Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single units were recorded in the striatum and in the globus pallidus (GP) of urethane-anesthetized rats under microiontophoretic administration of either Nomega-nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), or 3-morpholino-sydnonimin-hydrocloride (SIN-1, nitric oxide, NO donor). A steady baseline firing of sporadically discharging striatal neurons (basal firing rate <0.1 spikes/s) was evoked by a pulsed microiontophoretic ejection of glutamate. On striatal neurons, microiontophoretic application of SIN-1 induced a current-dependent inhibition (11/13), whereas L-NAME administration produced a clear excitation (9/9). On GP cells, the administration of SIN-1 had excitatory effects (10/15), whereas the administration of L-NAME reduced the neuronal activity (6/6). We hypothesize that NO could exert an intrinsic regulatory action on the activity of both striatal and GP cells.
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PMID:Nitric oxide-induced inhibition on striatal cells and excitation on globus pallidus neurons: a microiontophoretic study in the rat. 1275 74

The effect of homocysteine (HCY) on lipid peroxidation (LP), a current mechanism of oxidative neurotoxicity, was investigated in rat brain synaptosomes. LP was assessed by measuring the amount of thiobarbituric acid-reactive substances (TBARS) formed from synaptosomal fractions following HCY treatment. Increasing HCY concentrations (5-1000 micro M) enhanced the TBARS formation in brain synaptosomes in a concentration-dependent manner. When compared at equimolar concentrations (100 micro M), the oxidative potency of HCY was lower than that of the oxidant ferrous sulfate, similar to that produced by glutamate (Glu) and the mitochondrial toxin 3-nitropropionic acid, and higher than that of the Glu agonists, kainate and quinolinate. The N-methyl-D-aspartate receptor (NMDAr) antagonist dizocilpine (MK-801) completely blocked the HCY-induced LP at concentrations between 5 to 1000 micro M, whereas the well-known antioxidant N-acetylcysteine (NAC) was less effective, but still protective against the HCY oxidative toxicity at higher concentrations (400 and 1000 micro M). Three nitric oxide synthase (NOS) inhibitors, 7-nitroindazole (7-NI), Nomega-nitro-L-arginine (L-NARG) and Nomega-nitro-L-arginine methyl ester (L-NAME), were also tested on HCY-induced LP at increasing concentrations. Both nonspecific NOS inhibitors (L-NARG and L-NAME) decreased more effectively the HCY-induced LP than did the selective neuronal NOS inhibitor, 7-NI. These results show that submillimolar concentrations of HCY can induce oxidative injury to nerve terminals, and this effect involves NMDAr stimulation, NOS activation, and associated free radicals formation.
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PMID:Homocysteine-induced brain lipid peroxidation: effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition. 1283 15

The present study was performed to examine the neuroprotective effects of fangchinoline (FAN) and tetrandrine (TET), bis-benzylisoquinoline alkaloids, which exhibit the characteristics of Ca 2+ channel blockers, on H2O2 -induced neurotoxicity using cultured rat cerebellar granule neurons. H2O2 produced a concentration-dependent reduction of cell viability, which was blocked by (5 R,10 S)-(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine (MK-801), an N-methyl- D-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca 2+ channel blocker, and NG-nitro- L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor. Pretreatment with FAN and TET over a concentration range of 0.1 to 10 microM significantly decreased the H2O2 -induced neuronal cell death as assessed by a trypan blue exclusion test, a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and the number of apoptotic nuclei. In addition, FAN and TET inhibited the H2O2 -induced elevation of glutamate release into the medium, elevation of the cytosolic free Ca 2+ concentration ([Ca 2+] c ), and generation of reactive oxygen species (ROS). These results suggest that FAN and TET may mitigate the harmful effects of H2O2 -induced neuronal cell death by interfering with the increase of [Ca 2+] c, and then by inhibiting glutamate release and generation of ROS. Abbreviations. AP5:D(-)-2-amino-5-phosphonopentanoic acid DMSO:dimethyl sulfoxide FAN:fangchinoline H 2 DCF-DA:2',7'-dichlorodihydrofluorescin diacetate MK-801:(5 R,10 S)-(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,20-imine MTT:3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide L-NAME: NG-Nitro- L-arginine methyl ester NMDA: N-methyl- D-aspartate TET:tetrandrine
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PMID:Protective effects of fangchinoline and tetrandrine on hydrogen peroxide-induced oxidative neuronal cell damage in cultured rat cerebellar granule cells. 1286 67

