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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overactivation of glutamate receptors mediates neuronal death in several acute and chronic neurodegenerative diseases. The intracellular processes underlying this form of death, however, remain poorly understood. Depending on the severity of insult, N-methyl-D-aspartate (NMDA) receptor activation induces either apoptosis or necrosis. Cysteine proteases related to interleukin-1beta-converting enzyme (ICE), recently termed caspases, appear necessary for neuronal apoptosis in vivo and in vitro. To determine whether caspases play a role in NMDA-induced apoptosis, we used two functionally distinct approaches to decrease substrate cleavage by caspases. One is a novel peptide (V-ICEinh) that contains the caspase catalytic site and acts as a pseudoenzyme that binds caspase substrates and prevents their cleavage. The other is a pseudosubstrate peptide (Z-VAD x fmk) that inhibits caspase activity. Pretreatment with either V-ICEinh or Z-VAD-fmk protects cerebrocortical neurons from NMDA-induced apoptosis, suggesting a role for caspases in NMDA-induced apoptosis. To explore the signaling pathways involved, we looked at the effects of NMDA receptor activation on Ca2+ influx, production of reactive oxygen species (ROS), mitochondrial membrane potential, and lipid peroxidation. Neither NMDA-induced Ca2+ influx nor the initial collapse of mitochondrial membrane potential could be prevented by pretreatment with V-ICEinh or Z-VAD x fmk. In contrast, ROS formation and lipid peroxidation were completely blocked by both V-ICEinh and Z-VAD x fmk. Taken together, our results suggest that Ca2+ influx and mitochondrial depolarization occur upstream from caspase activation, whereas ROS formation and lipid peroxidation may be downstream events in the cascade leading to cortical neuronal apoptosis.
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PMID:Role of caspases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons. 972 20

Following a hypoxic-ischemic insult, the collapse of ion gradients results in the inappropriate release of excitatory neurotransmitters. Although excitatory amino acids such as glutamate are the likely extracellular mediators of the ensuing neuronal cell death, the intracellular events occurring downstream of glutamate receptor activation are much less clear. The present review attempts to summarize how Ca2+ overload of neurons following a hypoxic-ischemic insult is neurotoxic. In particular, the interlocked relation between mitochondrial Ca2+ accumulation and subsequent neuronal cell death is examined.
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PMID:Mechanisms of neuronal damage in brain hypoxia/ischemia: focus on the role of mitochondrial calcium accumulation. 983 72

A strain of Bacillus designated TA2.A1, isolated from a thermal spring in Te Aroha, New Zealand, grew optimally at pH 9.2 and 70 degrees C. Bacillus strain TA2.A1 utilized glutamate as a sole carbon and energy source for growth, and sodium chloride (>5 mM) was an obligate requirement for growth. Growth on glutamate was inhibited by monensin and amiloride, both inhibitors that collapse the sodium gradient (DeltapNa) across the cell membrane. N, N-Dicyclohexylcarbodiimide inhibited the growth of Bacillus strain TA2.A1, suggesting that an F1F0-ATPase (H type) was being used to generate cellular ATP needed for anabolic reactions. Vanadate, an inhibitor of V-type ATPases, did not affect the growth of Bacillus strain TA2.A1. Glutamate transport by Bacillus strain TA2.A1 could be driven by an artificial membrane potential (DeltaPsi), but only when sodium was present. In the absence of sodium, the rate of DeltaPsi-driven glutamate uptake was fourfold lower. No glutamate transport was observed in the presence of DeltapNa alone (i.e., no DeltaPsi). Glutamate uptake was specifically inhibited by monensin, and the Km for sodium was 5.6 mM. The Hill plot had a slope of approximately 1, suggesting that sodium binding was noncooperative and that the glutamate transporter had a single binding site for sodium. Glutamate transport was not affected by the protonophore carbonyl cyanide m-chlorophenylhydrazone, suggesting that the transmembrane pH gradient was not required for glutamate transport. The rate of glutamate transport increased with increasing glutamate concentration; the Km for glutamate was 2.90 microM, and the Vmax was 0.7 nmol. min-1 mg of protein. Glutamate transport was specifically inhibited by glutamate analogues.
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PMID:Sodium-dependent glutamate uptake by an alkaliphilic, thermophilic Bacillus strain, TA2.A1. 1032 19

Glutamate uptake is coupled to counter-transport of K+, and high external K+ concentrations can induce reversal of glutamate uptake in whole-cell patch-clamp and isolated membrane preparations. However, high external K+ causes little or no reversal of glutamate uptake in intact astrocytes, suggesting a regulatory mechanism not evident in membrane preparations. One mechanism by which intact cells could limit the effects of altered extracellular ion concentrations on glutamate transport is by compensatory changes in intracellular Na+ concentrations. This possibility was examined using astrocyte cultures treated in two ways to reduce the driving force for glutamate uptake: incubation in high K+ (with reciprocal reduction in Na+), and incubation with metabolic inhibitors to induce ATP depletion. ATP depletion produced a rise in intracellular Na+, a collapse of the membrane sodium gradient and a massive reversal of glutamate uptake. By contrast, incubation in high K+/low Na+ medium did not significantly alter the sodium gradient and did not induce glutamate uptake reversal. The sodium gradient was shown to be maintained under these conditions by compensatory reductions in intracellular Na+ that approximately matched the reductions in extracellular Na+. These findings suggest a mechanism by which astrocytes may limit reversal of glutamate uptake under high K+/low Na+ conditions, and further suggest a general mechanism by which Na(+)-dependent transport processes could be shielded from fluctuating extracellular ion concentrations.
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PMID:K(+)-induced reversal of astrocyte glutamate uptake is limited by compensatory changes in intracellular Na+. 1043 Apr 92

