Functional regulation of microglia by vitamin B12 alleviates ischemic stroke-induced neuroinflammation in mice.

Ischemic stroke is the second leading cause of death and disability worldwide, and efforts to prevent stroke, mitigate secondary neurological damage, and promote neurological recovery remain paramount. Recent findings highlight the critical importance of microbiome-related metabolites, including vitamin B12 (VB12), in alleviating toxic stroke-associated neuroinflammation. Here, we showed that VB12 tonically programmed genes supporting microglial cell division and activation and critically controlled cellular fatty acid metabolism in homeostasis.

Loss of LRP1 in Adult Neural Stem Cells Impairs Migration to Ischemic Lesions.

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We used Nestin-driven knockout of LRP1 and induction of td-tomato in neural stem cells of adult mice.

Neuroprotective Roles of the Adenosine A Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested that neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A receptor (AR) agonist.

Prevention of brain damage after traumatic brain injury by pharmacological enhancement of KCNQ (Kv7, "M-type") K currents in neurons.

Nearly three million people in the USA suffer traumatic brain injury (TBI) yearly; however, there are no pre- or post-TBI treatment options available. KCNQ2-5 voltage-gated K channels underlie the neuronal "M current", which plays a dominant role in the regulation of neuronal excitability. Our strategy towards prevention of TBI-induced brain damage is predicated on the suggested hyper-excitability of neurons induced by TBIs, and the decrease in neuronal excitation upon pharmacological augmentation of M/KCNQ K currents.

Acetazolamide Treatment Prevents Redistribution of Astrocyte Aquaporin 4 after Murine Traumatic Brain Injury.

After traumatic brain injury (TBI), multiple ongoing processes contribute to worsening and spreading of the primary injury to create a secondary injury. One major process involves disrupted fluid regulation to create vascular and cytotoxic edema in the affected area. Although understanding of factors that influence edema is incomplete, the astrocyte water channel Aquaporin 4 (AQP4) has been identified as an important mediator and therefore attractive drug target for edema prevention.

Progesterone modulates mTOR in the hippocampus of mice after traumatic brain injury.

The mechanistic target of rapamycin (mTOR) is an intracellular protein kinase that functions as an energy and nutrient sensor in the cellular microenvironment of neurons. Modulation of mTOR is vital when nutrient and energy sources become limited. Hypoxia, traumatic brain injury, cellular energy states, and growth factors all regulate the phosphorylation and total levels of mTOR in cells.

Does progesterone show neuroprotective effects on traumatic brain injury through increasing phosphorylation of Akt in the hippocampus?

There are currently no federally approved neuroprotective agents to treat traumatic brain injury. Progesterone, a hydrophobic steroid hormone, has been shown in recent studies to exhibit neuroprotective effects in controlled cortical impact rat models. Akt is a protein kinase known to play a role in cell signaling pathways that reduce edema, inflammation, apoptosis, and promote cell growth in the brain.

Spatial distribution of insulin-like growth factor binding protein-2 following hypoxic-ischemic injury.

Background: Insulin-like growth factor binding protein-2 (IGFBP-2) regulates the bioavailability, transportation, and localization of insulin-like growth factor-I (IGF-I), an effective neuroprotectant in animal stroke models especially when administered intranasally. Therefore, determining IGFBP-2's endogenous distribution in the normal and ischemic brain is essential in maximizing the neuroprotective potential of the intranasal IGF-I treatment approach. However, current data on IGFBP-2 is limited to mRNA and in situ hybridization studies.

Purinergic 2Y1 receptor stimulation decreases cerebral edema and reactive gliosis in a traumatic brain injury model.

Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults. Neuroprotective agents that may promote repair or counteract damage after injury do not currently exist. We recently reported that stimulation of the purinergic receptor subtype P2Y(1)R using 2-methylthioladenosine 5' diphosphate (2MeSADP) significantly reduced cytotoxic edema induced by photothrombosis.

The rostral migratory stream plays a key role in intranasal delivery of drugs into the CNS.

Background: The blood brain barrier (BBB) is impermeable to most drugs, impeding the establishment of novel neuroprotective therapies and strategies for many neurological diseases. Intranasal administration offers an alternative path for efficient drug delivery into the CNS. So far, the anatomical structures discussed to be involved in the transport of intranasally administered drugs into the CNS include the trigeminal nerve, olfactory nerve and the rostral migratory stream (RMS), but the relative contributions are debated.

Pre-ischemic exercise preserves cerebral blood flow during reperfusion in stroke.

Introduction: The neuroprotective nature of exercise has been well established and the mechanisms of this protection are still a subject of much research. This study aims to determine if cerebral blood flow is constituently higher during the ischemia or reperfusion events in stroke.

Materials And Methods: Adult male Sprague-Dawley rats were randomly assigned into exercise or non-exercise (control) groups.

Exercise pre-conditioning reduces brain inflammation in stroke via tumor necrosis factor-alpha, extracellular signal-regulated kinase 1/2 and matrix metalloproteinase-9 activity.

