Exacerbation of Brain Injury by Post-Stroke Exercise Is Contingent Upon Exercise Initiation Timing.

Accumulating evidence has demonstrated that post-stroke physical rehabilitation may reduce morbidity. The effectiveness of post-stroke exercise, however, appears to be contingent upon exercise initiation. This study assessed the hypothesis that very early exercise exacerbates brain injury, induces reactive oxygen species (ROS) generation, and promotes energy failure.

Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.

Objectives: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS.

Materials And Methods: Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks.

Combination therapy of normobaric oxygen with hypothermia or ethanol modulates pyruvate dehydrogenase complex in thromboembolic cerebral ischemia.

Pyruvate dehydrogenase complex (PDH) is a brain mitochondrial matrix enzyme. PDH impairment after stroke is particularly devastating given PDH's critical role in the link between anaerobic and aerobic metabolism. This study evaluates the restoration of oxidative metabolism and energy regulation with a therapeutic combination of normobaric oxygen (NBO) plus either therapeutic hypothermia (TH) or ethanol.

Combining Normobaric Oxygen with Ethanol or Hypothermia Prevents Brain Damage from Thromboembolic Stroke via PKC-Akt-NOX Modulation.

In a thromboembolic stroke model after reperfusion by recombinant tissue plasminogen activator (rt-PA), we aimed to determine whether therapeutic hypothermia (TH) and ethanol (EtOH) in combination with low concentration (60 %) of normobaric oxygen (NBO) enhanced neuroprotection, as compared to using each of these agents alone. We further aimed to elucidate a potential role of the NADPH oxidase (NOX), phosphorylated protein kinase B (Akt), and protein kinase C-δ (PKC-δ) pathway in oxidative stress and neuroprotection. In Sprague-Dawley rats, a focal middle cerebral artery (MCA) occlusion was induced by an autologous embolus in the following experimental groups: rt-PA treatment alone, rt-PA + NBO treatment, rt-PA + TH at 33 °C, rt-PA + EtOH, rt-PA + NBO + EtOH, rt-PA + NBO + TH, rt-PA + NOX inhibitor, rt-PA + EtOH + NOX inhibitor, or rt-PA + EtOH + Akt inhibitor.

Therapeutic effect of tPA in ischemic stroke is enhanced by its combination with normobaric oxygen and hypothermia or ethanol.

Background And Purpose: Our lab has previously elucidated the neuroprotective effects of normobaric oxygen (NBO) and ethanol (EtOH) in ischemic stroke. The present study further evaluated the effect of EtOH or hypothermia (Hypo) in the presence of low concentration of NBO and determined whether EtOH can substitute hypothermia in a more clinically relevant autologous embolus rat stroke model in which reperfusion was established by tissue-type plasminogen activator (t-PA).

Methods: At 1h of middle cerebral artery occlusion (MCAO) by an autologous embolus, rats received t-PA.

Reduced cerebral monocarboxylate transporters and lactate levels by ethanol and normobaric oxygen therapy in severe transient and permanent ischemic stroke.

Objectives: Neuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO) were previously demonstrated in transient and permanent ischemic stroke. Here we sought to identify whether the enhanced lactic acidosis and increased expression of monocarboxylate transporters (MCTs) observed after stroke might be attenuated by single and/or combined EtOH and NBO therapies.

Methods: Sprague-Dawley rats (n=96) were subjected to right middle cerebral artery occlusion (MCAO) for 2 or 4h (transient ischemia), or 28 h (permanent ischemia) followed by 3, 24h, or no reperfusion.

Ethanol and normobaric oxygen: novel approach in modulating pyruvate dehydrogenase complex after severe transient and permanent ischemic stroke.

Background And Purpose: Ischemic stroke induces metabolic disarray. A central regulatory site, pyruvate dehydrogeanse complex (PDHC) sits at the cross-roads of 2 fundamental metabolic pathways: aerobic and anaerobic. In this study, we combined ethanol (EtOH) and normobaric oxygen (NBO) to develop a novel treatment to modulate PDHC and its regulatory proteins, namely pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase, leading to improved metabolism and reduced oxidative damage.

Reduced apoptosis by combining normobaric oxygenation with ethanol in transient ischemic stroke.

Background And Purpose: The effect of normobaric oxygen (NBO) on apoptosis remains controversial. The present study evaluated the effect of NBO on ischemia-induced apoptosis and assessed the potential for improved outcomes by combining NBO administration with another neuroprotective agent, ethanol, in a rat stroke model.

Methods: Rats were subjected to right middle cerebral artery occlusion (MCAO) for 2h.

Hyperglycemia in stroke and possible treatments.

Hyperglycemia affects approximately one-third of acute ischemic stroke patients and is associated with poor clinical outcomes. In experimental and clinical stroke studies, hyperglycemia has been shown to be detrimental to the penumbral tissue for several reasons. First, hyperglycemia exacerbates both calcium imbalance and the accumulation of reactive oxygen species (ROS) in neurons, leading to increased apoptosis.

At low doses ethanol maintains blood-brain barrier (BBB) integrity after hypoxia and reoxygenation: a brain slice study.

Post-ischemia ethanol (EtOH) treatments have been shown to exhibit neuroprotective effects in stroke. However, the mechanisms underlying these effects and those on blood-brain barrier (BBB) integrity have yet to be elucidated. In the present study, we determined whether administering differing concentrations of EtOH alter the expressions of BBB integral proteins, including aquaporins-4 and -9 (AQP-4, AQP-9), matrix metallopeptidases-2 and -9 (MMP-2, MMP-9), zonula occludens-1 (ZO-1), and basal lamina (laminin).

