Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.99.1 (NADPH-diaphorase)
3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of 3-acetylpyridine (3-AP) were studied in rat striatum. Striatal injections of 3-AP produced dose-dependent lesions. The lesion size was significantly increased in 4- and 12-month-old rats compared to 1-month-old rats. Coinjection of the competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid (APV) or systemic administration of the noncompetitive NMDA antagonist MK-801, the competitive NMDA antagonist LY274614, or the glutamate release inhibitor lamotrigine partially but significantly attenuated striatal lesion volume. Consistent with an NMDA receptor-mediated excitotoxic effect, histologic studies showed that 3-AP lesions result in relative sparing of NADPH-diaphorase neurons. Using freeze clamp, 3-AP resulted in a marked depletion of ATP. Two-dimensional water-suppressed proton chemical shift magnetic resonance imaging showed a striatal depletion of the neuronal marker N-acetylaspartate but no focal increase in lactate during the first 3 h after intrastriatal 3-AP injections. Pretreatment with fructose-1,6-biphosphate attenuated the lesion volume significantly, which may be due to its ability to serve as a substrate for glycolytic metabolism, with resulting ATP production. The results of the present studies support the hypothesis that 3-AP produces an impairment of energy metabolism due to its substitution for niacinamide in the formation of NAD(P). Furthermore, 3-AP toxicity may involve a secondary excitotoxic mechanism mediated by NMDA receptors.
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PMID:3-Acetylpyridine produces age-dependent excitotoxic lesions in rat striatum. 792 44

To demonstrate the regional, cellular and subcellular distributions of non-N-methyl-D-aspartate glutamate receptors in rat brain, we generated antipeptide antibodies that recognize the C-terminal domains of individual subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-preferring glutamate receptors (i.e. GluR1, GluR4, and a region highly conserved in GluR2, GluR3 and GluR4c). On immunoblots, antibodies detect distinct proteins with mol. wts ranging from 102,000 to 108,000 in homogenates of rat brain. Immunocytochemistry shows that glutamate receptor subunits are distributed abundantly and differentially within neuronal cell bodies and processes in cerebral cortex, basal ganglia, limbic system, thalamus, cerebellum and brainstem. The precise patterns and cellular localizations of glutamate receptor subunit immunoreactivities are unique for each antibody. In neocortex and hippocampus, pyramidal neurons express GluR1 and GluR2/3/4c immunoreactivities; many non-pyramidal, calcium-binding, protein-enriched neurons in cerebral cortex are selectively immunoreactive for GluR1. In striatum, the cellular localizations of GluR1, GluR2/3/4c and GluR4 immunoreactivities are different; in this region, GluR1 co-localizes with many cholinergic neurons but is only present in a minor proportion of nicotinamide adenine dinucleotide phosphate diaphorase-positive striatal neurons. GluR1 co-localizes with most dopaminergic neurons within the substantia nigra. In several brain regions, astrocytes show GluR4 immunoreactivity. Within the cerebellar cortex, cell bodies and processes of Bergmann glia express intense GluR4 and GluR1 immunoreactivities; perikarya and dendrites of Purkinje cells show GluR2/3/4c immunoreactivity but no evidence of GluR1 or GluR4. Ultrastructurally, GluR subunit immunoreactivities are localized within cell bodies, dendrites and dendritic spines of specific subsets of neurons and, in the case of GluR1 and GluR4, in some populations of astrocytes. This investigation demonstrates that individual AMPA-preferring glutamate receptor subunits are distributed differentially in the brain and suggests that specific neurons and glial cells selectively express glutamate receptors composed of different subunit combinations. Thus, the co-expression of all AMPA receptor subunits within individual cells may not be obligatory for the functions of this glutamate receptor in vivo.
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PMID:AMPA glutamate receptor subunits are differentially distributed in rat brain. 838 83

Ibogaine causes degeneration of Purkinje cells (PKCs), presumably via activation of neurons in the inferior olive leading to release of glutamate at climbing fiber terminals. Following ibogaine administration, some Purkinje cells express NADPH-diaphorase and neuronal NOS (nNOS), neither of which is present normally in these cells. The induction of NOS is delayed in onset, dose-related, and detected in neurons adjacent to degenerated PKCs. The results demonstrate that nNOS induction can follow excitotoxic neuronal injury or perturbation. However, NO is unlikely to participate in the initial phase of PKC damage. Both the late induction of nNOS and the spatial relationship between damaged and nNOS-expressing PKCs are consistent with a role for NO in either neuronal recovery or delayed cell death following excitotoxic injury.
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PMID:Excitotoxic insult due to ibogaine leads to delayed induction of neuronal NOS in Purkinje cells. 852 25

