ischaemic stroke remains a major cause of disability and mortality, with current treatments constrained by a narrow therapeutic time window and the risk of complications such as haemorrhagic transformation and reperfusion injury. This study investigates the role of Dickkopf-related protein 2 (DKK2) in the pathophysiology of ischaemic stroke, exploring its potential as a therapeutic target. Methods: Dickkopf-related protein 2 levels were analysed in a murine model of transient middle cerebral artery occlusion (tMCAO) and in stroke patients with large vessel occlusion undergoing endovascular treatment. The causal role of DKK2 was explored using genetic knockout and viral targeting strategies to manipulate its expression, and using pharmacological approaches to assess its therapeutic potential. Mechanistic studies focused on the regulation of DKK2 by retinoid X receptor-alpha (RXRα) and its effects on neuronal injury and blood–brain barrier (BBB) integrity. Results: Dickkopf-related protein 2 was significantly up-regulated in both the brain and serum of mice after tMCAO. Serum DKK2 levels were elevated in stroke patients with larger infarct volumes, ICH, and worse functional outcomes. In murine models, systemic or neuron-specific DKK2 overexpression exacerbated infarction, neurological deficits, and BBB disruption, while genetic ablation or monoclonal antibody-mediated inhibition of DKK2 substantially ameliorated these parameters. Mechanistically, DKK2 was up-regulated in neurons by RXRα under ischaemia/reperfusion conditions both in vitro and in vivo, and this contributed to neuronal death and BBB disruption through suppression of canonical Wnt signalling. Conclusions: Dickkopf-related protein 2 plays a critical role in the progression of ischaemic stroke by modulating neuronal survival and BBB integrity. Targeting DKK2 represents a promising therapeutic approach to ischaemic brain injury, and the observational human data extend experimental findings to human cerebrovascular pathology, suggesting translational potential.