Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848771 (neurological disability)
 928 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The newer dihydropyridine calcium antagonists are structurally related to nifedipine, but may provide greater vascular selectivity and wider clinical utility. Five new dihydropyridines-nisoldipine, nicardipine, nimodipine, felodipine and nitrendipine-are reviewed with regard to their preclinical pharmacology, haemodynamic effects and clinical indications. Nisoldipine is a potent arterial vasodilator with minimal electrophysiological and negative inotropic effects. Although data are still preliminary, the drug has shown some efficacy in both exertional angina and essential hypertension. The dosing interval is not yet clearly established, but may be twice daily. Utility in congestive heart failure awaits confirmation, but preliminary studies are promising. Nicardipine is an especially potent peripheral, cerebral and coronary arterial vasodilator that causes 10-fold less myocardial depression in animals than nifedipine, and may provide important cardioprotective effects during ischaemia. Human haemodynamic studies have confirmed nicardipine's lack of negative inotropism, its ability to reduce coronary and peripheral vascular resistance, and its lack of effect on cardiac conduction. Several controlled trials have documented its efficacy in exertional angina, vasospastic angina, and essential hypertension. Nicardipine's potential as an antiatherosclerotic agent is currently under investigation. Nimodipine is undergoing a unique clinical development programme aimed at cerebrovascular disorders. In almost all species, nimodipine selectively increases cerebral blood flow and reverses cerebral artery spasm without altering cerebral oxidative metabolism or systemic blood pressure. In humans, a large, double-blind, placebo-controlled trial in subarachnoid haemorrhage showed that nimodipine significantly reduced the severity of neurological deficits associated with delayed cerebral vasospasm. Several uncontrolled trials with larger numbers of patients support these results. Nimodipine has also proved useful in reducing cerebral artery spasm during intracranial surgery, and in the prophylactic treatment of migraine headaches. A preliminary study of nimodipine in acute stroke showed promising results in limiting neurological disability. Felodipine is a very potent systemic arterial vasodilator with negligible myocardial depressant activity. It is also a renal artery vasodilator. Unlike the other new dihydropyridines, felodipine prolongs the A-H interval on electrophysiological testing, but only to about 50% of that observed with verapamil. Felodipine is undergoing clinical trials in essential hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:'Second generation' dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications. 331 91

Axonal degeneration within the spinal cord contributes substantially to neurological disability in multiple sclerosis (MS). Thus neuroprotective therapies that preserve axons, so that they maintain their integrity and continue to function, might be expected to result in improved neurological outcome. Sodium channels are known to provide a route for sodium influx that can drive calcium influx, via reverse operation of the Na+/Ca2+ exchanger, after injury to axons within the CNS, and sodium channel blockers have been shown to protect CNS axons from degeneration after experimental anoxic, traumatic, and nitric oxide (NO)-induced injury. In this study, we asked whether phenytoin, which is known to block sodium channels, can protect spinal cord axons from degeneration in mice with experimental allergic encephalomyelitis (EAE), which display substantial axonal degeneration and clinical paralysis. We demonstrate that the loss of dorsal corticospinal tract (63%) and dorsal column (cuneate fasciculus; 43%) axons in EAE is significantly ameliorated (corticospinal tract: 28%; cuneate fasciculus: 17%) by treatment with phenytoin. Spinal cord compound action potentials (CAP) were significantly attenuated in untreated EAE, whereas spinal cords from phenytoin-treated EAE had robust CAPs, similar to those from phenytoin-treated control mice. Clinical scores in phenytoin-treated EAE at 28 days were significantly improved (1.5, i.e., minor righting reflex abnormalities) compared with untreated EAE (3.8, i.e., near-complete hindlimb paralysis). Our results demonstrate that phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials, and improving clinical status in a model of neuroinflammation.
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PMID:Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. 1290 34

Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.
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PMID:A key role for TRPM7 channels in anoxic neuronal death. 1469 96

