Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the temporo-spatial expression of astrocyte glial fibrillary acidic protein (gfap) and sulfated glycoprotein 2 (sgp-2) mRNAs in comparison to 70-kDa heat shock protein (hsp70) mRNA by in situ hybridisation in rats subjected to permanent occlusion of the middle cerebral artery (MCA). Gfap mRNA started to increase in the cingulate cortex of the lesioned hemisphere 6 h after MCA occlusion and gradually spread over the lateral part of the ipsilateral cortex and the striatum from 12 h to 3 days, peaking at 3 days after MCA occlusion. Gfap mRNA also increased in the contralateral cingulate cortex and corpus callosum at 12 and 24 h. Hsp70 mRNA increased markedly in the ipsilateral cortex adjacent to the ischemic lesion, and slightly within the lesion area from 3 to 24 h and disappeared after 3 days. By 7 days, gfap and sgp-2 mRNAs were increased markedly in the peri-infarct area, and in the ipsilateral thalamus parallel with the delayed neuronal damage, whereas the widespread increase of gfap mRNA in the ipsilateral hemisphere declined. Post-occlusion treatment with the glutamate receptor antagonists MK-801 and NBQX slightly attenuate the induction of gfap but did not qualitatively affect the topical expression pattern. Within the cingulate cortex MK-801 treatment resulted in a significant decrease of the signal intensity at all survival times, reflecting most likely an attenuation of lesion-induced spreading depression like depolarization waves by MK-801. The area of hsp70 expression was reduced by both MK-801 and NBQX, most likely reflecting the decrease of the lesion area by both treatment regimens. Our study thus revealed an early and widespread increase of gfap mRNA in the non-ischemic area including the contralateral hemisphere starting between 3 and 6 h, and a delayed circumscribed expression in the peri-infarct border zone after 1 week. Comparison with the expression of hsp70 mRNA suggests that the absence of an early gfap mRNA induction in the peri-lesion zone reflects an impairment of astrocytic function which may be of importance for infarct growth during the early evolution of the pathological process.
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PMID:Monitoring the temporal and spatial activation pattern of astrocytes in focal cerebral ischemia using in situ hybridization to GFAP mRNA: comparison with sgp-2 and hsp70 mRNA and the effect of glutamate receptor antagonists. 891 67

Veratridine blocks Na(+)-channel inactivation and causes a persistant Na(+)-influx. Exposure of hippocampal slices to 10 microM veratridine led to a failure of synaptic transmission, repetitive spreading depression (SD)-like depolarizations of increasing duration, loss of Ca(+)-homeostasis, a large reduction of membrane potential, spongious edema and metabolic failure. Normalization of the amplitude of the negative DC shift evoked by high K+ ACSF 80 min after veratridine exposure was taken as the primary endpoint for neuroprotection. Compounds whose mechanisms of action includes Na(+)-channel modulation were neuroprotective (IC50-values in microM): tetrodotoxin 0.017, verapamil 1.18, riluzole 1.95, lamotrigine > or = 10, and diphenylhydantoin 16.1. Both NMDA (MK-801 and PH) and non-NMDA (NBQX) excitatory amino acid antagonists were inactive, as were NOS-synthesis inhibitor (nitro-L-arginine and L-NAME) Ca(2+)-channel blockers (cadmium, nimodipine) and a K(+)-channel blocker (TEA). Lubeluzole significantly delayed in time before the slices became epileptic, postponed the first SD-like depolarization, allowed the slices to better recover their membrane potential after a larger number of SD-like DC depolarizations, preserved Ca2+ and energy homeostasis, and prevented the neurotoxic effects of veratridine (IC50-value 0.54 microM). A concentration of lubeluzole, which was 40 x higher than its IC50-value for neuroprotection against veratridine, had no effect on repetitive Na(+)-dependent action potentials induced by depolarizing current in normal ACSF. The ability of lubeluzole to prevent the pathological consequences of excessive Na(+)-influx, without altering normal Na(+)- channel function may be of benefit in stroke.
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PMID:Altered Na(+)-channel function as an in vitro model of the ischemic penumbra: action of lubeluzole and other neuroprotective drugs. 903 12

Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inflammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-D-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A2 (PLA2) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA2 inhibitors preserved the wave propagation. NBQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COX-inhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, NG-nitro-L-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptors and PLA2, most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.
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PMID:Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. 917 47

1. It is generally considered that glutamate-mediated transmission can be altered from a physiological to neurotoxic action when extracellular glutamate levels become excessive subsequent to impaired uptake and/or excessive release. However, high extracellular glutamate does not consistently correlate with neuronal dysfunction and death in vivo. The purpose of this study was to examine in situ the local depolarizations, as indicated by negative shifts of the extracellular field (d.c.) potential, produced by local inhibition of high-affinity glutamate uptake, with or without co-application of exogenous glutamate, in three brain regions of anaesthetized rats. 2. Microdialysis probes incorporating an electrode were used to apply exogenous glutamate and/or its uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC), and to monitor the resulting changes in extracellular glutamate and d.c. potential at the sites of application within the cortex, striatum and hippocampus. 3. Perfusion of 1 to 10 mM L-trans-PDC markedly and concentration-dependently increased extracellular glutamate levels (by up to 1700% of basal level in the parietal cortex). Despite their large magnitude, glutamate changes were associated with minor negative shifts of the d.c. potential (< 2 mV), which were not suppressed by the N-methyl-D-aspartate (NMDA)-channel blocker, dizocilpine (MK-801, 2 mg kg-1, i.v.), or the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/ kainate-receptor antagonist, 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX, 30 mg kg-1, i.p.). L-trans-PDC had virtually identical concentration-dependent effects on dialysate glutamate in the hippocampus and striatum, but those induced in the cortex were around 40% larger (P < 0.002). In contrast, the associated depolarizations were around twice as large in the striatum and cortex as in the hippocampus (P < 0.002). Finally, co-application of L-trans-PDC did not enhance the d.c. potential changes evoked by perfusion of 5 or 20 mM glutamate. 4. As the neurotoxic potency of glutamate agonists is considered to be linked to excessive opening of glutamate-operated ion channels, these results challenge the notion that high extracellular glutamate levels may be the key to excitotoxicity in neurological disorders. In particular, they do not support the hypothesis that high extracellular glutamate causes the sudden negative shifts of the d.c. potential associated with ischaemia (i.e. anoxic depolarization), traumatic brain injury and spreading depression. Impaired uptake and excessive release of glutamate may well lead to excitotoxicity, but only at the synaptic level, not by spreading through the interstitial fluid.
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PMID:Effects of increased extracellular glutamate levels on the local field potential in the brain of anaesthetized rats. 931 49

The influence of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonists in combination with halothane anaesthesia on the respiratory system was investigated. Under 1.5% halothane anaesthesia, respiratory parameters including respiratory rate, minute volume, tidal volume, inspiratory and expiratory duration were measured before and after drug administration in rats. The AMPA receptor antagonists, 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione hydrochloride, YM90K (5 and 10 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX, 15 mg/kg), which were administered intravenously for 30 min, significantly reduced the respiratory rate (P < 0.01) and minute volume (P < 0.01) and increased the tidal volume (P < 0.05) compared with values obtained before drug administration. None of these drugs affected respiratory parameters in the absence of anaesthesia. A NMDA receptor antagonist, MK-801 (0.5 mg/kg), which was administered intravenously for 30 min, also significantly reduced respiratory rate (P < 0.01), minute volume (P < 0.01) and tidal volume (P < 0.01) and prolonged inspiratory duration (P < 0.05). These results suggest that both AMPA and NMDA receptor antagonists cause respiratory depression under halothane anaesthesia in rats, although the mechanisms may be different for the two types of antagonists.
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PMID:Respiratory effects of halothane and AMPA receptor antagonist synergy in rats. 954 95

