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)

Experiments were designed to study involvement of nitric oxide on vascular responses to ocular ischemia in the anesthetized rat. Anterior choroidal blood flow was measured using laser-Doppler flowmetry. In some experiments, cerebral cortical blood flow also was measured. Ischemia was produced by either occlusion of the cephalic blood supply or more locally via a ligature tightened around the eye stalk. Arterial blood pressure and choroidal blood flow was continuously measured before, during and after a 20 min ischemic challenge. Both methods of ischemia reduced choroidal blood flow (>90%) with no consistent ocular hyperemia seen upon reperfusion. No significant differences in response pattern between the two ischemia techniques were apparent. Treatment with the non-selective inhibitor of nitric oxide (L-NAME 2 mg/kg, i.v.) did not alter either basal choroidal blood flow or the pattern of reperfusion. A larger dose of L-NAME (50 mg/kg, i.v.) reduced both basal choroidal blood flow and the final reperfusion level (most likely due to continued depression of the basal ocular choroidal blood flow). Neither D-NAME nor the neuronal nitric oxide synthase inhibitor, 7-nitroindazole, altered basal anterior choroidal blood flow or the reperfusion pattern seen after reperfusion. The results confirm our previous observations that inhibition of endothelial nitric oxide lowers. basal choroidal blood flow in the rat eye. However, in contrast to the cerebral circulation where L-NAME greatly attenuates initial reperfusion to the cerebral cortex, inhibition of nitric oxide synthase does not appear to notably further influence anterior choroidal reperfusion.
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PMID:Effect of nitric oxide synthesis inhibition on post-occlusive choroidal blood flow in rats. 1067 32

The aim of the present study was to investigate whether the activation of muscarinic receptors is a preliminary step to the endogenous release of nitric oxide modulating nicotinic transmission within the prevertebral ganglia. This work has been performed in vitro in isolated rabbit coeliac ganglion. The electrical activity of the ganglionic neurons was recorded using intracellular recording techniques. When a train of pulses of supramaximal intensity was applied to the splanchnic nerves, gradual depression of fast nicotinic transmission occurred: the pulses do not systematically elicit action potentials, but very often elicit excitatory postsynaptic potentials only. The use of pharmacological agents that interfere with the nitric oxide pathway such as L-arginine (precursor of nitric oxide) or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (nitric oxide scavenger) demonstrated that nitric oxide modulates this depression phenomenon by facilitating or inhibiting the nicotinic transmission of the ganglionic neurons. A nitric oxide donor (diethylamine/nitric oxide complex) induced an inhibition of the nicotinic synaptic transmission. In the presence of the muscarinic receptors antagonist atropine, L-arginine and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide failed to modify the nicotinic transmission of the ganglionic neurons but diethylamine/nitric oxide complex was still able to inhibit it. These results demonstrate that in the coeliac ganglion, the activation of muscarinic cholinergic receptors is a prerequisite for the activation of neuronal nitric oxide synthase in preganglionic fibres. The nitric oxide released then exerts a facilitation or an inhibition of the nicotinic transmission of the ganglionic neurons. Atropine triggered a facilitation of the nicotinic transmission when superfused alone and an inhibition when superfused in the presence of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. These results confirm that muscarinic receptors activate the nitric oxide pathway modulating the nicotinic transmission of the prevertebral neurons. Our results also demonstrate that when the nitric oxide pathway is blocked, activation of muscarinic receptors leads to facilitation of the nicotinic transmission. Our study brings new insights concerning the modulation by nitric oxide and by muscarinic receptors of the synaptic transmission within the prevertebral ganglia.
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PMID:Muscarinic receptor activation is a prerequisite for the endogenous release of nitric oxide modulating nicotinic transmission within the coeliac ganglion in the rabbit. 1068 20

The purpose of this study was to determine the role of nitric oxide in the maintenance of basal lingual blood flow in the anesthetized rat. By using laser-Doppler flowmetry, blood flow was measured from the tongue before and after treatment with the nonselective inhibitor of nitric oxide synthase, L-NAME (0.2, 2.0, and 20 mg/kg), or the selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (40 mg/kg). Other groups of rats were treated with saline, D-NAME (2.0 mg/kg), L-arginine (200 mg/kg), L-arginine + L-NAME (200 + 2.0 mg/kg), or the 7-nitroindazole vehicle. L-NAME produced a dose-related depression in blood flow in the tongue (concurrent with increased arterial blood pressure), which was attenuated by prior administration of L-arginine. Lingual blood flow depression was not seen after administration of the inactive stereoisomer, D-NAME. In addition, the neuronally specific nitric oxide synthase inhibitor, 7-nitroindazole, failed to produce a significant depression of lingual blood flow. These results suggest that the tonic release of nitric oxide from the vascular endothelium plays an important role in maintaining basal blood flow in the tongue and that neuronally released nitric oxide is not involved in maintaining basal circulation in this vascular bed.
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PMID:Nitric oxide regulation of lingual blood flow in the rat. 1138

Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson's disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal.
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PMID:Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. 1151 69

To further understand the potential role of nitric oxide synthase (NOS) in schizophrenia and affective disorders, we determined the calcium-dependent constitutive NOS (cNOS) enzymatic activity and protein levels in the prefrontal cortex of postmortem brains of patients with unipolar, bipolar, and schizophrenic disorders and non-psychiatric controls (n = 15 for each group). Protein levels of two NOS isoforms, nNOS and eNOS, were not significantly different from the non-psychiatric controls in any of the patient groups. However, cNOS activity was significantly lower in schizophrenic patients (mean +/- S.E. = 19.1 +/- 3.2 cpm/microg/45 min) than in the control group (28.5 +/- 3.4, P < 0.05). Trends of lower cNOS activity were found in unipolar (20.3 +/- 2.6, P = 0.062) and bipolar patients (20.8 +/- 3.0, P = 0.079). Males had significantly higher NOS activity (25.4 +/- 2, n = 36, P = 0.01) than females (17.3 +/- 1.9, n = 24), but no significant diagnosis and gender interactions were found. To minimize potential effects of extended postmortem interval (PMI) on NOS activity and proteins, the PMI was limited to 30 h and the data (n = 38) were re-analyzed. cNOS activity was significantly (P < 0.05) lower in patients with schizophrenia (15.8 +/- 5.6, P = 0.026) and unipolar depression (18.8 +/- 3.2, P = 0.042) but not in patients with bipolar illness (22.9 +/- 3.4, P = 0.21) than in the control group (29.5 +/- 3.7). cNOS activity was significantly correlated with brain pH in the total sample (r = 0.28, P < 0.05, n = 60) and in the PMI controlled subgroup (r = 0.43, P < 0.01, n = 38). Our data provide evidence of reduced cNOS activity in the postmortem brains of patients with schizophrenia and depression.
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PMID:Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. 1236 86

Synaptic plasticity in the dentate gyrus is dependent on activation of the N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors. In this study, we show that synaptic plasticity in turn regulates NMDA receptors, since subunits of the NMDA receptor complex are bidirectionally and independently regulated in the dentate gyrus following activation of perforant synapses in awake animals. Low-frequency stimulation that produced a mild synaptic depression resulted in a decrease in the NMDA receptor subunits NR1 and NR2B 48 h following stimulation. High-frequency stimulation that produced long-term potentiation resulted in an increase in NR1 and NR2B at the same time point. Further investigations revealed that in contrast to NR2B, NR1 levels increased gradually after long-term potentiation induction, reaching a peak level at 48 h, and were insensitive to the competitive NMDA receptor antagonist 3-3(2-carboxypiperazin-4-yl) propyl-1-phosphate. The increased levels of NR1 and NR2B at 48 h were found associated with synaptic membranes and with increased NMDA receptor-associated proteins, postsynaptic density protein 95, neuronal nitric oxide synthase and Ca(2+)/calmodulin-dependent protein kinase II, alpha subunit. These data suggest that the persistence of long-term potentiation is associated with an increase in the number of NMDA receptor complexes, which may be indicative of an increase in synaptic contact area.
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PMID:Long-term regulation of N-methyl-D-aspartate receptor subunits and associated synaptic proteins following hippocampal synaptic plasticity. 1273 45

Nitric oxide (NO) from endothelial or neuronal NO synthases (eNOS or nNOS) may contribute both to the cerebrovascular responses to oxygen and potentially to the peroxynitrite-mediated toxic effects of hyperbaric oxygen (HBO(2)) on the central nervous system (CNS O(2) toxicity). In mice lacking eNOS or nNOS (-/-), regional cerebral blood flow (rCBF) and 3-nitrotyrosine (3-NT), a biochemical marker for peroxynitrite (ONOO(-)) formation, were measured in the brain during HBO(2) exposure. These variables were then correlated with EEG spiking activity related to CNS O(2) toxicity. In wild-type (WT) mice, HBO(2) exposure transiently reduced rCBF, but by 60 min rCBF was restored to baseline levels and above, followed by EEG spikes. Mice lacking nNOS also showed initial depression of rCBF followed by hyperemia but the delay in the onset of EEG discharges was greater. In contrast, in eNOS-deficient mice rCBF did not decrease and hyperemia was less pronounced during HBO(2). EEG spike latency was longer in eNOS(-/-) compared to WT or nNOS(-/-) mice. 3-NT gradually increased in all strains during HBO(2) but accumulation was slower in nNOS(-/-) mice, consistent with less ONOO(-) production. These results indicate that NOS-deficient mice have different cerebrovascular responses and tolerance to HBO(2) depending on which enzyme isoform is affected. The data suggest a key role for eNOS-dependent NO production in cerebral vasoconstriction and in the development of hyperoxic hyperemia preceding O(2) seizures, whereas neuronal NO may mediate toxic effects of HBO(2) mainly by its reaction with superoxide to generate the stronger oxidant, peroxynitrite.
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PMID:Oxygen seizure latency and peroxynitrite formation in mice lacking neuronal or endothelial nitric oxide synthases. 1278 20