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, are inflammatory demyelinating diseases of the central nervous system. The inflammatory attacks lead to glial dysfunction and death, axonal damage, and neurological deficits. Numerous studies in rat suggest that extracellular calcium influx, via voltage-gated calcium channels (VGCC), contributes to white matter damage in acute spinal cord injury and stroke. Our immunohistochemical finding that mouse spinal cord axons display subunits of L-type VGCC also supports this hypothesis. Furthermore, we hypothesized that VGCC also play a role in EAE, and possibly, MS. In our study, administration of the calcium channel blockers (CCB) bepridil and nitrendipine significantly ameliorated EAE in mice, compared with vehicle-treated controls. Spinal cord samples showed reduced inflammation and axonal pathology in bepridil-treated animals. Our data support the hypothesis that calcium influx via VGCC plays a significant role in the development of neurological disability and white matter damage in EAE and MS.
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PMID:Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. 1529 30

Multiple Sclerosis is the most common inflammatory demyelinating disease of the central nervous system and is the leading cause of non traumatic neurological disability in young adults. In recent years it has become increasingly evident that axonal degeneration is a key player in the pathogenesis of disability in MS but the mechanisms that lead to axonal damage are not fully understood. It seems likely that the causes of axonal damage vary at different stages of the disease and several theories have evolved that address the mechanisms leading to axonal loss in the acute stages of demyelination. There has been relatively little attention given to investigation of the mechanisms involved in chronic axonal loss in the progressive stages of MS. We propose a hypothesis that mitochondria play a key role in this chronic axonal loss. Following demyelination there is redistribution of sodium channels along the axon and mitochondria are recruited to the demyelinated regions to meet the increased energy requirements necessary to maintain conduction. The mitochondria present within the chronically demyelinated axons will be functioning at full capacity. The axon may well be able to function for many years due to these adaptive mechanisms but we propose that eventually, despite antioxidant defences, free radical damage will accumulate and mitochondrial function will become compromised. ATP concentration within the axon will decrease and the effect on axonal function will be profound. The actual cause of cell death could be due to a number of mechanisms related to mitochondrial dysfunction including failure of ionic homeostasis, calcium influx, mitochondrial mediated cell death or impaired axonal transport. Whatever the cause of axonal loss our hypothesis is that mitochondria are central to this process. We explore steps to test this hypothesis and discuss the possible therapeutic approaches which target the mitochondrial mechanisms that may contribute to chronic axonal loss.
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PMID:Mitochondrial dysfunction plays a key role in progressive axonal loss in Multiple Sclerosis. 1569 81

Brain ischemia results in neuronal injury and neurological disability. The present study examined the effect of mild (6% O2) and severe (2% O2) hypoxia on mitochondria of rat cortical synaptosomes. During mild and severe hypoxia, JO2 and ATP production significantly decreased and mitochondrial membranes depolarized. Synaptosomal calcium concentration increased slightly, albeit not significantly. After a 1 h re-oxygenation period, JO2, ATP production and mitochondrial membrane potential returned to control levels in synaptosomes incubated in 6% O2. In synaptosomes incubated in 2% O2, however, the ATP production was not restored after re-oxygenation and intrasynaptosomal Ca2+ significantly increased. The results indicate that both mild and severe hypoxia influence the physiology of synaptosomal mitochondria; the modifications are reversible after mild hypoxia and but partly irreversible after severe hypoxia.
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PMID:The effect of mild and severe hypoxia on rat cortical synaptosomes. 1625 47

The concept of multiple sclerosis (MS) as a demyelinating disease is deeply ingrained. Although the existence of a neurodegenerative component has always been apparent, it has only recently become emphasized. Thus, in recent years several studies have identified axonal degeneration as the major determinant of irreversible neurological disability in patients with MS. Axonal injury begins at disease onset and remains clinically silent for many years; irreversible neurological disability develops when a threshold of axonal loss is reached and CNS compensatory mechanisms are exhausted. The precise mechanisms of axonal loss are poorly understood, and three hypotheses have been proposed: 1) The damage is caused by an inflammatory process, 2) There is an excessive accumulation of intra-axonal Ca2+, 3) Demyelinated axons undergo degeneration due to lack of trophic support by myelin, or myelin forming cells. Although MS has traditionally been regarded as a disease of white matter, demyelination can also occur in the cerebral cortex. Cortical lesions exhibit neuronal injury represented by dendritic and axonal transection as well as neuronal apoptosis. Because conventional nuclear magnetic resonance (NMR) is limited in its ability to provide specific information about axonal pathology in MS, new techniques such as, diffusion-weighted MRI, proton magnetic resonance spectroscopy, functional MRI, as well as novel techniques designed to measure atrophy have been developed to monitor MS evolution. Recognition that MS is in part a neurodegenerative disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment.
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PMID:[Neuronal injury in multiple sclerosis]. 1713 82

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults, affecting some two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability [Frohman EM, Racke MK, Raine CS (2006) N Engl J Med 354:942-955]. More recently, MS has become increasingly viewed as a neurodegenerative disorder in which neuronal loss, axonal injury, and atrophy of the CNS lead to permanent neurological and clinical disability. Although axonal pathology and loss in MS has been recognized for >100 years, very little is known about the underlying molecular mechanisms. Progressive axonal loss in MS may stem from a cascade of ionic imbalances initiated by inflammation, leading to mitochondrial dysfunction and energetic deficits that result in mitochondrial and cellular Ca2+ overload. In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD), a key regulator of the mitochondrial permeability transition pore (PTP), developed EAE, but unlike WT mice, they partially recovered. Examination of the spinal cords of CyPD-knockout mice revealed a striking preservation of axons, despite a similar extent of inflammation. Furthermore, neurons prepared from CyPD-knockout animals were resistant to reactive oxygen and nitrogen species thought to mediate axonal damage in EAE and MS, and brain mitochondria lacking CyPD sequestered substantially higher levels of Ca2+. Our results directly implicate pathological activation of the mitochondrial PTP in the axonal damage occurring during MS and identify CyPD, as well as the PTP, as a potential target for MS neuroprotective therapies.
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PMID:Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. 1746 82

Multiple sclerosis (MS), an inflammatory demyelinating disease, is a major cause of neurological disability in young adults in the developed world. Although the progressive neurological disability that most patients with MS eventually experience results from axonal degeneration, little is known about the mechanisms of axonal injury in MS. Accumulating evidence suggests that the increased energy demand of impulse conduction along excitable demyelinated axons and reduced axonal ATP production induce a chronic state of virtual hypoxia in chronically demyelinated axons. In response to such a state, key alterations that contribute to chronic necrosis of axons might include mitochondrial dysfunction (due to defective oxidative phosphorylation or nitric oxide production), Na+ influx through voltage-gated Na+ channels and axonal AMPA receptors, release of toxic Ca2+ from the axoplasmic reticulum, overactivation of ionotropic and metabotropic axonal glutamate receptors, and activation of voltage-gated Ca2+ channels, ultimately leading to excessive stimulation of Ca2+-dependent degradative pathways. The development of neuroprotective therapies that target these mechanisms might constitute effective adjuncts to currently used immune-modifying agents.
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PMID:Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. 1923 38

Dysmyelination contributes to several human diseases including multiple sclerosis, Charcot-Marie-Tooth, leukodystrophies, and schizophrenia and can result in serious neurological disability. Properly formed, compacted myelin sheaths are required for appropriate nerve conduction velocities and the health and survival of neurons. Many different molecular mechanisms contribute to dysmyelination and many of these mechanisms originate at the level of the endoplasmic reticulum. The endoplasmic reticulum is a critical organelle for myelin biosynthesis and maintenance as the site of myelin protein folding quality control, Ca2+ homeostasis, cholesterol biosynthesis, and modulation of cellular stress. This review paper highlights the role of the endoplasmic reticulum and its resident molecules as an upstream and dynamic contributor to myelin and myelin pathologies.
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PMID:Endoplasmic reticulum quality control and dysmyelination. 2596 34


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