Although AMPA receptors are known to be widely involved in excitatory synaptic neurotransmission at the spinal level, very little is known about their role in modulating motor activity in mammals. In curarized decerebrate or spinalized rabbit preparations, fictive locomotion was monitored on hindlimb nerves after either activation or blockade of AMPA receptors. In decerebrate preparations, the administration of the antagonist, NBQX (3.5 mg/kg i.p.) or the agonist, AMPA (0.5 mg/kg i.v.) produced, in both cases, a depression of locomotor activities induced by stimulation of cutaneous afferents (evoked locomotor activity). This potent effect was transient with AMPA (recovery after 20 min) and followed by the occurrence of spontaneous locomotor sequences, while no recovery was observed with NBQX treatment. In spinal preparations where a continuous 'spontaneous' locomotor activity resulted from the pharmacological activation of noradrenergic descending pathways (nialamide-DOPA pretreatment), the same drugs injected at higher doses (5 mg/kg NBQX i.p. and 1 mg/kg AMPA i.v.) only weakly affected the frequency of 'spontaneous' and evoked locomotor bursts while they exerted inhibitory and facilitatory effects on the burst amplitude respectively. The results suggest that AMPA receptors are involved at spinal level: 1) in direct mediation of cutaneous afferent excitatory effects on the posterior locomotor generators (pLG); 2) in indirect mediation of a supraspinal descending inhibition controlling, likely presynaptically, the cutaneous afferent activation; and 3) in transmission to motoneurons of the output signals from the pLG. Finally, tight spinal interactions between potent descending noradrenergic pathways and spinal AMPA neurotransmission were disclosed.
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PMID:Involvement of AMPA receptors in posterior locomotor activity in the rabbit: an in vivo study. 963 91

We determined the conditions (immaturity, species, anesthesia, receptor blockade selectivity) under which glutamate receptor blockade produces respiratory depression in mammals. In unrestrained 0- to 2-day-old neonate and adult mice and cats, ventilation was measured by the barometric method, before and after separate or sequential administration of a non-NMDA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline, 2-200 mg kg(-1) in mice, 10-40 mg kg(-1) in cats), and a NMDA receptor antagonist, dizocilpine (3 mg kg(-1) in mice, 0.15-1.0 mg kg(-1) in cats). NBQX or dizocilpine alone did not decrease ventilation in awake adults, but NBQX strongly depressed ventilation in neonate awake mice and in adult anesthetized animals. Given together, dizocilpine and NBQX always profoundly depressed ventilation by producing a lethal apnea in neonate mice, and an apneustic pattern of breathing in adults of both species and in neonate cats. We conclude that blockade of either NMDA or non-NMDA receptors is innocuous in awake adults. The factors which may potentiate respiratory depression are (1) anesthesia, (2) immaturity, and (3) combined blockade of both receptors types. The mechanism of depression is species-dependent and age-dependent.
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PMID:Respiratory effects of glutamate receptor antagonists in neonate and adult mammals. 965 39

Functional interaction between ionotropic and metabotropic glutamate receptors (iGluR and mGluR respectively) was studied in cerebellar granule cell cultures using quisqualate (QA), the most potent agonist of phosphoinositide hydrolysis coupled mGluR, and N-methyl-D-aspartate (NMDA) or kainate (KA) that activate different classes of iGluR. Two h exposure to NMDA or KA resulted in a marked reduction (about 75%) of QA-evoked PI hydrolysis. The efficacy of the two agonists was about the same, but the potencies were different (IC50 for NMDA about 35 microM and for KA about 70 microM). NMDA-induced depression of QA-stimulated PI hydrolysis was relatively long lasting but reversible. Recovery required protein synthesis. In nominally Ca2+-free medium both NMDA and KA failed to attenuate QA-stimulated PI hydrolysis. The effect of NMDA was prevented by the NMDA receptor antagonist MK801, but not by the wide spectrum protein kinase inhibitor staurosporin nor by the nitric oxide synthase inhibitor N omega-nitro-L-arginine. Cycloheximide and concanavalin A were also ineffective. The effect of KA was prevented by the selective non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX). Voltage sensitive Ca2+ channel antagonists together with MK801 did not counteract the inhibition by KA of the QA response. Both NMDA and KA attenuated PI hydrolysis evoked by the muscarinic receptor agonist carbachol (about 30%), indicating that the activation of iGluRs exerts a relatively general inhibitory effect on the function of different PLC-coupled metabotropic receptors. Consistent with this observation is that treatments either with KA and NMDA induced an inhibition (about 30%) of NaF-stimulated PI hydrolysis which occurs through the direct activation of G proteins. Our observations show that ionotropic glutamate receptor stimulation induces a long lasting suppression of QA-evoked PI breakdown through a Ca2+ dependent mechanism which seems to involve receptor coupled transduction systems downstream from mGluR. Such a Ca2+-dependent cross-talk involving ionotropic and metabotropic receptors may play a role in certain events of synaptic plasticity.
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PMID:Calcium influx via ionotropic glutamate receptors causes long lasting inhibition of metabotropic glutamate receptor-coupled phosphoinositide hydrolysis. 975 22

