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Repurposing the KCa3.1 Blocker Senicapoc for Ischemic Stroke
AbstractSenicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC50 of 7  nM, reduced Ca2+ signaling induced by the purinergic agonist ATP, suppressed express...
Source: Translational Stroke Research - April 24, 2023 Category: Neurology Source Type: research

Alpha-Asarone Ameliorates Neurological Dysfunction of Subarachnoid Hemorrhagic Rats in Both Acute and Recovery Phases via Regulating the CaMKII-Dependent Pathways
AbstractEarly brain injury (EBI) is the leading cause of poor prognosis for patients suffering from subarachnoid hemorrhage (SAH), particularly learning and memory deficits in the repair phase. A recent report has involved calcium/calmodulin-dependent protein kinase II (CaMKII) in the pathophysiological process underlying SAH-induced EBI. Alpha-asarone (ASA), a major compound isolated from the Chinese medicinal herbAcorus tatarinowii Schott, was proven to reduce secondary brain injury by decreasing CaMKII over-phosphorylation in rats ’ model of intracerebral hemorrhage in our previous report. However, the effect of ASA o...
Source: Translational Stroke Research - February 13, 2023 Category: Neurology Source Type: research

Gut Microbiota in Ischemic Stroke: Role of Gut Bacteria-Derived Metabolites
AbstractIschemic stroke (IS) remains a leading cause of death and long-term disability globally. Several mechanisms including glutamate excitotoxicity, calcium overload, neuroinflammation, oxidative stress, mitochondrial damage, and apoptosis are known to be involved in the pathogenesis of IS, but the underlying pathophysiology mechanisms of IS are not fully clarified. During the past decade, gut microbiota were recognized as a key regulator to affect the health of the host either directly or via their metabolites. Recent studies indicate that gut bacterial dysbiosis is closely related to hypertension, diabetes, obesity, d...
Source: Translational Stroke Research - October 24, 2022 Category: Neurology Source Type: research

Cannabidiol ’s Multifactorial Mechanisms Has Therapeutic Potential for Aneurysmal Subarachnoid Hemorrhage: a Review
AbstractSubarachnoid hemorrhage (SAH) is a major health burden that accounts for approximately 5% of all strokes. The most common cause of a non-traumatic SAH is the rupture of a cerebral aneurysm. The most common symptom associated with SAH is a headache, often described as “the worst headache of my life.” Delayed cerebral ischemia (DCI) is a major factor associated with patient mortality following SAH and is often associated with SAH-induced cerebral vasospasm (CV). Cannabidiol (CBD) is emerging as a potential drug for many therapeutic purposes, including epilepsy , anxiety, and pain relief. We aim to review the pote...
Source: Translational Stroke Research - September 15, 2022 Category: Neurology Source Type: research

Recurrent Transient Ischemic Attack Induces Neural Cytoskeleton Modification and Gliosis in an Experimental Model
AbstractTransient ischemic attack (TIA) presents a high risk for subsequent stroke, Alzheimer ’s disease (AD), and related dementia (ADRD). However, the neuropathophysiology of TIA has been rarely studied. By evaluating recurrent TIA-induced neuropathological changes, our study aimed to explore the potential mechanisms underlying the contribution of TIA to ADRD. In the current study, we es tablished a recurrent TIA model by three times 10-min middle cerebral artery occlusion within a week in rat. Neither permanent neurological deficit nor apoptosis was observed following recurrent TIA. No increase of AD-related biomarker...
Source: Translational Stroke Research - July 22, 2022 Category: Neurology Source Type: research

Calcium/Calmodulin –Dependent Protein Kinase II in Cerebrovascular Diseases
AbstractCerebrovascular disease is the most common life-threatening and debilitating condition that often leads to stroke. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key Ca2+ sensor and an important signaling protein in a variety of biological systems within the brain, heart, and vasculature. In the brain, past stroke-related studies have been mainly focused on the role of CaMKII in ischemic stroke in neurons and established CaMKII as a major mediator of neuronal cell death induced by glutamate excitotoxicity and oxidative stress following ischemic stroke. However, with growing underst...
Source: Translational Stroke Research - March 13, 2021 Category: Neurology Source Type: research

