Astrocyte involvement in blood–brain barrier function: a critical update highlighting novel, complex, neurovascular interactions

Neurological disorders have been linked to a defective blood–brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence of improved experimental models allow BBB permeability prediction and the development of new brain-targeted therapies. As NVU constituents, astrocytes are the most numerous glial cells, characterized by a heterogeneity that occurs as a result of developmental and context-based gene expression profiles and the differential expression of non-coding ribonucleic acids (RNAs). Due to their heterogeneity and dynamic responses to different signals, astrocytes may have a beneficial or detrimental role in the BBB’s barrier function, with deep effects on the pathophysiology of (and on the progression of) central nervous system diseases. The implication of astrocytic-derived extracellular vesicles in pathological mechanisms, due to their ability to pass the BBB, must also be considered. The molecular mechanisms of astrocytes’ interaction with endothelial cells at the BBB level are considered promising therapeutic targets in different neurological conditions. Nevertheless, a personalized and well-founded approach must be addressed, due to the temporal and spatial heterogeneity of reactive astrogliosis states during disease

Oxidative Stress in Amyotrophic Lateral Sclerosis: Synergy of Genetic and Environmental Factors

Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular processes. Notably, oxidative stress has been demonstrated to play a crucial role in ALS pathogenesis. In addition to already recognized and exhaustively studied genetic mutations involved in oxidative stress production, exposure to various environmental factors (e.g., electromagnetic fields, solvents, pesticides, heavy metals) has been suggested to enhance oxidative damage. This review aims to describe the main processes influenced by the most frequent genetic mutations and environmental factors concurring in oxidative stress occurrence in ALS and the potential therapeutic molecules capable of diminishing the ALS related pro-oxidative status

The Role of Biomarkers in Atherothrombotic Stroke—A Systematic Review

Stroke represents the primary debilitating disease in adults and is the second-highest cause of death worldwide. Atherosclerosis, the most prevalent etiology for vascular conditions, is a continuous process that gradually creates and develops endothelial lesions known as atherosclerotic plaques. These lesions lead to the appearance of atherothrombotic stroke. In the last decades, the role of biological biomarkers has emerged as either diagnostic, prognostic, or therapeutic targets. This article aims to create a list of potential biomarkers related to atherothrombotic stroke by reviewing the currently available literature. We identified 23 biomarkers and assessed their roles as risk factors, detection markers, prognostic predictors, and therapeutic targets. The central aspect of these biomarkers is related to risk stratification, especially for patients who have not yet suffered a stroke. Other valuable data are focused on the predictive capabilities for stroke patients regarding short-term and long-term prognosis, including their influence over the acute phase treatment, such as rt-PA thrombolysis. Although the role of biomarkers is anticipated to be of extreme value in the future, they cannot yet compete with traditional stroke neuroimaging markers but could be used as additional tools for etiological diagnosis

The direct deleterious effect of Th17 cells in the nervous system compartment in multiple sclerosis and experimental autoimmune encephalomyelitis: one possible link between neuroinflammation and neurodegeneration

The processes of demyelination and neurodegeneration in the central nervous system (CNS) of multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) are secondary to numerous pathophysiological mechanisms. One of the main cellular players is the Th17 lymphocyte. One of the major functions described for Th17 cells is the upregulation of pro-inflammatory cytokines, such as IL-17 at the level of peripheral and CNS inflammation. This review will focus on the newly described and unexpected, direct role played by the Th17 cells in the CNS of MS patients and EAE models. Th17 and their main cytokine, IL-17, are actively involved in the onset and maintenance of the immune cascade in the CNS compartment as Th17 were found to achieve brain-homing potential. Direct interaction of myelin oligodendrocyte glycoprotein - specific Th17 with the neuronal cells firstly induces demyelination and secondly, extensive axonal damage. The Th17 cells promote an inflammatory B cell response beyond the BBB through the presence of infiltrating Th follicles. Due to their role in preventing remyelination and direct neurotoxic effect, Th17 cells might stand for an important connection between neuroinflammation and neurodegeneration in a devastating disease like MS. The Th17 cell populations have different mechanisms of provoking an autoimmune attack not only in the periphery but also in the CNS of MS patients

Neuroprotection in Stroke—Focus on the Renin-Angiotensin System: A Systematic Review