We evaluated the ability of spinally administered nitric oxide (NO) synthase inhibitor to modulate antinociceptive action of intrathecal (i.t.) morphine in rats by measuring the early and late phases of flinching and licking/biting in the formalin test. To determine the contribution of spinal NO and glutamate, we measured the release of NO metabolites (nitrite/nitrate) and glutamate from the spinal cord in rats, using a microdialysis probe placed in the lumbar space. The i.t. administration of NG-nitro L-arginine methyl ester (L-NAME) produced a dose-dependent reduction in the number of flinches during the late phase, whereas there were no significant alterations in the late phase licking/biting, and early phase flinching and licking/biting. Spinal administration of morphine at low doses produced a significant antinociceptive activity in the early and late phases of the flinching behaviour, whereas higher doses of morphine were required to obtain a significant effect in the licking/biting behaviour during both phases. Combination of L-NAME with morphine resulted in an enhanced reduction in the early and late phase flinching. Enhanced antinociceptive activity was observed in the late phase licking/biting by i.t. combined administration of L-NAME (400 nmol) and morphine (1.25 nmol). In the present study, we have confirmed our prior results that injection of formalin (5.0%) into the plantar surface of the paw evoked a biphasic spinal release of nitrite/nitrate and a transient release of glutamate. Formalin-evoked release of nitrite/nitrate and glutamate was also reduced markedly by i.t. combined administration of L-NAME and morphine. These behavioural and biochemical results suggest that i.t. administered L-NAME may enhance morphine-induced antinociception through an increased inhibition of nitrite/nitrate and glutamate releases evoked by formalin injection at the spinal cord level.
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PMID:Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats. 1456 32

In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.
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PMID:Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. 1457 99

The purpose of this study was to investigate changes in nitric oxide (NO) synthesis induced by exogenous glutamate perfusion into the cerebral cortex, and the effects of mild hypothermia on this glutamate-induced NO synthesis. Glutamate-induced cortical lesions were produced by perfusion of 0.5 M glutamate solution via a microdialysis probe, and the extracellular concentrations of NO end-products (nitrite and nitrate) were measured by microdialysis in normothermic (37 degrees C) and hypothermic (32 degrees C) rats. The levels of NO end-products in the normothermia group were elevated markedly by glutamate perfusion, and this change was completely attenuated by the induction of hypothermia. The glutamate-induced increases were also attenuated markedly by both Nomega-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI). These results suggest that the perfusion of exogenous glutamate into the cortex induces NO synthesis, that is derived primarily from the activity of neuronal NO synthase. These results also demonstrate that hypothermia prevents this glutamate-induced increase in NO, suggesting that the protection afforded by the hypothermic condition is most likely linked to its inhibition of the glutamate-induced NO synthesis.
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PMID:Mild hypothermia inhibits exogenous glutamate-induced increases in nitric oxide synthesis. 1465 5

Nitric oxide (NO) is produced in mammals by different isoforms of NO synthase (NOS), including the constitutive mitochondrial enzyme (mtNOS). Here we demonstrate that the concentration of NO resulting from a mitochondrial NOS activity increases under hypoxic conditions in isolated rat liver mitochondria. We show that mitochondrially derived NO mediates the impairment of active (state 3) respiration as measured in the presence of the substrates glutamate and malate after reoxygenation. Simultaneously, NO induces oxidative stress in mitochondria, characterized by an increase in the amount of protein carbonyls and a decrease in glutathione (GSH). Both the accumulation of oxidative stress markers during and the impaired respiration after reoxygenation were prevented by blocking NO production with the NOS inhibitor L-NAME. These observations suggest that mitochondria are exposed to high amounts of NO generated by a mitochondrial NOS upon hypoxia/reoxygenation. Such increased NO levels, in turn, inhibit mitochondrial respiration and may cause oxidative stress that leads to irreversible impairment of mitochondria.
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PMID:Nitric oxide produced in rat liver mitochondria causes oxidative stress and impairment of respiration after transient hypoxia. 1465 81