Objective: We sought to determine whether cerebral inflammation in ischemic rats was reduced by a neuroprotective action of pre-ischemic tumor necrosis factor-alpha up-regulation, which down-regulated matrix metalloproteinase-9 activity via extracellular signal-regulated kinase 1/2 phosphorylation.

Material And Methods: Adult male Sprague-Dawley rats were subjected to 30 minutes of exercise on a treadmill for 3 weeks. Stroke was induced by a 2 hour middle cerebral artery occlusion using an intraluminal filament.

Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation.

Object: Individually, the cytokines erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) have both been shown to reduce neuronal damage significantly in rodent models of cerebral ischemia. The authors have previously shown that EPO and IGF-I, when administered together, provide acute and prolonged neuroprotection in cerebrocortical cultures against N-methyl-D-aspartate-induced apoptosis. The aim of this study was to determine whether intranasally applied EPO plus IGF-I can provide acute neuroprotection in an animal stroke model and to show that intranasal administration is more efficient at delivering EPO plus IGF-I to the brain when compared with intravenous, subcutaneous, or intraperitoneal administration.

Role of tumor necrosis factor-alpha and matrix metalloproteinase-9 in blood-brain barrier disruption after peripheral thermal injury in rats.

Object: A relationship has been found between peripheral thermal injury and cerebral complications leading to injury and death. In the present study, the authors examined whether tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase-9 (MMP-9) play a causative role in blood-brain barrier (BBB) disruption after peripheral thermal injury.

Methods: Thirty-two male Sprague-Dawley rats were subjected to thermal injury.

Blood brain barrier (BBB) dysfunction associated with increased expression of tissue and urokinase plasminogen activators following peripheral thermal injury.

Emerging data suggests the serine proteases, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA), may play a detrimental role in traumatic states leading to compromise of the blood brain barrier (BBB). The purpose of our study was to define the role of endogenous tPA and uPA on the BBB following peripheral burn injuries. Adult male Sprague-Dawley rats (n=46) were studied in control and thermal injury groups.

Preischemic induction of TNF-alpha by physical exercise reduces blood-brain barrier dysfunction in stroke.

This study explores the neuroprotective action of tumor necrosis factor-alpha (TNF-alpha) induced during physical exercise, which, consequently, reduces matrix metalloproteinase-9 (MMP-9) activity and ameliorates blood-brain barrier (BBB) dysfunction in association with extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation. Adult male Sprague-Dawley rats were subjected to exercise on a treadmill for 3 weeks. A 2-h middle cerebral artery occlusion and reperfusion was administered to exercised and nonexercised animals to induce stroke.

Forced, not voluntary, exercise effectively induces neuroprotection in stroke.

Previous treadmill exercise studies showing neuroprotective effects have raised questions as to whether exercise or the stress related to it may be key etiologic factors. In this study, we examined different exercise regimens (forced and voluntary exercise) and compared them with the effect of stress-only on stroke protection. Adult male Sprague-Dawley rats (n = 65) were randomly assigned to treatment groups for 3 weeks.

Peripheral thermal injury causes early blood-brain barrier dysfunction and matrix metalloproteinase expression in rat.

High mortality incidence after serious systemic thermal injury is believed to be linked to significant increases in cerebral permeability, ultimately leading to irreversible blood-brain barrier (BBB) breakdown. The aim of this study was to investigate whether disruption of microvascular integrity in a rat thermal injury model is associated with early matrix metalloproteinase (MMP) expression. A total of 35 Sprague-Dawley rats were studied in thermal injury and control groups, each group containing two subgroups, one for brain edema and Evans blue analysis and another for MMP mRNA analysis.

Resuscitation from hemorrhagic shock with HBOC-201 in the setting of traumatic brain injury.

Outcomes after mild or moderate head trauma are worsened with associated hypotension, and secondary brain injury can be reduced with timely resuscitation. This study was performed to investigate HBOC-201 as a resuscitation therapy in a combined hemorrhagic shock and brain injury model. Anesthetized rats sustained moderate brain injury using a controlled cortical impact device, followed by rapid hemorrhage to a mean arterial pressure of 30 mmHg.

Peripheral thermal injury causes blood-brain barrier dysfunction and matrix metalloproteinase (MMP) expression in rat.

Mortality after serious systemic thermal injury may be linked to significant increases in cerebral vascular permeability and edema due to blood-brain barrier (BBB) breakdown. This BBB disruption is thought to be mediated by a family of proteolytic enzymes known as matrix metalloproteinases (MMPs). The gelatinases, MMP-2 and MMP-9, digest the endothelial basal lamina of the BBB, which is essential for maintaining BBB integrity.

Reversal of attenuation of cerebrovascular reactivity to hypercapnia by a nitric oxide donor after controlled cortical impact in a rat model of traumatic brain injury.

Object: Traumatic brain injury (TBI) attenuates the cerebral vasodilation to hypercapnia. Cortical spreading depression (CSD) also transiently reduces hypercapnic vasodilation. The authors sought to determine whether the CSD elicited by a controlled cortical impact (CCI) injury masks the true effect of TBI on hypercapnic vasodilation, and whether a nitric oxide (NO) donor can reverse the attenuation of hypercapnic vasodilation following CCI.