Nitric oxide serves as a messenger molecule in some neuronal systems that use glutamate as a transmitter and it has been shown that glutamate mediates the transmission of photic signals by retinal ganglion cell axons terminating in the hypothalamic suprachiasmatic nucleus, site of the circadian pacemaker in rodents. Recent experiments have demonstrated that pharmacological treatments which block nitric oxide synthesis by nitric oxide synthase prevent glutamate-induced phase shifts of the cell firing rhythm in suprachiasmatic nucleus slice preparation in vitro; similar treatments were found to inhibit light transmission to the suprachiasmatic nucleus as well as light-induced phase shifts in activity rhythms in vivo, implicating nitric oxide in circadian light signalling in vivo. There is limited information, however, about the presence and function of nitric oxide synthase-containing neurons within retinorecipient regions of the rodent suprachiasmatic nucleus. In the present study we used NADPH-diaphorase histochemistry and immunostaining for the nuclear phosphoprotein Fos to assess the co-distribution of nitric oxide synthase-containing neurons and light-responsive cells in the rat suprachiasmatic nucleus region. A strong convergence between NADPH-diaphorase-stained cell bodies and fibres and cells that expressed Fos in response to photic stimulation was noted in the anterior periventricular nucleus, suprachiasmatic preoptic nucleus, retrochiasmatic area, the inter-suprachiasmatic nucleus region, and the dorsal aspect of the optic chiasm, below the suprachiasmatic nucleus. A similar convergence between NADPH-diaphorase-stained fibres and Fos-immunoreactive cells was noted inside the suprachiasmatic nucleus, but the number of NADPH-diaphorase-stained elements found in this region was substantially low compared with that found in retinorecipient regions bordering the nucleus. In many cases both inside and outside the suprachiasmatic nucleus, the Fos-immunoreactive cells appeared to make direct contact with NADPH-diaphorase-stained cells or fibres, but no co-localization of Fos immunoreactivity and NADPH-diaphorase histochemical activity within individual cells was detected. Extensive co-distribution of NADPH-diaphorase-stained cells and fibres and cells that express Fos in response to photic stimulation in the suprachiasmatic nucleus region is in line with the hypothesis that nitric oxide participates in the mechanism mediating circadian light signalling in the suprachiasmatic nucleus. However, lack of co-localization of the two markers to individual cells rules out the possibility that retinorecipient cells in the suprachiasmatic region synthesize and release nitric oxide when photically-activated. Instead, the results support the possibility that photic stimulation triggers nitric oxide synthesis in nitric oxide synthase-containing neurons located near the photically-activated cells.
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PMID:Distribution of NADPH-diaphorase staining and light-induced Fos expression in the rat suprachiasmatic nucleus region supports a role for nitric oxide in the circadian system. 855 48