Reduction of brain edema and expression of aquaporins with acute ethanol treatment after traumatic brain injury.

Object: Previous studies have demonstrated that traumatic brain injury (TBI) causes brain edema by allowing excessive water passage through aquaporin (AQP) proteins. To establish the potential neuroprotective properties of ethanol as a post-TBI therapy, in the present study the authors determined the effect of ethanol on brain edema, AQP expression, and functional outcomes in a post-TBI setting.

Methods: Adult male Sprague-Dawley rats weighing between 425 and 475 g received a closed head TBI in which Maramarou's impact-acceleration method was used.

Glycerol accumulation in edema formation following diffuse traumatic brain injury.

Traumatic brain injury (TBI) induces brain edema via water and glycerol transport channels, called aquaporins (AQPs). The passage of glycerol across brain cellular compartments has been shown during edema. Using a modified impact/head acceleration rodent model of diffuse TBI, we assessed the role of hypoxia inducible factor (HIF)-1alpha in regulating AQP9 expression and glycerol accumulation during the edema formation.

Clazosentan, a novel endothelin A antagonist, improves cerebral blood flow and behavior after traumatic brain injury.

Objectives: The purpose of this study was to test the efficacy of a novel endothelin receptor A antagonist on blood flow and behavioral outcome given 30 minutes following traumatic brain injury.

Methods: Male Sprague-Dawley rats (400-450 g) were used in this study. All animals were scanned for initial blood flow using arterial spin labeling magnetic resonance imaging (n = 72 total).

Differential effects of endothelin receptor A and B antagonism on behavioral outcome following traumatic brain injury.

Objectives: Previously we have reported that endothelin receptor A and B antagonists elicit differential effects on cerebral blood flow and cellular damage. In summary, endothelin receptor A antagonists restore microcirculation and diminish cellular damage after injury, while endothelin receptor B antagonists had no effect on either parameter. However, what is not known is the effect of either antagonist on behavioral outcome.

Endothelin receptor A antagonism reduces the extent of diffuse axonal injury in a rodent model of traumatic brain injury.

Objectives: While endothelin-1 and its receptors have traditionally been associated with mediating vasoreactivity, we have recently shown that the vast majority of endothelin receptor A expression following traumatic brain injury is localized within the neuron. While it has been suggested that endothelin receptor A plays a role in influencing neuronal integrity, the significance of neuronally expressed endothelin receptor A remains unclear. One report suggests that endothelin-1 signaling mediates diffuse axonal injury.

Endothelin receptors A and B are expressed in distinct cellular compartments of rat hippocampus following global ischemia: an immunocytochemical study.

Objectives: The syntheses of endothelin receptors A and B were previously shown to be upregulated in rat dorsal hippocampus after traumatic brain injury. Here we characterize endothelin receptor A and endothelin receptor B cellular distribution in hippocampus after permanent global brain ischemia and their possible association to nerve cell injury.

Methods: Twenty-minute global ischemia was induced using the Pulsinelli's four-vessel occlusion in conjunction with systemic hypovolemia in male rats.

Polyadenylated mRNA staining reveals distinct neuronal phenotypes following endothelin 1, focal brain ischemia, and global brain ischemia/ reperfusion.

Objectives: Most work on ischemia-induced neuronal death has revolved around the relative contributions of necrosis and apoptosis, but this work has not accounted for the role of ischemia-induced stress responses. An expanded view recognizes a competition between ischemia-induced damage mechanisms and stress responses in the genesis of ischemia-induced neuronal death. An important marker of post-ischemic stress responses is inhibition of neuronal protein synthesis, a morphological correlate of which is the compartmentalization of mRNA away from ribosomes in the form of cytoplasmic mRNA granules.

The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury.

Object: The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) permeability alterations and brain edema formation in a rodent traumatic brain injury (TBI) model.

Methods: The brains of adult male Sprague-Dawley rats (400-425 g) were injured using the Marmarou closed-head force impact model. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (2ME2, an inhibitor of HIF-1α), was administered intravenously 30 minutes after injury.

Sequential abnormalities in type 1 diabetic encephalopathy and the effects of C-Peptide.

Diabetic encephalopathy is a recently recognized complication in type 1 diabetes. In this review, we summarize a series of experimental results obtained longitudinally in the spontaneously type 1 diabetic BB/Wor-rat, and bringing out the beneficial effects of C-peptide replacement. It is increasingly clear that lack of insulin and C-peptide, and perturbations of their signaling cascades in type 1 diabetes are detrimental to the regulation of neurotrophic factors and their receptors.

Differential effects of endothelin receptor A and B antagonism on cerebral hypoperfusion following traumatic brain injury.

Objectives: Our laboratory has previously shown that endothelin 1 (ET-1), a powerful vasoconstrictor, and its receptors, A (ETrA) and B (ETrB), are up-regulated following trauma. This up-regulation coincides temporally with enhanced vasoreactivity in cerebral cortical microvessels, which leads to a state of chronic hypoperfusion for up to 48 hours following traumatic brain injury (TBI). However, the direct contribution of either receptor up-regulation to decreased cerebral blood flow (CBF) after closed head trauma has not been determined.

Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide.

Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide.