Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clomethiazole has been marketed for several years as a sedative/antiepileptic. Astra is now developing it for the potential treatment of stroke. An NDA is expected to be filed in 1999/2000. A North American phase III trial for large stroke has commenced. This will include 1200 patients. Two other smaller scale phase III studies with clomethiazole have also commenced in North America for intracerebral hemorrhage (n=200) and safety in combination with TPA (n=100 to 200) (Genentech). A large-scale phase III trial has been completed in which clomethiazole was evaluated for its ability to reduce nerve damage in acute cerebrovascular ischemia. The multicenter, international trial, called CLASS (Clomethiazole Acute Stroke Study), analyzed 1360 patients and found no significant treatment effect. However, a subgroup of patients who presented with large stroke, experienced a significant benefit. Of these (n=545), 41% treated patients were functionally independent after 90 days, compared to 30% patients on placebo. Clomethiazole reduced functional disability and brain damage in the marmoset permanent MCAO model. Clomethiazole is thought to act through a GABAergic pathway, whereby it augments GABA's depressive effect on the CNS, giving the drug both hypnotic and neuroprotectant properties.
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PMID:Clomethiazole (Astra Arcus AB). 1616 Sep 52

Pyruvate given in large doses may be neuroprotective in stroke, but it is not known to what degree the brain metabolizes pyruvate. Intravenous injection of [3-13C]pyruvate led to dose-dependent labelling of cerebral metabolites so that at 5 min after injection of 18 mmoles [3-13C]pyruvate/kg (2 g sodium pyruvate/kg), approximately 20% of brain glutamate and GABA were labelled, as could be detected by 13C nuclear magnetic resonance spectrometry ex vivo. Pyruvate, 9 mmoles/kg, was equivalent to glucose, 9 mmoles/kg, as a substrate for cerebral tricarboxylic acid (TCA) cycle activity. Inhibition of the glial TCA cycle with fluoroacetate did not affect formation of [4-13C]glutamate or [2-13C]GABA from [3-13C]pyruvate, but reduced formation of [4-13C]glutamine by 50%, indicating predominantly neuronal metabolism of exogenous pyruvate. Extensive formation of [3-13C]lactate from [2-13C]pyruvate demonstrated reversible carboxylation of pyruvate to malate and equilibration with fumarate, presumably in neurones, but anaplerotic formation of TCA cycle intermediates from exogenous pyruvate could not be detected. Too rapid injection of large amounts of pyruvate led to seizure activity, respiratory arrest and death. We conclude that exogenous pyruvate is an excellent energy substrate for neurones in vivo, but that care must be taken to avoid the seizure-inducing effect of pyruvate given in large doses.
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PMID:Brain metabolism of exogenous pyruvate. 1618 32

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.
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PMID:Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice. 1638 Jul 13

Before exocytotic release of the inhibitory neurotransmitter GABA, this amino acid has to be stored in synaptic vesicles. Accumulation of GABA in vesicles is achieved by a specific membrane-integrated transporter termed vesicular GABA transporter. This vesicular protein is mainly located at presynaptic terminals of GABAergic interneurons. In the present study we investigated the effects of focal ischemia on the expression of the vesicular GABA transporter. Vesicular GABA transporter mRNA and protein expression was examined after photothrombosis in different cortical and hippocampal brain regions of Wistar rats. In situ hybridization and quantitative real-time RT-PCR were performed to analyze vesicular GABA transporter mRNA. Both vesicular GABA transporter mRNA-stained perikarya and mRNA expression levels remained unaffected. Vesicular GABA transporter protein-containing synaptic terminals and somata were visualized by immunohistochemistry. The pattern of vesicular GABA transporter immunoreactivity as well as the protein expression level revealed by semiquantitative image analysis and by Western blot remained stable after stroke. The steady expression of vesicular GABA transporter mRNA and protein after photothrombosis indicates that the exocytotic release mechanism of GABA is not affected by ischemia.
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PMID:Stable expression of the vesicular GABA transporter following photothrombotic infarct in rat brain. 1661 31

Brain edema is a serious consequence of hemispheric stroke and traumatic brain injury and contributes significantly to patient mortality. In the present study, we measured water contents in hippocampal slices as an in vitro model of edema formation. Excitotoxic conditions induced by N-methyl-D-aspartate (NMDA, 300 microM), as well as ischemia induced by oxygen-glucose deprivation (OGD), caused cellular edema formation as indicated by an increase of slice water contents. In the presence of furosemide, an inhibitor of the Na,K,Cl-cotransporter, NMDA-induced edema were reduced by 64% while OGD-induced edema were unaffected. The same observation, i.e., reduction of excitotoxic edema formation but no effect on ischemia-induced edema, was made with chloride transport inhibitors such as DIDS and niflumic acid. Under ischemic conditions, modulation of GABAA receptors by bicuculline, a GABA antagonist, or by diazepam, a GABAergic agonist, did not significantly affect edema formation. Further experiments demonstrated that low chloride conditions prevented NMDA-induced, but not OGD-induced, water influx. Omission of calcium ions had no effect. Our results show that NMDA-induced edema formation is highly dependent on chloride influx as it was prevented by low-chloride conditions and by various compounds that interfere with chloride influx. In contrast, OGD-induced edema observed in brain slices was not affected by modulators of chloride fluxes. The results are discussed with reference to ionic changes occurring during tissue ischemia.
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PMID:Effects of chloride flux modulators in an in vitro model of brain edema formation. 1701 30

Excitotoxicity is associated with stroke, brain trauma, and a number of neurodegenerative disorders. In the brain, during excitotoxic insults, neurons undergo rapid swelling in both the soma and dendrites. Focal swellings along the dendrites called varicosities are considered to be a hallmark of acute excitotoxic neuronal injury. However, it is not clear what pathway is involved in the neuronal anion flux that leads to the formation and resolution of excitotoxic varicosities. Here, we assessed the roles of the volume-sensitive outwardly rectifying (VSOR) Cl- channel in excitotoxic responses in mouse cortical neurons. Whole-cell patch-clamp recordings revealed that the VSOR Cl- channel in cultured neurons was activated by NMDA exposure. Moreover, robust expression of this channel on varicosities was confirmed by on-cell and nystatin-perforated vesicle patch techniques. VSOR channel blockers, but not blockers of GABA(A) receptors and Cl- transporters, abolished not only varicosity resolution after sublethal excitotoxic stimulation but also necrotic death after sustained varicosity formation induced by prolonged NMDA exposure in cortical neurons. The present slice-patch experiments demonstrated, for the first time, expression of the VSOR Cl- channels in somatosensory pyramidal neurons. NMDA-induced necrotic neuronal death in slice preparations was largely suppressed by a blocker of the VSOR Cl- channel but not of the GABA(A) receptor. These results indicate that VSOR Cl- channels exert dual, reciprocal actions on neuronal excitotoxicity by serving as major anionic pathways both for varicosity recovery after washout of an excitotoxic stimulant and for persistent varicosity formation under prolonged excitotoxic insults leading to necrosis in cortical neurons.
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PMID:Roles of volume-sensitive chloride channel in excitotoxic neuronal injury. 1728 19

Thyroid hormones are of primary importance for the perinatal development of the central nervous system, and for normal function of the adult brain. These hormones primarily regulate the transcription of specific target genes. They increase the cortical serotonergic neurotransmission, and play an important role in regulating central noradrenergic and GABA function. Thyroid deficiency during the perinatal period results in mental retardation. Hypothyroidism of the adults causes most frequently dementia and depression. Other less common clinical pictures include myxoedema coma, dysfunction of cerebellum and cranial nerves. Hypothyroidism also increases predisposition of stroke. Peripheral diseases frequently include polyneuropathy, carpal tunnel syndrome, myalgic state, and rarely myokymia. Nearly all the hyperthyroid patients show minor psychiatric signs, and infrequently psychosis, dementia, confusion state, depression, apathetic thyrotoxicosis, thyrotoxic crisis, seizures, pyramidal signs, or chorea occur. The peripheral complications may be indicated by chronic thyrotoxic myopathy, infiltrative ophthalmopathy, myasthenia gravis, periodic hypokalemic paralysis and polyneuropathy. Generalized resistance to thyroid hormone was confirmed in a number of patients with attention deficit-hyperactivity disorder. Significantly elevated antithyroid antibody titers characterize Hashimoto's encephalopathy. This condition is a rare, acute - subacute, serious, life threatening, but steroid-responsive, relapsing-remitting, autoimmune disease.
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PMID:[Some neurologic and psychiatric complications in endocrine disorders: the thyroid gland]. 1734 50

