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

Neurodegeneration associated with neurological disorders such as epilepsy, Huntington's Chorea, Alzheimer's disease, and olivoponto cerebellar atrophy or with energy failure such as ischemia, hypoxia, and hypoglycemia proceeds subsequent to overexposure of neurons to excitatory amino acids of which glutamate and aspartate may be quantitatively the most important. The toxic action of glutamate and aspartate is mediated through activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) and non-NMDA subtypes. Antagonists for these receptors can act as neuroprotectants both in in vitro model systems (e.g., cultured neurons) and in vivo. Activation of receptors leads to an increase in the intracellular Ca++ concentration and also to an increase in other second messengers such as cGMP. Thus, Ca++ channel antagonists may have neuroprotective action under certain conditions.
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PMID:Role of Ca+2 and other second messengers in excitatory amino acid receptor mediated neurodegeneration: clinical perspectives. 918 41

Injuries to certain parts of the brain may induce neuronal death in distant areas innervated by the sites of the primary lesion. Such characteristic pathological changes, known as anterograde transneuronal degeneration, may occur at the next and more distant synaptic levels and play a part in the slow progression of some types of system degeneration. Delayed transneuronal degeneration of the substantia nigra pars reticulata (SNr) is one example of this form of cell death, and it occurs as a consequence of a neostriatal lesion caused by focal ischemia, Huntington's disease, or experimental axon-sparing injections of neurotoxin. Ever since the demonstration by Saji and Reis that the administration of GABA receptor agonist effectively prevented delayed transneuronal degeneration of the SNr, the degeneration of nigral reticulata cells has been attributed to the loss of striatal inhibition (Fig. 1A). The latter process severely upset the balance of membrane potential of nigral reticulata cells, producing an effect resembling excitotoxicity. In this report, we describe a continuous intraventricular MK-801 infusion technique that is useful in clarifying the role of glutamatergic action via N-methyl-D-aspartate (NMDA) receptor subclasses involved in exo-focal postischemic death of the SNr.
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PMID:Continuous intraventricular drug infusion for the in vivo study of transneuronal degeneration in the striatonigral system of the rat. 938 18

To evaluate the relative ability of those striatal neuron types containing calbindin or parvalbumin to withstand a Ca(2+)-mediated excitotoxic insult, we injected the NMDA receptor-specific excitotoxin quinolinic acid (QA) into the striatum in mature adult rats and 2 months later examined the relative survival of striatal interneurons rich in parvalbumin and striatal projection neurons rich in calbindin. To provide standardization to the survival of striatal neuron types thought to be poor in Ca2+ buffering proteins, the survival was compared to that of somatostatin-neuropeptide Y (SS/NPY)-containing interneurons and enkephalinergic projection neurons, which are devoid of or relatively poorer in such proteins. The various neuron types were identified by immunohistochemical labeling for these type-specific markers and their relative survival was compared at each of a series of increasing distances from the injection center. In brief, we found that parvalbuminergic, calbindinergic, and enkephalinergic neurons all showed a generally comparable gradient of neuronal loss, except just outside the lesion center, where calbindin-rich neurons showed significantly enhanced survival. In contrast, striatal SS/NPY interneurons were more vulnerable to QA than any of these three other types. These observed patterns of survival following intrastriatal QA injection suggest that calbindin and parvalbumin content does not by itself determine the vulnerability of striatal neurons to QA-mediated excitotoxicity in mature adult rats. For example, parvalbuminergic striatal interneurons were not impervious to QA, while cholinergic striatal interneurons are highly resistant and SS/NPY+ striatal interneurons are highly vulnerable. Both cholinergic and SS/NPY+ interneurons are devoid of any known calcium buffering protein. Similarly, calbindin does not prevent striatal projection neuron vulnerability to QA excitotoxicity. Nonetheless, our data do suggest that calbindin may offer striatal neurons some protection against moderate excitotoxic insults, and this may explain the reportedly slightly greater vulnerability of striatal neurons that are poor in calbindin to ischemia and Huntington's disease.
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PMID:Relative resistance of striatal neurons containing calbindin or parvalbumin to quinolinic acid-mediated excitotoxicity compared to other striatal neuron types. 950 Sep 58

Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD) and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are spared in these pathological conditions. We have investigated whether a different sensitivity to ionotropic glutamatergic agonists might account for this differential vulnerability. Intracellular recordings were obtained from morphologically identified striatal spiny neurons and LA cholinergic interneurons by using a rat brain slice preparation. The two striatal neuronal subtypes had strikingly different intrinsic membrane properties. Both subtypes responded to cortical stimulation with excitatory postsynaptic potentials: these potentials, however, had a different time course and pharmacology in the two classes of cells. Interestingly, membrane depolarizations and inward currents produced by exogenous glutamate receptor agonists (AMPA, kainate, and NMDA) were remarkably larger in spiny neurons than in LA interneurons. Moreover, concentrations of agonists producing reversible membrane changes in LA interneurons caused irreversible depolarizations in spiny cells. Our data suggest that the different physiological responses induced by the activation of ionotropic glutamate receptors may account for the cell type-specific vulnerability of striatal neurons in ischemia and HD.
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PMID:Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: implications for ischemia and Huntington's disease. 958 52

Intrastriatal injections of the mitochondrial toxins malonate and 3-nitropropionic acid produce selective cell death similar to that seen in transient ischemia and Huntington's disease. The extent of cell death can be attenuated by pharmacological or surgical blockade of cortical glutamatergic input. It is not known, however, if dopamine contributes to toxicity caused by inhibition of mitochondrial function. Exposure of primary striatal cultures to dopamine resulted in dose-dependent death of neurons. Addition of medium supplement containing free radical scavengers and antioxidants decreased neuronal loss. At high concentrations of the amine, cell death was predominantly apoptotic. Methyl malonate was used to inhibit activity of the mitochondrial respiratory chain. Neither methyl malonate (50 microM) nor dopamine (2.5 microM) caused significant toxicity when added individually to cultures, whereas simultaneous addition of both compounds killed 60% of neurons. Addition of antioxidants and free radical scavengers to the incubation medium prevented this cell death. Dopamine (up to 250 microM) did not alter the ATP/ADP ratio after a 6-h incubation. Methyl malonate, at 500 microM, reduced the ATP/ADP ratio by approximately 30% after 6 h; this decrease was not augmented by coincubation with 25 microM dopamine. Our results suggest that dopamine causes primarily apoptotic death of striatal neurons in culture without damaging cells by an early adverse action on oxidative phosphorylation. However, when combined with minimal inhibition of mitochondrial function, dopamine neurotoxicity is markedly enhanced.
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PMID:Toxicity of dopamine to striatal neurons in vitro and potentiation of cell death by a mitochondrial inhibitor. 960 5

Glutamate neurotoxicity has been implicated in acute neurological disorders such as ischemia, and in chronic neurodegenerative diseases such as Huntington's disease (HD). Recently, a link between excitotoxicity and impairment of energy metabolism has been proposed. Important evidence suggests that metabolic inhibition exacerbates the toxic effect of glutamate. During hypoxic/ischemia metabolic disturbances are obvious, and several metabolic defects have been found in HD patients. Disruption of the ionic gradients during inhibition of metabolism can lead to glutamate release, impairment of glutamate transport, and activation of NMDA receptors. Glutamate receptor activation results in calcium influx which is a determinant step leading to cell death. Additionally mitochondrial failure results in an inadequate buffering of the calcium load induced by glutamate contributing to cell death.
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PMID:The role of excitotoxicity and metabolic failure in the pathogenesis of neurological disorders. 971 34

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.
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PMID:Nitric oxide synthases: targets for therapeutic strategies in neurological diseases. 1044 86