The effect of the AMPA antagonist NBQX (10 microM), NMDA antagonist ketamine (100 microM) and 5-HT1A agonist 8-OH-DPAT (1, 10 and 100 microM) on the properties of a KCl-induced spreading depression (SD) was studied in parietal cortical slices of adult rats. Whereas NBQX did not significantly affect the SD, ketamine significantly (p < 0.01) reduced the amplitude of the first SD peak (12.8 +/- 4.6 mV) and blocked the second SD peak when compared with the controls (19.8 +/- 5.2 mV and 25 +/- 5 mV, respectively). Ketamine also decreased the SD duration at half maximal amplitude from 34.9 +/- 12.4 s to 22.2 +/- 12 s (p < 0.05). 8-OH-DPAT attenuated the duration of the SD from 42 +/- 15.6 s to 21.2 +/- 10.6 s (p < 0.05, 100 microM). These data indicate that not only NMDA receptor blockade, but also activation of the 5-HT1A receptor attenuates the SD and may be beneficial in the reduction of ischemic injury following focal cerebral ischemia.
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PMID:Effects of ionotropic glutamate receptor blockade and 5-HT1A receptor activation on spreading depression in rat neocortical slices. 1057 86

A simple and reproducible animal model of global ischemia, induced by decapitation in 30-day-old Wistar rats, has been developed. It allows to perform electrophysiological analysis of the postischemic reperfusion period in the brain slices. Periods of ischemia up to 40 min increase population spikes measured in the CA1 area of the hippocampus during 2-5 h of reperfusion. Thus after 30-min decapitation-induced ischemia (at t(ischem)=25 degrees C), the mean amplitude of the recorded maximum orthodromic population spikes was 159% of the control obtained in the non-ischemic animals. Longer ischemic episodes result in the depression of the population spikes. After 2 h of ischemia, the amplitude of population spikes was about 89% of control. After 3 h of decapitation ischemia, the neurons could not be reactivated. The duration of ischemic episode needed for the irreversible depression of the electrical activity of the brain neurons drastically depends on the temperature at which the ischemic brain is maintained. Thus, only 2 h were needed at 30 degrees C as compared to nearly 3 h at 25 degrees C. We have found that intraperitoneal injection of neuroprotectors which precedes decapitation enables reactivation of the post-ischemic neurons even after very long periods of global ischemia. Thus, MK-801, a non-competitive NMDA receptors antagonist, or NBQX, a blocker of AMPA receptors, administrated 15 min before the long-term (90 min) decapitation ischemia (30 degrees C), induced dose-dependent recovery of population spike with ED(50) values 0.2 mg/kg and 3 mg/kg respectively. Our results demonstrate that, in spite of the high vulnerability of hippocampal neurons to hypoxia and ischemia, their electrical activity can be restored after prolonged (more then 1 h) decapitation ischemia. Administration of NMDA or AMPA antagonists enhances recovery.
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PMID:Electrical responses in hippocampal slices after prolonged global ischemia: effects of neuroprotectors. 1077 94


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