Cortical spreading depression (CSD) is characterized by slowly propagating waves of neuronal/astrocytic depolarization and metabolic changes, followed by a period of quiescent neuronal and electroencephalographic activity. CSD acts as a preconditioning stimulus in brain, reducing cell death when elicited up to several days prior to an ischemic insult. Precise mechanisms associated with this neuroprotection are not known, although CSD increases the expression of a number of potentially neuroprotective genes/proteins. The nitric oxide (NO) system may be of particular importance, as it is acutely activated and chronically up-regulated in cerebral cortex by CSD, and NO can ameliorate and exacerbate cell death under different conditions. Several molecules have recently been identified that modulate the production and/or cellular actions of NO, but it is not known whether their expression is altered by CSD. Therefore, the present study examined the effect of CSD on the spatiotemporal expression of PIN, CAPON, PSD-95, Mn-SOD and Cu/Zn-SOD mRNA in the rat brain. In situ hybridization using specific [35S]-labelled oligonucleotides revealed that levels of PIN mRNA were significantly increased in the cortex and claustrum ( approximately 30-180%; p </= 0.01) after 6 h and 1 and 2 days, but were again equivalent to contralateral (control) cortical values at 7, 14 and 28 days. CAPON mRNA levels were increased ( approximately 30-180%; p </= 0.05) in the ipsilateral cortical hemisphere at 6 h and 2 days post treatment, but not at the other times examined. In contrast, levels of PSD-95, Mn- and Cu/Zn-SOD mRNA were not altered at any time after CSD. These results suggest that following CSD, nNOS activity and NO levels may be tightly regulated by both transcriptional and translational alterations in a range of nNOS adaptor proteins, which may contribute to CSD-induced neuroprotection against subsequent ischemia.
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PMID:Neuronal-NOS adaptor protein expression after spreading depression: implications for NO production and ischemic tolerance. 1471 93

Certain disorders of the nervous system may have their origin in disturbances in the development of synaptic connections and network structure that may not become overt until later in life. As inflammatory cytokines can influence synaptic activity in neuronal cultures, we analysed whether cytokine exposure during synaptogenesis can lead to imbalances in a neuronal network. Short-term application of interferon-gamma (IFN-gamma), but not tumour necrosis factor-alpha, during peak synaptogenesis (but not before or after) in Sprague-Dawley rat hippocampal cultures, caused both a decrease in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) and an increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). These effects were only detected in recordings made weeks later. This was not due to a depression of glutamatergic synapses or to a change in the relative number of neurons containing glutamic acid decarboxylase (GAD). There was an increase in the average amplitude of miniature IPSCs, and in GAD-expressing neurons the amplitude of miniature EPSCs were larger as well as the responses to glutamate. This indicates that IFN-gamma-treatment induced increased inhibition via postsynaptic changes. These effects of IFN-gamma treatment were not observed when neuronal nitric oxide synthase was inhibited. Our study therefore shows that exposure to IFN-gamma during a restricted period of development, which coincides with the peak of excitatory synaptogenesis, can cause progressive changes in synaptic activity in the network. Thus, cytokine exposure at a critical period of development may constitute a 'hit-and-run' mechanism for certain nervous system disorders that become manifest after a latency period.
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PMID:Exposure to interferon-gamma during synaptogenesis increases inhibitory activity after a latent period in cultured rat hippocampal neurons. 1521 75

Nitric oxide (NO) was recently proposed to be involved in the sleep-wake cycle and cortical spreading depression. As a structural correlate of these functions, we found that bNOS IR was expressed by three cell types in the prefrontal cortex, viz. bipolar, multipolar, and stellate cells. Dendrites of bipolar cells established bundles resulting in a columnoid organization; in addition, the monoclonal antibody mAb 35 which labels subunits alpha1, alpha3 and alpha5 of nAChR, also visualized apical axons proceeding alongside the columnoids. In contrast, alpha-bungarotoxin which labels the alpha7-subunit of nAChR, visualized only perikarya of interneurons from where the apical axons arose. In the prefrontal cortex of monkeys which were anesthetized for 6-24 hours, only traces of the columnoid organization were found, while perikaryal bNOS and nAChR were invariably expressed. It is suggested that interactions between NO and presynaptically released ACh might be involved in cortical functions such as the sleep/wake cycle.
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PMID:Cytochemical correlates of the sleep-wake interface: concerted expression of brain-derived nitric oxide synthase (bNOS) and the nicotinic acetylcholine receptor (nAChR) in a columnoid organization of the primate prefrontal cortex. 1525 97


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