Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of nerve cell death in neuronal degenerative disease is unknown, but it has been hypothesized that excitotoxic mechanisms may play a role. Such mechanisms may play a role in diseases such as Huntington's disease, Parkinson's disease, amyotropic lateral sclerosis, and Alzheimer's disease. In these illnesses, the slowly evolving neuronal death is unlikely to be due to a sudden release of glutamate, such as occurs in ischemia. One possibility, however, is that a defect in mitochondrial energy metabolism could secondarily lead to slow excitotoxic neuronal death, by making neurons more vulnerable to endogenous glutamate. With reduced oxidative metabolism and partial cell membrane depolarization, voltage-dependent N-methyl-D-aspartate (NMDA) receptor ion channels would be more easily activated. In addition, several other processes involved in buffering intracellular calcium may be impaired. Recent studies in experimental animals showed that mitochondrial toxins can result in a pattern of neuronal degeneration closely resembling that seen in Huntington's disease, which can be blocked with NMDA antagonists. NMDA antagonists also block neuronal degeneration induced by 1-methyl-4-phenylpyridium, which has been implicated in experimental models of Parkinson's disease. The delayed onset of neurodegenerative illnesses could be related to the progressive impairment of mitochondrial oxidative phosphorylation, which accompanies normal aging. If defective mitochondrial energy metabolism plays a role in cell death in neurodegenerative disorders, potential therapeutic strategies would be to use excitatory amino acid antagonists or agents to bypass bioenergetic defects.
 ...
PMID:Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? 134 66

Glutamate is the major excitatory neurotransmitter in the mammalian brain, with receptors on every neuron in the central nervous system; it has major roles in fast synaptic transmission and in the establishment of certain forms of memory. More than 20 years ago Olney and his colleagues described the 'Excitotoxic Hypothesis' which postulates that, in addition to its normal function in the healthy brain, glutamate can kill neurons by prolonged, receptor-mediated depolarization resulting in irreversible disturbances in ion homeostasis. Therefore, glutamate is a two-edged sword; in certain undefined, adverse conditions it undergoes a transition from neurotransmitter to neurotoxin. Its toxicity has been implicated in the death of neurons in ischemia, epilepsy, and the neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Recent advances in the molecular cloning of the genes for the glutamate family of receptors has revealed a plethora of receptor subtypes and an unexpected level of complexity in the mechanisms of receptor expression and function.
 ...
PMID:Cloning of the genes for excitatory amino acid receptors. 135 85

Neuronal degeneration that occurs in both ischemia and degenerative neurologic illnesses may involve excitotoxic mechanisms. In the present study, we examined whether cortical lesions with agonists acting at subtypes of glutamate receptors result in selective patterns of neuronal death. Injections of quinolinic acid, NMDA, homocysteic acid, kainic acid (KA), and alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) were made at 2 sites in the dorsolateral frontoparietal cortex in rats. After 1 week, the cerebral cortex was either dissected for neurochemical studies, or animals were perfused for histologic evaluation. Concentrations of somatostatin (SS), neuropeptide Y (NPY), substance P (SP), cholecystokinin (CCK), and vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay, while amino acids and catecholamines were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. NMDA agonists (quinolinic acid, homocysteic acid, and NMDA itself) resulted in dose-dependent reductions in glutamate and GABA, while SS, NPY, SP, CCK, and VIP were either unchanged or significantly increased in concentration. KA and AMPA at doses that resulted in comparable GABA depletions caused significant reductions in SS concentrations. Markers of cortical afferents were spared. All excitotoxins resulted in dose-dependent marked increases in uric acid concentrations. Histologic examination verified that lesions with NMDA agonists produced relative sparing of NADPH-diaphorase, SS, VIP, and CCK neurons. These results show that NMDA excitotoxin lesions result in a pattern of selective neuronal damage in the cerebral cortex that is similar to that which occurs in both ischemia and Huntington's disease.
 ...
PMID:Neurochemical characterization of excitotoxin lesions in the cerebral cortex. 167 Jul 82

Antagonists for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may have therapeutic potential as neuroprotectant agents in conditions of neuronal degeneration that include brain ischemia, Huntington's chorea, and Alzheimer's disease. Here we have investigated the pharmacological actions of LY274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY274614 potently displaced NMDA receptor ([3H]CGS19755) binding (IC50 = 58.8 +/- 10.3 nM), but had no appreciable affinity at [3H]AMPA or [3H]kainate receptor sites at up to 10,000 nM. NMDA-induced convulsions in neonatal rats or NMDA-induced lethality in mice are potently and selectively antagonized by i.p. or p.o. LY274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neurodegenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY274614 (2.5 to 20 mg/kg i.p.). LY274614 is an effective neuroprotectant agent against NMDA receptor-induced toxicity when administered systemically and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.
 ...
PMID:Neuroprotectant effects of LY274614, a structurally novel systemically active competitive NMDA receptor antagonist. 183 88