The objective of this study was to evaluate the role of mitochondrial Ca2+ uptake (MCU) in modulation (shaping) of the glutamate (Glu)-induced changes in neuronal cytoplasmic Ca2+ ([Ca2+]i). In order to block MCU, nerve cells were treated with mitochondrial inhibitors (MI) inducing collapse of the mitochondrial potential (Delta Psim). Measurements of changes in [Ca2+]i were performed using either the low-affinity (fura-2FF) or high-affinity (fura-2) Ca2+ indicators. Loading of nerve cells with rhodamine 123 made it possible to monitor changes in Delta Psim. In the first series of experiments it was shown that blockade of MCU in fura-2FF-loaded cells with a cocktail of rotenone (2 microM)+oligomycin (2.5 microg/ml) greatly (2.53+/-0.4 times, n=61) increased the [Ca2+]i response to a 1-min Glu (100 microM) pulse. In fura-2-loaded cells, this increase was small (less than 1.3 times) or absent. In the second series of experiments, cocktails of rotenone+oligomycin or FCCP (1 microM)+oligomycin were applied during a prolonged Glu application. This produced strong mitochondrial depolarisation and an additional [Ca2+]i increase. In most cells the latter could be reversed or prevented by a removal of external Ca2+. The MI-induced additional [Ca2+]i increase was especially pronounced in cells loaded with fura-2FF. In some neurones a removal of external Ca2+ did not produce a decrease in [Ca2+]i during combined Glu+MI application, suggesting an impairment of [Ca2+]i extrusion mechanisms of these cells. The conclusion is drawn that MCU makes a considerable contribution to regulation of [Ca2+]i responses caused by Ca2+ influx via Glu-activated ionic channels. The reasons for a quantitative difference between [Ca2+]i responses observed in fura-2- and fura-2FF-loaded neurones are discussed.
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PMID:Blockade of mitochondrial Ca2+ uptake by mitochondrial inhibitors amplifies the glutamate-induced calcium response in cultured cerebellar granule cells. 1048 Oct 57

Carbamoyl phosphate synthetase (CPS) plays a key role in both arginine and pyrimidine biosynthesis by catalyzing the production of carbamoyl phosphate. The enzyme from Escherichi coli consists of two polypeptide chains referred to as the small and large subunits. On the basis of both amino acid sequence analyses and X-ray structural studies, it is known that the small subunit belongs to the Triad or Type I class of amidotransferases, all of which contain a cysteine-histidine (Cys269 and His353) couple required for activity. The hydrolysis of glutamine by the small subunit has been proposed to occur via two tetrahedral intermediates and a glutamyl-thioester moiety. Here, we describe the three-dimensional structures of the C269S/glutamine and CPS/glutamate gamma-semialdehyde complexes, which serve as mimics for the Michaelis complex and the tetrahedral intermediates, respectively. In conjunction with the previously solved glutamyl-thioester intermediate complex, the stereochemical course of glutamine hydrolysis in CPS has been outlined. Specifically, attack by the thiolate of Cys269 occurs at the Si face of the carboxamide group of the glutamine substrate leading to a tetrahedral intermediate with an S-configuration. Both the backbone amide groups of Gly241 and Leu270, and O(gamma) of Ser47 play key roles in stabilizing the developing oxyanion. Collapse of the tetrahedral intermediate leads to formation of the glutamyl-thioester intermediate, which is subsequently attacked at the Si face by an activated water molecule positioned near His353. The results described here serve as a paradigm for other members of the Triad class of amidotranferases.
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PMID:The small subunit of carbamoyl phosphate synthetase: snapshots along the reaction pathway. 1058 38