Stroke is the primary cause of disability in the adult population. Hypertension represents the leading risk factor being present in almost half the patients. The renin-angiotensin system is involved in the physiopathology of stroke and has an essential impact on hypertension as a risk factor. This article targeted the role of the renin-angiotensin system in stroke neuroprotection by reviewing the current literature available. The mechanism of action of the renin-angiotensin system was observed through the effects on AT1, AT2, and Mas receptors. The neuroprotective properties ascertained by angiotensin in stroke seem to be independent of the blood pressure reduction mechanism, and include neuroregeneration, angiogenesis, and increased neuronal resistance to hypoxia. The future relationship of stroke and the renin-angiotensin system is full of possibilities, as new agonist molecules emerge as potential candidates to restrict the impairment caused by stroke

Cytokine Secretion Dynamics of Isolated PBMC after Cladribine Exposure in RRMS Patients

Cladribine (CLD) treats multiple sclerosis (MS) by selectively and transiently depleting B and T cells with a secondary long-term reconstruction of the immune system. This study provides evidence of CLD’s immunomodulatory role in peripheral blood mononuclear cells (PBMCs) harvested from 40 patients with untreated relapsing-remitting MS (RRMS) exposed to CLD. We quantified cytokine secretion from PBMCs isolated by density gradient centrifugation with Ficoll–Paque using xMAP technology on a FlexMap 3D analyzer with a highly sensitive multiplex immunoassay kit. The PBMC secretory profile was evaluated with and without CLD exposure. PBMCs isolated from patients with RRMS for ≤12 months had significantly higher IL-4 but significantly lower IFN-γ and TNF-α secretion after CLD exposure. PBMCs isolated from patients with RRMS for >12 months had altered inflammatory ratios toward an anti-inflammatory profile and increased IL-4 but decreased TNF-α secretion after CLD exposure. CLD induced nonsignificant changes in IL-17 secretion in both RRMS groups. Our findings reaffirm CLD’s immunomodulatory effect that induces an anti-inflammatory phenotype

Postpartum Acute Basilar Artery Occlusion Secondary to Vertebral Artery Dissection. Case Report and Literature Review

Female patients in the peripartum and postpartum periods have an increased risk of stroke than nonpregnant women. Cerebrovascular complications of pregnancy represent a significant cause of maternal mortality and morbidity and are potentially disabling. Acute basilar artery occlusion secondary to spontaneous vertebral artery dissection in the postpartum period is an infrequent entity and a major diagnostic and treatment challenge. In the present case, a 37-year-old female patient, eight weeks after caesarean delivery, presented with a history of sudden cervical pain, followed by headache and dizziness. Some hours later, she was found unconscious by her family and was transferred to the emergency department, where a neurological status assessment suggested vertebrobasilar stroke. The imagistic workup revealed right vertebral artery dissection and basilar artery occlusion without constituted ischemic lesions. The patient underwent endovascular intervention with dilation of the narrowed vertebral artery and stent retriever basilar artery thrombectomy, with a favourable clinical outcome. This report first presents the details of this case and the relevant literature data on postpartum arterial dissections and the subsequent ischemic complications and available treatment options

Postpartum Cerebral Venous Thrombosis—A Single-Center Experience

Background: Cerebral venous thrombosis (CVT) is a rare variant of stroke in the general population, but an important subtype among pregnancy- and puerperium-related cases. Studies describing its risk factors and clinical characteristics are limited. The aim of our study is to disclose these aspects and compare with cases unrelated to pregnancy and puerperium. Materials and Methods: We performed a retrospective analysis including 88 consecutive cases from a tertiary neurology clinic with a diagnosis of CVT. Ten of the 88 cases (11.3%) appeared during the postpartum period. Results: The mean age of the puerperal CVT cases was 26.5 years. The main pregnancy-related risk factors besides puerperium were cesarean delivery (5/10), preeclampsia (2/10), and stillbirth (1/10). General risk factors for thrombosis, i.e., infection, smoking, and primary hypercoagulability, were identified in 50% of cases. Onset was in the first 3 weeks after delivery, with a mean value of 9.6 ± 5.6 days. Headache was present in 90% of postpartum CVT cases and in 76.1% of non-postpartum female cases. Seizures were more frequent in the postpartum group (60% vs. 34.8%). Onset was acute (p = 0.02), suggesting a more favorable short-term outcome. Conclusions: The early postpartum period represents an important risk for the development of CVT. Cesarean delivery and preeclampsia, besides general risk factors such as infection, smoking, and primary thrombophilia, contribute to enhanced risk. Puerperium-related CVT presents a more favorable outcome compared with CVT with other etiologies