To investigate the neuroprotective effect of taurine and the involved mechanisms, middle cerebral artery occlusion (MCAO) was induced with suture for 2h in rat, and the brain tissue was then reperfused. The infarct volume and cerebral damage area were measured, respectively, with 2,3,5-triphenyltetrazolium chloride (TTC) staining and MRI. Nissl staining was used for histological observation, and immunohistochemistry and Western-blot analysis for detecting the activated caspase-3 expression. Both pre- (200mgkg(-1)) and post-treatment of taurine decreased the neurology deficit score, infarct volume and brain water content. Taurine post-treatment (67, 200 and 600mgkg(-1)) showed a dose-dependent neuroprotective effect. Taurine (200mgkg(-1)) significantly decreased neuronal loss in the cerebral cortex and hippocampus, and reduced the expression of caspase-3 as well. The neuroprotective effect of taurine was partly blunted by strychnine or bicuculline alone, and almost completely blocked by coapplication of both antagonists of glycine and GABA(A) receptors. It is suggested that taurine exerts a neuroprotective role on the brain when administered before or after MCAO. Such effect is possibly mediated by the activation of both GABA(A) receptors and strychnine-sensitive glycine receptors. Moreover, inhibition of caspase-3 expression is involved in this neuroprotective effect. These results imply a potential therapeutic use of taurine for stroke.
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PMID:Neuroprotective effect of taurine against focal cerebral ischemia in rats possibly mediated by activation of both GABAA and glycine receptors. 1738 36

Elevation of brain temperature after stroke can lead to severe brain injury and even a moderate hyperthermia correlates with increased nervous damage. The role of endogenous cryogens in the pathways that down-regulate body temperature are of overwhelming interest in view of their effectiveness in protecting brain from such damage. The aim of the present work was to study whether heat stress (HS) or fever generates brain homeostatic responses aimed at counteracting the resulting rise in body temperature. Conscious rabbits, with cannulas chronically implanted in the cisterna magna and lateral ventricle, underwent HS (50 min, 40 degrees C) or were injected with 25 ng of endogenous pyrogen IL-1beta, while cerebrospinal fluid (CSF) levels of amino acids involved in central mechanisms of thermoregulation like taurine, GABA, aspartate and glutamate were monitored. The concentrations of some CSF cations (Na(+), K(+), Mg(2+) and Ca(2+)) were also determined in view of their purported role (sodium and calcium in particular) in establishing the thermal set point within the hypothalamus. Results show that during HS-induced hyperthermia, CSF taurine and GABA levels were significantly increased. On the contrary, IL-1beta caused an increase in CSF taurine and, concurrently, a decrease in CSF GABA. Aspartate and glutamate did not change in both conditions. Furthermore, among CSF cations, only calcium and sodium underwent changes. In particular, calcium content increased both in HS- and febrile-animals, while CSF sodium decreased significantly only under IL-1beta-injected treatment. In conclusion, GABA and taurine contribute as endogenous cryogens in a different fashion to the central mechanisms, which regulate dissipation of body heat in hyperthermia or heat production in fever, possibly in coordination with extracellular calcium and sodium.
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PMID:Changes in CSF composition during heat stress and fever in conscious rabbits. 1764 32

Motor cortex stimulation (MCS) was proposed by Tsubokawa in 1991 for the treatment of post-stroke thalamic pain. Since that time, the indications have been increased and included trigeminal neuropathic pain and later other types of central and peripheral deafferentation pain. The results reported in the literature are quite good; the mean long-term success rate is 80% in facial pain and 53% in non-facial pain. Our own results are less impressive: 4 of 14 patients (28%) experienced a greater than 40% pain relief, but in 2 of them the effect faded with time. Only few minor complications have been reported. The accurate placement of the epidural electrode over the motor cortex that somatotopically corresponds to the painful area is believed to be essential for pain relief. Predictive factors included the response to pharmacological tests, the relative sparing from the disease process of the cortico-spinal tract and the sensory system, and the analgesic response achieved during the test period of MCS. A possible predictive factor might be a test of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. MCS may act by rebalancing the control of non-nociceptive sensory inputs over nociceptive afferents at cortical, thalamic, brainstem and spinal level. In addition, it may interfere with the emotional component of nociceptive perception. Biochemical processes involving endorphins and GABA may also be implicated in the mechanism of MCS. It is time for a large multicenter prospective randomized double blind study evaluating not only the effect of MCS on pain (based on the available guidelines for assessment of neuropathic pain), but also the optimal electrode placement and stimulation parameters, and the possible relationship with the response to rTMS. New electrode design and a new generation of stimulators may help in improving the results.
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PMID:Motor cortex stimulation for chronic non-malignant pain: current state and future prospects. 1769 Dec 88


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