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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overdistraction and derotation of the scoliotic spine during surgery represent potential complications that could lead to spinal cord dysfunction and paralysis. Neuronal loss and, consequently, the inability to regain function may be attributable to primary damage (eg, mechanical), secondary cell death (eg, such as that produced by ischemia) or a combination of both. Beyond intraoperative recognition and removal of the rods, effective strategies to prevent this neuronal loss have yet to be developed. This emphasizes the need for a clearer understanding of the molecular events that contribute to neuronal injury in the central nervous system. Considerable evidence has indicated that the excitatory transmitter L-glutamate and the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor may contribute to the secondary neuronal death observed in a wide variety of neurological insults, including ischemia. The current investigation was undertaken to elucidate the potential role of the NMDA receptor in spinal cord pathology. Isolated rat spinal cords were exposed to anoxic physiologic solutions in the presence and absence of Ca++, NMDA receptor agonists, and a noncompetitive NMDA receptor antagonist. The extent of neuronal damage was assessed by quantitating the degradation of the cytoskeletal neurofilament protein. A substantial increase in the loss of neurofilament protein was observed in spinal cords exposed to anoxic conditions in the presence of Ca++ as compared with the absence of Ca++. Exposure to excitatory amino acid agonists (L-glutamate or NMDA) further potentiated the degradation of the neurofilament protein; an effect that was reversed by a noncompetitive NMDA receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitotoxins can produce protein degradation in the spinal cord. 197 92

An accumulation of experimental data suggests that N-methyl-D-aspartate (NMDA) receptor antagonists will prevent ischemic neuronal injury following transient global ischemia and reduce infarct volumes following focal ischemic insults. The excitotoxic hypothesis states that the excitatory amino acid neurotransmitter L-glutamate has neurotoxic properties that can be attenuated by antagonism of the NMDA receptor. In vitro work has shown that a variety of NMDA antagonists will prevent the death of neurons grown in culture and subsequently exposed to either brief periods of hypoxia or glutamate exposure. In vivo it has been shown that glutamate is released following ischemia, that the NMDA receptors remain functional both during and following ischemia, and that the concentration of NMDA receptors is highest in those regions that are most sensitive to ischemic neuronal injury. Once stimulated, these receptors mediate a lethal influx of calcium. Experiments with global ischemia have reported a cytoprotective effect by either prior removal of glutamate afferents or pretreatment with either competitive or noncompetitive receptor antagonists. Some of these data have been challenged and one suggestion that has been made is that the observed pharmacoprotection may be the result of coincidental drug-induced hypothermia. Numerous studies using a variety of models of focal ischemia have shown that the volume of a cortical infarct can be reduced with NMDA antagonists given either before or after an ischemic insult. These data are more consistent than those achieved for models of global ischemia and have led to proposals for clinical trials. Novel compounds that antagonize the NMDA receptor are now the subject of phase I clinical studies that are envisaged as a prelude to randomized acute stroke trials. The hypothesis that blockade of excitatory amino acid receptors will prevent neuronal death presages a new era in acute stroke treatment.
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PMID:Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted? 214 95

We have investigated the role of NMDA receptors in the rat dorsal horn in mediating neuronal responses to noxious hindlimb ischemia, induced by acute occlusion of the femoral artery, as well as in the hyperalgesia evident when noxious mechanical stimuli were applied to the ischemic limb. Two specific NMDA antagonists, D-2-amino-5-phosphonovalerate (APV) and ketamine hydrochloride were applied intrathecally directly on to the spinal cord, in enflurane-anaesthetised rats. Both APV (1 microM and 100 microM) and ketamine (1 mM and 100 mM) inhibited the increase of dorsal horn neuronal firing rate induced by ischemia, but did not alter the neuronal response to noxious pinching or innocuous brushing of the receptive field. Both agents, however, abolished the hyperalgesia to noxious pinching induced by ischemia. Our results support the hypothesis that the excitatory amino acids are involved in the transmission of nociceptive information in the spinal dorsal horn, and also favour a central mechanism for hyperalgesia at the spinal level, possibly also mediated by the NMDA receptor.
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PMID:N-methyl-D-aspartate receptors mediate responses of rat dorsal horn neurones to hindlimb ischemia. 214