The neurotransmitter glutamate plays an important role in the control of gonadotropin-releasing hormone (GnRH) secretion. Recent evidence suggests that the novel transmitter nitric oxide may also play a role in controlling GnRH release and may be an important mediator of glutamate effects. To explore the role of nitric oxide in these events, the present study determined the distribution of the enzyme which catalyzes nitric oxide production, nitric oxide synthase (NOS) in the hypothalamus, its association with GnRH neurons, and whether NOS neurons contain NMDA receptors. NOS was localized by staining hypothalamic sections from female rats for NADPH-diaphorase activity. Specific antibodies for GnRH and the NMDAR1 receptor subunit were used for double-staining to determine NOS association with GnRH neurons and the presence of NMDA R1 receptor subunits in hypothalamic NOS neurons. The studies showed intense NOS cell body and fiber staining in the organum vasculosum of the lamina terminalis (OVLT) where numerous GnRH cell bodies are located. Other major GnRH cell body sites such as the median preoptic nucleus (MPN) and medial preoptic area (MPOA) displayed moderate staining of NOS cell bodies and fibers. Intense NOS staining was also observed in the median eminence, ventromedial nucleus, paraventricular nucleus and supraoptic nucleus of the hypothalamus. While no GnRH neurons were found to double stain for NOS in the hypothalamus, GnRH neurons were frequently surrounded by NOS neurons in the OVLT, MPN and MPOA with potential contacts between NOS and GnRH neurons in these areas. In addition, there was significant overlap of GnRH and NOS fibers in the lateral portion of the internal zone of the median eminence where GnRH fibers and terminals converge. Double-staining studies for NADPH-diaphorase and NMDA R1 receptor subunit showed that many NOS neurons in the OVLT, MPOA, ventromedial nucleus, paraventricular nucleus and supraoptic nucleus co-localize the NMDA R1 receptor subunit. Localization of NMDA R1 receptor subunit immunoreactivity in B-NOS neurons in the hypothalamus was further confirmed by using combined immunohistochemistry-in situ hybridization. Finally, the functional importance of this co-localization was shown by the finding that central administration of a nitric oxide synthase inhibitor blocked the ability of NMDA to induce LH secretion. Taken as a whole, these studies provide evidence which support a role for nitric oxide as an important regulator of GnRH neurons in the female. They also suggest that hypothalamic NOS neurons are targets for glutamate regulation as evidenced by co-localization of the NMDA R1 receptor subunit.
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PMID:Histochemical localization of nitric oxide neurons in the hypothalamus: association with gonadotropin-releasing hormone neurons and co-localization with N-methyl-D-aspartate receptors. 858 18

NADPH diaphorase expression in neurones and glial cells was examined in primary cultures of embryonic cerebellum and cerebral cortex with (i) increasing age in culture and (ii) the exogenous application of glutamate. In neurone-enriched cultures from both regions, NADPH diaphorase histochemistry selectively labelled discrete sub-populations of neurones and glial cells. Double labelling of the cultures showed that 2-4% of the cells with a neuronal phenotype were NADPH diaphorase-positive. Although the total numbers of neurones present in the cultures declined with increased age of cultures, there was no change in the percentage of NADPH diaphorase-positive neurones with time. In contrast, the percentage of NADPH diaphorase-positive glial cells increased from around 10% at 7 days in culture to more than 50% after 3 or more weeks in both cortical and cerebellar cultures. The age-related increase in staining was due to a greater number of cells expressing NADPH diaphorase activity rather than increased activity of existing enzyme. There was a strong correlation between the decline in neuronal cell population and the increase in the number of NADPH diaphorase positive glial cells. To determine whether or not there was a relationship between the loss of neurones and the increased expression of NADPH diaphorase in glia, neurotoxicity experiments were performed using glutamate. In both cortical and cerebellar cultures, glutamate had a significant neurotoxic effect, with a 30-50% loss of neurons 24 h after application. There was no preferential survival of NADPH diaphorase-positive neurones over the rest of the population, suggesting that NADPH diaphorase positive neurones are not selectively spared in these cultures. Glutamate had no effect on the survival of glial cells. However, glutamate cause a significant increase in the NADPH diaphorase staining of the glia. As with the aging cultures, this increase was due to an increased number of cells with enzyme activity rather than increase in the intensity of staining. The increase in NADPH diaphorase staining was not related to the expression of GFAP and was independent of the presence of neurones, since glutamate also increased NADPH diaphorase activity in pure glial cultures. In both neurone-enriched and pure glial cultures, the increase in NADPH diaphorase activity was independent of extracellular calcium and was not attenuated by the NMDA receptor antagonist dizocilpine (MK 801). However, the increase in activity could be blocked by dexamethasone. The precise identity of the enzyme responsible for these effects is unknown, but these data are consistent with the NADPH diaphorase activity we observed being due to an inducible astrocytic form of nitric oxide synthase. The strong correlation between the increased glial expression of NADPH diaphorase and decreased neuronal survival in both aging and glutamate-treated cultures suggests that NADPH diaphorase expression in glial cells may be an important factor governing the survival of neurones in culture.
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PMID:Correlation of neuronal loss with increased expression of NADPH diaphorase in cultured rat cerebellum and cerebral cortex. 859 72

Tegmental cholinergic neurons vary their discharge patterns across the sleep-wake cycle, and glutamate is suggested to play an important role in determining these firing patterns. Cholinergic and noncholinergic neurons in the mesopontine tegmentum have different susceptibilities to various excitotoxins, presumably because of heterogeneity in the expression of glutamate receptor subtypes in this area. By using a double-labeling procedure that combines nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase) histochemistry and avidin-biotin-peroxidase immunocytochemistry with diaminobenzidine as the chromogen, we compared the colocalization of AMPA receptor subunits GluR1, GluR2/3, and GluR4, kainate receptor subunits GluR5/6/7, and an NMDA receptor subunit NMDAR1 on NADPH-diaphorase-positive (cholinergic) neurons in the mesopontine tegmentum. Throughout the brainstem, neurons immunoreactive for GluR2/3 and NMDAR1 were most numerous, whereas neurons labeled for GluR1, GluR4, and GluR5/6/7 were less common. Specifically within the mesopontine tegmentum, the proportion of double-labeled neurons in the diaphorase-containing cell population was highest with GluR1 (43%) and lowest with GluR5/6/7 (12%). Regardless of the receptor subunit type, the greatest numbers of double-labeled neurons were observed in the pedunculopontine tegmental nucleus pars compacta and the fewest in the dorsal aspect of the laterodorsal tegmental nucleus. In addition, there were regional differences in the relative expression of receptor subunits and diaphorase-positive neurons across the subdivisions of the tegmental cholinergic column. Because each ionotropic subunit confers distinctive properties to a receptor channel, the present results suggest that mesopontine cholinergic neurons have nonuniform responses to glutamate and are also discriminable from basal forebrain cholinergic neurons in terms of glutamate receptor configuration.
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PMID:Colocalization of ionotropic glutamate receptor subunits with NADPH-diaphorase-containing neurons in the rat mesopontine tegmentum. 872 91

The cellular abundance of neuronal nitric oxide synthase and somatostatin messenger RNAs was compared in the caudate nucleus, putamen and sensorimotor cortex of Huntington's disease and control cases. Neuronal nitric oxide synthase messenger RNA was significantly decreased in the caudate nucleus and putamen, but not in the sensorimotor cortex in Huntington's disease; the decrease in neuronal nitric oxide synthase messenger RNA became more pronounced with the severity of the disease. Somatostatin gene expression was significantly decreased in the dorsal putamen in Huntington's disease, but was essentially unchanged in all other regions examined. The density of neurons expressing detectable levels of neuronal nitric oxide synthase messenger RNA was reduced in the striata of Huntington's disease cases with advanced pathology; the density of neurons expressing detectable levels of somatostatin messenger RNA was similar in control and Huntington's disease cases. Neuropeptide Y-, somatostatin- and NADPH-diaphorase-positive neurons were consistently present throughout the striatum across all the grades of the disease. Neuronal nitric oxide synthase and NADPH-diaphorase activity (a histochemical marker for nitric oxide synthase-containing neurons) co-localize with somatostatin and neuropeptide Y in interneurons in the human striatum and cerebral cortex. Although the neurodegeneration associated with Huntington's disease is most evident in the striatum (particularly the dorsal regions), neuronal nitric oxide synthase/neuropeptide Y/somatostatin interneurons are relatively spared. Nitric oxide released by neuronal nitric oxide synthase-containing neurons may mediate glutamate-induced excitotoxic cell death, a mechanism proposed to be instrumental in causing the neurodegeneration seen in Huntington's disease. The results described here suggest that although the population of interneurons containing somatostatin, neuropeptide Y and neuronal nitric oxide synthase do survive in the striatum in Huntington's disease they are damaged during the course of the disease. The results also show that the reduction in neuronal nitric oxide synthase and somatostatin messenger RNAs is most pronounced in the more severely affected dorsal regions of the striatum. Furthermore, the loss of neuronal nitric oxide messenger RNA becomes more pronounced with the severity of the disease; thus implying a down-regulation in neuronal nitric oxide synthase messenger RNA synthesis, and potentially neuronal nitric oxide synthase protein levels, in Huntington's disease.
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PMID:Decreased neuronal nitric oxide synthase messenger RNA and somatostatin messenger RNA in the striatum of Huntington's disease. 873 28