Endoplasmic Reticulum Interaction Supports Energy Production and Redox Homeostasis in Mitochondria Released from Astrocytes
In this study, we investigated the molecular mechanisms that underlie mitochondria secretion, redox status, and functional regulation in the extracellular environment. Exposure of rat primary astrocytes to NAD or cADPR elicited an increase in mitochondrial calcium through ryanodine receptor (RyR) in the endoplasmic reticulum (ER). Importantly, CD38 stimulation with NAD accelerated ATP production along with increasing glutathione reductase (GR) and dipicolinic acid (DPA) in intracellular mitochondria. When RyR was blocked by Dantrolene, all effects were clearly diminished. Mitochondrial functional assay showed that these ac...
Source: Translational Stroke Research - January 21, 2021 Category: Neurology Source Type: research

TRPM7 Mediates Neuronal Cell Death Upstream of Calcium/Calmodulin-Dependent Protein Kinase II and Calcineurin Mechanism in Neonatal Hypoxic-Ischemic Brain Injury
In this study, we employed a mouse model of hypoxic-ischemic brain cell death which mimics the pathophysiology of hypoxic-ischemic encephalopathy (HIE). HIE is a major public health issue and an important cause of neonatal deaths worldwide; however, the available treatments for HIE remain limited. Its survivors face life-long neurological challenges including mental retardation, cerebral palsy, epilepsy and seizure disorders, motor impairments, and visual and auditory impairments. Through a proteomic analysis, we identified calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphatase calcineurin as potential med...
Source: Translational Stroke Research - January 12, 2021 Category: Neurology Source Type: research

p5 Peptide-Loaded Human Adipose-Derived Mesenchymal Stem Cells Promote Neurological Recovery After Focal Cerebral Ischemia in a Rat Model
In conclusion, administration of hADMSC-loaded p5 peptide to post-stroke rats created conditions that supported survival of drug-loaded hADMSCs after cerebral ischemia, suggesting its therapeutic potential in patients with stroke.
Source: Translational Stroke Research - May 5, 2020 Category: Neurology Source Type: research

Human Milk Oligosaccharide 2 ′-Fucosyllactose Reduces Neurodegeneration in Stroke Brain
In conclusion, our data suggest that 2’-FL has neuroprotective action through inhibition of Ca++i, inflammation, and apoptosis. Posttreatment with 2 ’-FL facilitates neural repair in stroke brain.
Source: Translational Stroke Research - January 1, 2020 Category: Neurology Source Type: research

Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels
AbstractHippocampal injury and cognitive impairments are common after cardiac arrest and stroke and do not have an effective intervention despite much effort. Therefore, we developed a new approach aimed at reversing synaptic dysfunction by targeting TRPM2 channels. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in mice was used to investigate cognitive deficits and the role of the calcium-permeable ion channel transient receptor potential-M2 (TRPM2) in ischemia-induced synaptic dysfunction. Our data indicates that absence (TRPM2−/−) or acute inhibition of TRPM2 channels with tatM2NX reduced hippocampal cell dea...
Source: Translational Stroke Research - June 27, 2019 Category: Neurology Source Type: research

High Circulatory Phosphate Level Is Associated with Cerebral Small-Vessel Diseases
AbstractHigh phosphate is linked to vascular calcification and endothelial dysfunction; however, its relationship with cerebral small-vessel diseases (CSVDs) is still unknown. Study subjects were prospectively recruited from the community-based I-Lan Longitudinal Aging Study. CSVDs including lacunes, white matter hyperintensities (WMHs), and cerebral microbleeds were evaluated using 3T magnetic resonance images. Multivariate analyses were performed to study the associations between circulatory phosphate level and the presence of CSVDs. In vitro experiments included human brain microvascular endothelial cell (HBMEC) studies...
Source: Translational Stroke Research - June 25, 2018 Category: Neurology Source Type: research

Therapy with the Combination of Amlodipine and Irbesartan Has Persistent Preventative Effects on Stroke Onset Associated with BDNF Preservation on Cerebral Vessels in Hypertensive Rats
In this study, we investigated the significant beneficial effects of the combination therapy using amlodipine and irbesartan against stroke onset in hypertensive rats. The animals were fed an 8 % sodium diet and assigned to (1) vehicle, (2) amlodipine (2 mg/kg/day), (3) irbesartan (20 mg/kg/day), and (4) amlodipine + irbesartan groups. The drugs were given orally until 35 days, and incidences of stroke-related signs and mortality and blood pressure (BP) were monitored. Cerebral blood flow (CBF), brain water content, weight of the brain and left ventricle, and histological evaluations were conducted for the treated grou...
Source: Translational Stroke Research - December 23, 2014 Category: Neurology Source Type: research