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.
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PMID:Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium. 214 19

The effect of treatment with the potent, non-competitive NMDA receptor-channel antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d] cyclohepten-5,10-imine maleate (MK-801) on ischemia-induced brain damage was studied in a well-characterized model of focal neocortical infarction in spontaneously hypertensive rats. Anesthesia exposure was minimized to the surgical procedure and the infarcts were allowed to mature over a 24-h period. Pretreatment with 5 mg/kg i.p. MK-801 (n = 11 control, n = 12 treated animals) 30 min before induction of focal cerebral ischemia had no statistically significant influence on infarct volumes. However, pre- and post-treatment with MK-801 5 mg/kg i.p. 30 min before induction of ischemia and 2.5 mg/kg each at 8 and 16 h after onset of ischemia, reduced infarct volumes in two separate studies by 29% (investigator J.T., n = 5 control and n = 7 treated animals) and 20% (investigator U.D., n = 8 control and n = 8 treated animals), respectively. The combined reduction in infarct volume in MK-801-treated animals for both investigators was 23% (P = 0.016, ANOVA). The findings indicate a smaller neuroprotective effect of MK-801 in spontaneously hypertensive rats subjected to focal ischemia than in previous reports using normotensive animals.
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PMID:Pre- and post-treatment with MK-801 but not pretreatment alone reduces neocortical damage after focal cerebral ischemia in the rat. 214 95

The adrenal stress hormones glucocorticoids (GCs) impair the ability of hippocampal neurons to survive neurological insults, including hypoxia-ischemia and seizure. These insults are thought to be toxic via a cascade of excessive synaptic concentrations of excitatory neurotransmitters (e.g. glutamate), activation of the NMDA receptor, and pathologic mobilization of cytosolic calcium post-synaptically. We tested whether GCs exacerbate these insults by exacerbating this 'NMDA cascade'. We sought a toxin which damaged independently of the NMDA cascade, and whose toxicity was enhanced by GCs. After testing a number of neurotoxins, we found that the antimetabolite 3-acetylpyridine (3AP) fit this requirement. We then tested if blockade of the NMDA receptor blocks the ability of GCs to enhance 3AP toxicity. Hippocampi were microinfused with 160 micrograms of 3AP. Elevating circulating GC concentrations to the range seen during major stressors for a week before and after microinfusion caused a significant increase in 3AP-induced damage (when compared to adrenalectomized rats kept GC-free for the same period). Infusing the NMDA receptor blocker APV with 3AP did not alter the toxicity in adrenalectomized rats. However, APV reduced 3AP-induced damage in GC-treated rats to levels seen in adrenalectomized rats. This suggests that GCs endanger hippocampal neurons by enhancing glutamatergic signals and/or enhancing vulnerability to such signals. As a possible explanation for this observation, GCs inhibit glucose uptake into hippocampal neurons, and numerous steps in the NMDA cascade are exacerbated when neuronal energy stores are diminished.
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PMID:Glucocorticoid endangerment of hippocampal neurons is NMDA-receptor dependent. 214 1

Energy depletion is a primary factor initiating ischemic damage to neurons. In a separate report, we demonstrated that in vitro ischemia inhibits protein synthesis in the CA1 pyramidal neurons of the hippocampal slice via a mechanism involving extracellular calcium and N-methyl-D-aspartate (NMDA) receptor activation during the ischemic episode. In this study, we tested whether these agents accelerated the ischemic energy depletion beyond tolerable levels. ATP and phosphocreatine (PCr) were measured immediately after different durations of in vitro ischemia in the presence or absence of calcium and the NMDA receptor antagonist ketamine. The results support the contention that extracellular calcium does not contribute to the ischemic energy depletion. NMDA receptor activation accelerates the fall in ATP and PCr, but only during the first 45 s of the ischemia. Using protein synthesis inhibition as a functional indicator of ischemic damage in the hippocampal slice, we demonstrated that greater than 2 min of ischemia is necessary to inhibit protein synthesis. Thus, this threshold duration of ischemia indicates that events occurring between 2 and 5 min ischemia result in a prolonged protein synthesis inhibition.
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PMID:NMDA receptor activation accelerates ischemic energy depletion in the hippocampal slice and the demonstration of a threshold for ischemic damage to protein synthesis. 215 12