Elasmobranchs possess a well-developed cerebellum with an associated cerebellar nucleus. To determine whether the organization of this nucleus is comparable with that of the deep cerebellar nuclei of mammals, we studied the dogfish cerebellar nucleus with light microscopic methods (Nissl stain, Golgi method, reduced silver stain, NADPH-diaphorase histochemistry and immunocytochemistry) and with electron microscopy. We found the dogfish cerebellar nucleus to consist of about 1,050 large neurons, the ratio of Purkinje cells to cerebellar nucleus neurons being about 17:1. Immunocytochemistry showed large glutamatergic neurons in the main portions of the nucleus and small glutamate- and/or alpha-aminobutyric acid (GABA)-immunoreactive cells in the subventricular region of the nucleus. Large glutamatergic neurons corresponded to bipolar or triangular cells revealed by Golgi methods. Application of horseradish peroxidase to the cerebellar cortex produced the labelling of beaded fibres of Purkinje cells in the cerebellar nucleus. Unlike in mammals, GABAergic innervation of the cerebellar nucleus was scare: Purkinje cell axon terminals in the cerebellar nucleus did not appear to be GABA-immunoreactive, most GABAergic fibres being found in the subventricular neuropile. Some fibres immunoreactive to serotonin and somatostatin were also observed in the subventricular neuropile of the cerebellar nucleus. Three neuron types were distinguished with electron microscopy (types A to C). Type A cells were abundant and smooth-surfaced, and appeared to correspond to Golgi-impregnated neurons and large glutamate-immunoreactive cells. Type B neurons were scarce and possessed dendrites covered by sessile or stalked spines. Type C neurons were small cells located mainly in the medialmost region of the nucleus and corresponded to subventricular glutamate- and GABA-immunoreactive cells. Six types of synaptic bouton were observed (types I to VI). The most abundant (type I boutons) made symmetrical contacts and appeared to correspond to Purkinje cell axons. Type I boutons were the only type observed on perikarya and initial axon segments of type A cells. Type IV and type V boutons made complex glomerular-like asymmetrical contacts with spines of type B cells. Type VI boutons appeared to correspond to peptidergic and/or monoaminergic axons. The functional significance of these results is discussed.
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PMID:Organisation of the cerebellar nucleus of the dogfish, Scyliorhinus canicula L.: a light microscopic, immunocytochemical, and ultrastructural study. 874 38

The alteration of certain neuropeptide levels is a dramatic and consistent finding in the brains of AD patients. Levels of SS, which is normally present in high concentrations in cerebral cortex /75/, are consistently decreased in the neocortex, hippocampus and CSF of AD patients. In addition, decreased levels of SS correlate regionally with the distribution of neurofibrillary tangles in AD /47/. Most available evidence suggests that the subset of SS-containing neurons which lack NADPH diaphorase may be relatively vulnerable to degeneration in AD. CRF is another neuropeptide with frequently observed changes in AD. Levels of CRF, which is normally present in low concentrations in cortical structures /75/, are decreased in the neocortex and hippocampus of AD patients. However, levels of CRF in the CSF of AD patients are not consistently reduced, but this is likely a reflection of the relatively low levels of CRF normally present in cerebral cortex. Studies of deep gray structures in AD brains reveal elevated levels of GAL in the nucleus basalis. The ability of GAL to inhibit cholinergic neurotransmission has generated considerable interest, since degeneration of cholinergic neurons in the basal forebrain consistently occurs in AD. In addition, the presence of NADPH diaphorase in GAL-containing neurons may underlie the relative resistance of these neurons to degeneration. From the aforementioned studies, it appears that the neurons which are relatively resistant to neurodegeneration in AD contain NADPH diaphorase. It is hypothesized that the presence of NADPH diaphorase protects these neurons from neurotoxicity mediated by glutamate or nitric oxide. Although one recent study /147/ has reported an elevation of the microtubule-associated protein tau in the CSF of AD patients (and this could become a useful antemortem diagnostic tool for AD), no similar CSF abnormality has been found for any of the neuropeptides. Thus, the measurement of CSF neuropeptide levels presently remains unhelpful in the diagnosis and treatment of AD. Future research on neuropeptides and their potential roles in the pathogenesis, diagnosis, and treatment of AD will likely involve further development of pharmacological modulators of neuropeptide systems, together with the further study of brain neuropeptidases.
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PMID:Neuropeptide changes in cortical and deep gray structures in Alzheimer's disease. 884 72


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