Acute neurological injury from hypoxia-ischemia, hypoglycemia, and trauma is thought to be predominantly mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain and the subsequent influx of calcium ions through receptor-operated channels. Several chronic degenerative diseases, such as Huntington's disease and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex found on Guam, may share a similar pathogenesis due to a glutamate-like toxin. This laboratory recently reported that exposure to a reducing agent, such as dithiothreitol (DTT), selectively increases ionic current flow through NMDA-activated channels in several types of central neurons; conversely, oxidizing agents reverse this effect. To investigate the novel influence of redox modulation on NMDA neurotoxicity, in the present in vitro study we monitored survival of an identified central neuron, the retinal ganglion cell, approximately 24 h after a brief exposure to DTT. To determine the degree of killing specifically related to activation of the NMDA receptor, 2-amino-5-phosphonovalerate (APV, a selective NMDA antagonist) was added to sibling cultures. APV-preventable, glutamate-induced death was increased 70 +/- 9% with DTT treatment. This effect was totally blocked by the concomitant addition of an oxidizing agent, 5,5-dithiobis-2-nitrobenzoic acid (DTNB). These findings suggest that the enhanced killing following chemical reduction with DTT is mediated at the NMDA receptor site, and that the redox state of the NMDA receptor is crucial for the survival of neurons facing glutamate-related injury.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons. 197 Jan 45

Amino acids such as L-glutamate und L-aspartate are major excitatory neurotransmitters in the mammalian central nervous system (CNS) and potential neurotoxins (excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e. N-methyl-D-aspartate- (NMDA), kainate- and quisqualate-receptors. In this review interest is focused primarily on the NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the NMDA-receptor-ionophore complex has an agonist binding site for glutamate, NMDA and related EAAs which is coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for glycine, phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the NMDA receptor. An additional polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of NMDA-mediated neurotransmission may have antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of NMDA-receptor antagonists in neurological diseases such as hypoxia/ischemia, hypoglycemia, epilepsy and chronic neurodegenerative disorders (Huntington's, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, and AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences]. 197 26

The pattern of ischemia-induced cell death was examined with histochemical methods in the striatum of adult gerbils 4 and 7 days after transient forebrain ischemia. The results showed a massive loss of immunoreactivity to enkephalin and tachykinins, peptides present in striatal efferent neurons. In contrast, neurons expressing acetylcholinesterase activity, or choline acetyltransferase immunoreactivity, as well as neurons immunoreactive for somatostatin, were relatively preserved in areas of severe neuronal loss. The selective vulnerability of subpopulations of striatal neurons to transient ischemia in the adult is similar to that observed in the neonate and after local injections of agonists of N-methyl-D-aspartate receptors, but not of agonists of other glutamate receptor subtypes. It also presents striking similarities to the pattern of neuronal death observed in Huntington's disease. The results further support a role for overstimulation of a subtype of excitatory amino acid receptor in ischemia-induced cell death and show that the selective sparing of subpopulations of striatal interneurons after ischemic injury is not related to immaturity of these neurons but also occurs in the adult.
 ...
PMID:Ischemic damage in the striatum of adult gerbils: relative sparing of somatostatinergic and cholinergic interneurons contrasts with loss of efferent neurons. 197 9

Evidence from experimental and clinical studies suggests the involvement of the endogenous opioid system in several neurologic and psychiatric disorders (Alzheimer's, Huntington's and Parkinson's diseases, drug-induced movement disorders, Gilles de la Tourette syndrome, stroke, ischemia, brain and spinal cord injury, epilepsy, schizophrenia and affective disorders). However, its involvement is rather a secondary one, perhaps being a severe consequence of a primary, nonopioid disturbance. Thus, treatment of an opioidergic manifestation of a disorder of nonopioidergic origin is necessarily symptomatic and targets only the restoration of the opioid system; such treatment may be beneficial in ameliorating the clinical symptoms of the disorder.
 ...
PMID:The opioid system in neurologic and psychiatric disorders and in their experimental models. 218 70

Glutamate is the putative neurotransmitter of several clinically important pathways, including cortical association fibers, corticofugal pathways such as the pyramidal tract, and hippocampal, cerebellar, and spinal cord pathways. The excitatory actions of glutamate are mediated by multiple, distinct receptor types and potent receptor antagonists have recently been developed. Glutamate also has neurotoxic properties and can produce "excitotoxic" lesions reminiscent of human neurodegenerative disorders. Abnormally enhanced glutamatergic neurotransmission may cause excitotoxic cell damage and lead to the neuronal death associated with olivopontocerebellar atrophy, Huntington's disease, status epilepticus, hypoxia/ischemia, and hypoglycemia. Pharmacologic manipulation of the glutamatergic system may have great potential for the rational treatment of a variety of neurologic diseases.
 ...
PMID:The role of glutamate in neurotransmission and in neurologic disease. 242 40

Positron computed tomography is a noninvasive medical imaging technique. Biologically active, radiolabeled compounds are administered intravenously to patients and the distribution of the radioactivity is quantitatively measured. By using appropriate mathematical models and labeled compounds, quantitative measurements of local metabolism, blood flow and volume, protein synthesis, transport, receptor binding, drug kinetics, and concentrations can be obtained noninvasively. This technique goes beyond medical imaging; it allows local analytic assays of biochemical reactions. In the heart, the technique measures local blood flow as well as myocardial free fatty acid and glucose metabolism, and can clinically evaluate patients with ischemic heart disease or cardiomyopathies. In the brain, positron computed tomography can be used to examine alterations in blood flow and metabolism including ischemia and degenerative disorders (Huntington's disease and Alzheimer's disease), cerebral tumors, and epilepsy. In normal persons, positron computed tomography shows cerebral activations resulting from physiologic stimulation (auditory and visual).
 ...
PMID:Positron computed tomography for studies of myocardial and cerebral function. 621 2


1 2 3 4 5 6 7 8 9 10 Next >>