Evidence has accumulated to implicate the excitatory amino acid neurotransmitters, glutamate and aspartate, in the pathophysiology of central nervous system (CNS) ischemic injury. It appears from both in vivo and in vitro experiments that they exert their excitotoxic effects in CNS ischemia by their actions at the N-methyl-D-aspartate (NMDA) receptor complex. In the present study, we examined the effects of MK-801 and ketamine, two noncompetitive NMDA receptor antagonists, in a model of spinal cord ischemia in conscious rabbits produced by occluding the infrarenal aorta for 25 min. Five minutes after reperfusion, animals were treated with either saline, ketamine, or MK-801. By 6 h postreperfusion, all treatment groups exhibited an initial recovery of hindlimb motor function, after which the saline- and ketamine-treated groups had a similar progressive deterioration in function over the next 48 h. However, the MK-801-treated rabbits continued to recover motor function such that neurological scores in these rabbits were significantly improved relative to those of the saline-treated animals at 48 h. Histopathological evaluation showed that MK-801-treated rabbits tended to have a lesser degree of central gray matter necrosis. These results indicate that MK-801 protected against the secondary deterioration associated with this model and strengthen the potential therapeutic use of NMDA receptor antagonists in the treatment of CNS ischemia.
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PMID:Effects of NMDA receptor antagonists following spinal ischemia in the rabbit. 216 75

The rat hippocampal slice was developed as a model for investigating the effects of ischemia on protein synthesis in different cell types, as synthesis is an early functional indicator of cell damage. Five min of in vitro ischemia inhibited protein synthesis in CA1 pyramidal and subicular neurons 3 h later, despite recovery of the energy charge. Morphology of these neurons was also affected. In contrast, glia and capillary endothelial cells showed increased synthesis at this time point, and no apparent structural changes. Exposure of slices to buffer lacking calcium and containing the non-competitive NMDA receptor blocker ketamine, during the 5 min ischemia, prevented both the inhibition of protein synthesis and the morphologic changes in the neurons. However, if buffer only lacked calcium, or only contained ketamine, both forms of ischemic damage occurred. Thus, the neuronal protein synthesis inhibition and the impaired morphology appear to be mediated by either extracellular calcium or NMDA receptor activation. In contrast to the neurons, the ischemia-induced stimulation of protein synthesis in glia and capillary endothelial cells was not affected by the above treatments, indicating that neither NMDA receptor activation nor extracellular calcium is necessary for this effect.
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PMID:In vitro ischemia and protein synthesis in the rat hippocampal slice: the role of calcium and NMDA receptor activation. 216 18

L-Glutamate and related excitatory amino acids (EAA) are firmly established as major excitatory synaptic transmitter substances in the vertebrate central nervous system. Questions which have been addressed include: How many receptors are there for the EAAs?; What ion channels and/or 'second-messenger' systems are regulated by these receptors?; What are the roles of EAAs in higher neural functions?; Are they involved in neurological disorders? EAA receptors appear not only to mediate normal synaptic transmission along excitatory pathways but also to participate in the modification of synaptic connections during development. However, overaction of receptors can also mediate neuronal degeneration and even cell death. NMDA receptor antagonists markedly attenuate neuronal necrosis. Therefore, it appears that ischemia- and hypoglycemia-associated brain damage results not from a lack of energy substrates but rather via the mediation of NMDA receptors and 'excitotoxic' mechanisms. The action of ketamine anesthesia is closely associated with a block of the NMDA receptor. Ketamine binds to a site within the lumen of the NMDA-activated channel and can become trapped there when the channel closes. Current evidence indicated that NMDA receptor antagonists will be of value for the treatment of delayed neuronal death. NMDA receptor will lead to understanding the mechanisms underlying learning and memory, the control of neuronal excitability and neuronal death.
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PMID:[Synaptic mechanisms of excitatory amino acids and NMDA receptor mediated brain excitability]. 217 10


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