Tinnitus has been defined as the perceptual correlate of altered spontaneous neural activity occurring without an external auditory stimulus. Hyperacusis, defined as a collapse of tolerance to sound, is present in 40-86% of those who suffer from disabling forms of tinnitus. Both phenomena often are induced or exacerbated by physical or psychological stress. Biological systems known to regulate the body's overall response to stress use and release endogenous neuroactive opioid peptides. These stress-related neuromodulators consist of products derived from three genetically distinct precursor hormones. Two of these precursor hormones are proenkephalin and prodynorphin. Enkephalin and dynorphin-related peptides exist within the efferent olivocochlear systems (lateral and medial) of several mammalian species, including humans. Prodynorphin derivatives, however, may be restricted exclusively to lateral efferent neurons. Descending lateral efferent axons terminate solely on primary (type I) auditory dendrites innervating cochlear inner hair cells in most species. This action indicates that they play an important role in modulating auditory nerve sensitivity and spontaneous discharge. In a fashion similar to that exhibited by the observed excitatory mechanism of action of dynorphins in the spinal cord, sodium salicylate (aspirin) recently was shown to facilitate the excitatory effects of glutamate in the cochlea. This article provides support for a neurochemical model in which endogenous dynorphins may induce hyperacusis and can contribute to the induction, maintenance, or exacerbation of tinnitus in the auditory periphery by altering auditory type I neural excitability to glutamate.
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PMID:Endogenous dynorphins: possible role in peripheral tinnitus. 1075 26

The roles of mild uncoupling caused by free fatty acids (mediated by plant uncoupling mitochondrial protein (PUMP) and ATP/ADP carrier (AAC)) and non-coupled respiration (alternative oxidase (AO)) on H(2)O(2) formation by plant mitochondria were examined. Both laurate and oleate prevent H(2)O(2) formation dependent on the oxidation of succinate. Conversely, these free fatty acids (FFA) only slightly affect that dependent on malate plus glutamate oxidation. Carboxyatractylate (CAtr), an inhibitor of AAC, completely inhibits oleate- or laurate-stimulated oxygen consumption linked to succinate oxidation, while GDP, an inhibitor of PUMP, caused only a 30% inhibition. In agreement, CAtr completely restores the oleate-inhibited H(2)O(2) formation, while GDP induces only a 30% restoration. Both oleate and laurate cause a mild uncoupling of the electrical potential (generated by succinate), which is then followed by a complete collapse with a sigmoidal kinetic. FFA also inhibit the succinate-dependent reverse electron transfer. Diamide, an inhibitor of AO, favors the malate plus glutamate-dependent H(2)O(2) formation, while pyruvate (a stimulator of AO) inhibits it. These results show that the succinate-dependent H(2)O(2) formation occurs at the level of Complex I by a reverse electron transport. This generation appears to be prevented by mild uncoupling mediated by FFA. The anionic form of FFA appears to be shuttled by AAC rather than PUMP. The malate plus glutamate-dependent H(2)O(2) formation is, conversely, mainly prevented by non-coupled respiration (AO).
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PMID:The role of mild uncoupling and non-coupled respiration in the regulation of hydrogen peroxide generation by plant mitochondria. 1082 50

Status epilepticus is common and associated with significant mortality and complications. It affects approximately 50 patients per 100,000 population annually and recurs in >13%. History of epilepsy is the strongest single risk factor for generalized convulsive status epilepticus. More than 15% of patients with epilepsy have at least one episode of status epilepticus and low antiepileptic drug levels are a potentially modifiable risk factor. Other risks include young age, genetic predisposition, and acquired brain insults. Fever is a very common risk in children, as is stroke in adults. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Neuronal injury leading to temporal lobe epilepsy is probably mediated by excess excitation via activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and consequent elevated intracellular calcium that causes acute necrosis and delayed apoptotic cell death. Some forms of nonconvulsive status epilepticus may also lead to neuronal injury by this mechanism, but others may not. Based on clinical and experimental observations, complex partial status epilepticus is more likely to result in neuronal injury similar to generalized convulsive status epilepticus. Absence status epilepticus is much less likely to result in neuronal injury, and complications because it may be mediated primarily through excess inhibition. Future research strategies to prevent complications of status epilepticus include the study of new drugs (including NMDA antagonists, new drug delivery systems, and drug combinations) to stop seizure activity and prevent acute and delayed neuronal injury that leads to the development of epilepsy.
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PMID:Status epilepticus: risk factors and complications. 1088 37

This paper reviews literature on the topic of cold stress, near-drowning and hypothermia, written mainly since the last review of this type in this journal. The main effects of cold stress, especially in cold water immersion, include the "cold shock" response, local cooling causing decrements in physical and mental performance, and ultimately core cooling as hypothermia occurs. The section on cold-water submersion (near-drowning) includes discussion regarding the various mechanisms for brain and body cooling during submersion. The mechanisms for cold-induced protection of the anoxic brain are discussed with attention given to decreased brain temperature and the Q10 principle, the mammalian dive reflex and a newly considered mechanism; cold-induced changes in neurotransmitter release (i.e., glutamate and dopamine). The section on the post-cooling period includes the post-rescue collapse and subsequent rewarming strategies used in the field, during emergency transport or in medical facilities. Recent research on topics such as inhalation warming, body-to-body warming, radio wave therapy, warm water immersion, exercise, body cavity lavage, and cardiopulmonary bypass is reviewed. Information on new methods of warming, including arteriovenous anastomoses (AVA) warming (by application of heat- with or without negative pressure application-to distal extremities in an effort to increase AVA blood flow), forced-air warming, and peripheral vascular extracorporeal warming, are discussed.
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PMID:Cold stress, near drowning and accidental hypothermia: a review. 1090 37


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