Differential sensitivity to glutamate has been proposed to contribute to the cell-type-specific vulnerability observed in neurological disorders affecting the striatum such as Huntington's disease (HD) and global ischemia. Under these pathological conditions striatal spiny neurons are selectively lost while large aspiny (LA) cholinergic interneurons are spared. We studied the electrophysiological effects of metabotropic glutamate receptor (mGluR) activation in striatal spiny neurons and LA interneurons in order to define the role of these receptors in the pathophysiology of the striatum. DCG-IV and L-SOP, agonists for group II and III mGluRs respectively, produced a presynaptic inhibitory effect on corticostriatal glutamatergic excitatory synaptic potentials in both spiny neurons and LA interneurons. Activation of group I mGluRs by the selective agonist 3,5-DHPG produced no detectable effects on membrane properties and glutamatergic synaptic transmission in spiny neurons while it caused a slow membrane depolarization in LA interneurons coupled to increased input resistance. In combined electrophysiological and microfluorometric recordings, 3,5-DHPG strongly enhanced membrane depolarizations and intracellular Ca2+ accumulation induced by NMDA applications in spiny neurons but not in LA interneurons. Activation of protein kinase C (PKC) by phorbol 12,13-diacetate mimicked this latter action of 3,5-DHPG while the facilitatory effect of 3,5-DHPG was prevented by calphostin C, an inhibitor of PKC. These data indicate that a positive interaction between NMDA receptors and group I mGluRs, via PKC activation, is differently expressed in these two neuronal subtypes. Our data also suggest that differential effects of the activation of group I mGluRs, but not of group II and III mGluRs, might partially account for the selective vulnerability to excitotoxic damage observed within the striatum.
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PMID:Metabotropic glutamate receptors and cell-type-specific vulnerability in the striatum: implication for ischemia and Huntington's disease. 1044 21

Striatal neurones receive myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide and adenosine. All these neurotransmitter systems interact each other and with voltage-dependent conductances to regulate the efficacy of the synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurones on this converging information dictates the final output of the striatum to the other basal ganglia structures. Recent morphological, immunohistochemical and electrophysiological findings demonstrated that the striatum also contains different interneurones, whose role in physiological and pathological conditions represents an intriguing challenge in these years. The use of the in vitro brain slice preparation has allowed not only the detailed investigation of the direct pre- and postsynaptic electrophysiological actions of several neurotransmitters in striatal neurones, but also the understanding of their role in two different forms of corticostriatal synaptic plasticity, long-term depression and long-term potentiation. These long-lasting changes in the efficacy of excitatory transmission have been proposed to represent the cellular basis of some forms of motor learning and are altered in animal models of human basal ganglia disorders, such as Parkinson's disease. The striatum also expresses high sensitivity to hypoxic-aglycemic insults. During these pathological conditions, striatal synaptic transmission is altered depending on presynaptic inhibition of transmitter release and opposite membrane potential changes occur in projection neurones and in cholinergic interneurones. These ionic mechanisms might partially explain the selective neuronal vulnerability observed in the striatum during global ischemia and Huntington's disease.
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PMID:Synaptic transmission in the striatum: from plasticity to neurodegeneration. 1072 75

Nitric oxide (NO), an intercellular messenger and a normal metabolic product, takes an active part in the regulation of physiologically significant functions of the cardiovascular, immune, and nervous systems. At the same time when produced in excess amounts, NO as a free radical and an agent that gives rise to highly toxic oxidants (peroxynitrile, nitric dioxide, nitron ion), becomes a cause of neuronal damage and death in some brain lesions (parkinsonism, Alzheimer's disease, Huntington's chorea). Numerous experimental data show the ambiguous effects of NO on the development of cerebral infarct. NO as an active vasodilatory and antithrombogenic agent may reduce cerebral damage in early ischemia. There is evidence for the involvement of NO in the body's adaptation to oxygen starvation and ischemic tolerance formation. In the postischemic period, NO is a major factor of neuronal necrosis and apoptosis. The currently established ideas on the processes of cerebral NO production and on the pathogenetic mechanisms of this agent's cytotoxicity open up new vistas for selective blockers of various NO synthesis enzymes (neuronal, endothelial, glial cellular, and macrophagal and neutrophilic NO synthases) used in the treatment of acute vascular abnormalities of the central nervous system.
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PMID:[The role of nitric oxide and other free radicals in ischemic brain pathology]. 1083 6


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