Injection of high-dose of morphine into the spinal lumbar intrathecal (i.t.) space of rats elicits a nociceptive behavioural syndrome characterized by periodic bouts of spontaneous agitation and severe vocalization. The induced behavioural response such as vocalization and agitation was observed dose-dependently by i.t. administration of morphine (125-500 nmol). Pretreatment with naloxone (s.c. and i.t.), an opioid receptor antagonist, failed to reverse the morphine-induced behavioural response. The excitatory effect of morphine was inhibited dose-dependently by pretreatment with 3-((+)2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist and MK-801, a non-competitive NMDA receptor antagonist. The non-selective nitric oxide (NO) synthase inhibitor N(G)-nitro L-arginine methyl ester (L-NAME) inhibited dose-dependently the behavioural response to high-dose i.t. morphine (500 nmol), whereas D-NAME was without affecting the response to high-dose i.t. morphine. In the present study, we measured NO metabolites (nitrite/nitrate) in the extracellular fluid of rat dorsal spinal cord using in vivo microdialysis. The i.t. injection of morphine (500 nmol) evoked significant increases in NO metabolites and glutamate from the spinal cord. Not only NO metabolites but also glutamate released by high-dose morphine were reduced significantly by pretreatment with L-NAME (400 nmol). Pretreatment with CPP and MK-801 showed a significant reduction of the NO metabolites and glutamate levels elevated by high-dose i.t. morphine. These results suggest that the excitatory action of high-dose i.t. morphine may be mediated by an NMDA-NO cascade in the spinal cord.
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PMID:The role of spinal nitric oxide and glutamate in nociceptive behaviour evoked by high-dose intrathecal morphine in rats. 1465 10

The effects of agmatine (Agm) on the discharges of neurons in CA1 area of hippocampal slices were examined by using extracellular recording technique. The results are as follows. (1) In response to the application of Agm (0.1-1.0 micromol/L) into the superfusate for 2 min, the spontaneous discharge rates (SDR) of 38/47 (80.9%) neurons were decreased significantly in a dose-dependent manner, while that of 9/47 (19.1%) neurons showed no change in discharge rate; (2) pretreatment with L-glutamate (L-Glu, 0.2 mmol/L) led to a marked increase in SDR of 9/12 (75%) neurons in an epileptiform pattern and that of 2/12 (25%) neurons were not affected, then after Agm (1.0 micromol/L) was applied into the superfusate for 2 min, the epileptiform discharges were suppressed significantly; (3) in 7 neurons, perfusion of the selective L-type calcium channel agonist, Bay K-8644 (0.1 micromol/L), induced an increase in the SDR of 6/7 (85.7%) neurons, while that of 1/7 (14.3%) neuron showed no change, and the discharges were also decreased by application of Agm (1.0 micromol/L) into the superfusate; and (4) application of NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) into the superfusate 5 min later also significantly increased the SDR in all 13 (100%) neurons; then Agm (1.0 micromol/L) applied into the superfusate inhibited the discharges of 11/13 (84.6%) neurons, while those of 2/13 (15.4%) neurons were not affected. These results suggest that agmatine can inhibit the spontaneous discharges and L-glutamate-, Bay K-8644- and L-NAME-induced discharges of hippocampal CA1 neurons. These inhibitory effects of agmatine may be related to the blockade of NMDA receptors and a reduction in calcium influx in hippocampal neurons
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PMID:[Effects of agmatine on neuronal discharges in rat hippocampal CA1 area]. 1469 91

Increased activity of glutamate N-methyl-d-aspartate (NMDA) receptors is the dominant mechanism by which nitric oxide (NO.) is generated. By using a selective direct-current amperometry method, we characterized real time NO* release in vivo in response to chemical stimulation of NMDA receptors in the rat striatum. The application of NMDA caused the appearance of a sharp and transient oxidation signal. Concentration-response studies (10-500 microM) indicated an EC(50) of 48 microM. The NMDA-induced amperometric signal was suppressed by focal application of the nitric-oxide synthase inhibitor L-nitro-arginine methyl ester (L-NAME, 100 microM) or D-(-)-2-amino-5-phosphonopentanoic acid (AP-5, 100 microM) or by systemic injection of dizocilpine (1 mg/kg i.p.), drugs that, when given alone, had no effect on baseline oxidation current. Repeated injections of NMDA at short intervals (approximately 80 s) resulted in a progressive reduction of the amperometric signal with a decay half-life of 1.36 min. Sixty min after the last NMDA application the amperometric response was restored to initial levels. Finally, the coapplication of glycine (50 or 100 microM), which, when given alone had no effect, potentiated the NMDA-induced response. Thus, NMDA receptor-mediated activation of striatal NO* system shuts off quickly and undergoes rapid desensitization, suggesting a feedback inhibition of NMDA receptor function. To the extent of NO* release can represent a correlate of NMDA receptor activity, its amperometric detection could be useful to assess in vivo the state of excitatory transmission under physiological, pharmacological, or pathological conditions.
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PMID:Pulse of nitric oxide release in response to activation of N-methyl-D-aspartate receptors in the rat striatum: rapid desensitization, inhibition by receptor antagonists, and potentiation by glycine. 1472 19


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