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)

Persistent sensory abnormalities consequent to injury may involve prolonged neuroplastic changes in the spinal cord similar to those in long-term potentiation. Molecular markers, like the putative nitric oxide synthase, nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), can be useful indicators of increased neuronal activity. Peripheral nerve injury markedly increased NADPH-d-labeling in sensory regions of the spinal cord, paralleling induction of abnormal pain (hyperalgesia). Both NADPH-d activation and hyperalgesia were reversed by transplantation of opioid/catecholamine-producing adrenal medullary tissue into the spinal subarachnoid space. These results suggest that adrenal medullary transplants can attenuate abnormal neuronal activity consequent to injury.
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PMID:Induction of spinal NADPH-diaphorase by nerve injury is attenuated by adrenal medullary transplants. 800 64

Purposes of this work were to develop an enzyme system as an in vitro model of the NADPH-dependent component of nitric oxide synthase (NOS) and examine the plausible down-regulation of this system and brain NOS by copper (II)2(3,5-diisopropylsalicylate)4[Cu(II)2(3,5-DIPS)4] as a mechanism accounting for its analgesic, anticonvulsant, and other pharmacological activities. Porcine heart diaphorase (PHD) was found to oxidize 114 microM NADPH with the corresponding reduction of an equivalent amount of 2,6-dichlorophenolindophenol (DCPIP). Addition of Cu(II)2(3,5-DIPS)4 to the reaction mixture decreased the reduction of DCPIP without substantially affecting the oxidation of NADPH. The IC50 for Cu(II)2(3,5-DIPS)4 in inhibiting the reduction of DCPIP was 1.5 microM. Mechanistically, this inhibition of DCPIP reduction was found to be due to the ability of Cu(II)2(3,5-DIPS)4 to serve as a catalytic electron acceptor for reduced PHD, which was enhanced by the presence of a large concentration of DCPIP and inhibited by a large concentration of NADPH. Oxidation of NADPH by PHD in the absence of DCPIP was linearly related to the concentration of Cu(II)2(3,5-DIPS)4 through the concentration range of 5-25 microM Cu(II)2(3,5-DIPS)4 with 50% recovery of NADPH oxidation by PHD at a concentration of 16 microM Cu(II)2(3,5-DIPS)4. Whole rat brain tissue sections incubated in medium containing an NADPH-generating system and nitroblue tetrazolium chloride (NBT) were less intensely stained when Cu(II)2(3,5-DIPS)4 was added to the medium. It is concluded that Cu(II)2(3,5-DIPS)4 serves as an electron acceptor in down-regulating PHD reduction of DCPIP and in down-regulating NOS in brain tissue sections. A decrease in NO synthesis in animal models of seizure, pain, and other disease states with Cu(II)2(3,5-DIPS)4 may account for the anticonvulsant, analgesic, and other pharmacological activities of this complex.
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PMID:Down-regulation of NADPH-diaphorase (nitric oxide synthase) may account for the pharmacological activities of Cu(II)2 (3,5-diisopropylsalicylate)4. 942 75

We investigated the chemical and anatomical features of nitric oxide synthase (NOS)-containing neurons in the paraventricular and supraoptic nuclei in the rat hypothalamus using combinations of enzyme histochemistry, in situ hybridization and immuno-histochemistry. Neurons expressing NOS mRNA completely overlapped with NADPH-diaphorase-positive neurons. Topographical distribution of NOS was segregated from that of CRF-containing parvicellular neurons in the posterior paraventricular nucleus but overlapped with that of magnocellular neurons. In the paraventricular nucleus, 70% of oxytocin neurons contained NOS, which corresponded to one half of NOS neurons. About one third of vasopressin-immunoreactive neurons were NADPH-diaphorase-positive and the same proportion of NADPH-diaphorase-positive neurons were vasopressin-immunoreactive. In the supraoptic nucleus, 50% of oxytocin neurons were NADPH-diaphorase-positive, which corresponded to 40% of NOS neurons. About 25% of vasopressin neurons were NADPH-diaphorase-positive, and 30% of NADPH-diaphorase-positive neurons were vasopressin-immunoreactive. When NADPH-diaphorase histochemistry was performed first, subsequent immunostaining was markedly perturbed. Using fluoro-gold as a retrograde tracer, 4% of NADPH-diaphorase-positive neurons were shown to contribute to the descending projection to the spinal cord. About 40%-50% of NADPH-diaphorase-positive neurons exhibited Fos immunoreactivity after injection of lipopolysaccharide or hypertonic saline, while only 10%-15% of these neurons expressed Fos in response to immobilization or pain. Endogenous NO may be involved in the regulation of magnocellular functions, especially when the internal environment is disturbed.
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PMID:Nitric oxide synthase-containing magnocellular neurons of the rat hypothalamus synthesize oxytocin and vasopressin and express Fos following stress stimuli. 895 94

In a previous study we found that nitric oxide (NO) plays an essential role in the hemodynamic regulation of the feline dental pulp. However, no evidence for the presence of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) containing nerve fibers was found in the rat and cat dental pulps. In the present study, we are first to report the presence of a small number of NADPH-d positive and/or NO synthase immunoreactive perivascular and solitary varicose axons in the dental pulp and abundant number of similar axons in the gingiva of cats and dogs. These fibres may travel within the inferior alveolar nerve and might participate in sensory (i.e. pain) as well as in autonomic (i.e. regulation of blood flow) innervation of the dental pulp and gingiva.
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PMID:Nitric oxide synthase containing nerves in the cat and dog dental pulp and gingiva. 918 Feb 11

We report the development of a 'second-messenger' model in an attempt to re-evaluate the role of K+ as a desensitising agent. Despite unequivocal validation of the effectiveness of potassium-based dentifrices in the management of dentine hypersensitivity, the mechanism(s) of action of K+ remains unclear. Although experimental paradigms of the Nernst equation demonstrate a direct inhibitory effect of K+ ion upon nerve conduction, in vivo considerable constraints can be argued to preclude this mechanism of action. Indeed, measurements of solution velocity within individual dentinal tubules obtained by scanning electrochemical microscopy indicate that outward movement of tubular fluid may represent a far greater barrier to the inward diffusion of K+ ions than previously estimated from measurements of hydraulic conductance across bulk dentine. Despite such probable limited penetration of dentine tubules, K+ ions may desensitise deeply-located nerve terminals through activation of a second-messenger transduction pathway that is capable of controlling the gain of K+-evoked effects which remain physically restricted to the more superficial aspects of the tubule. In addition to a direct effect upon transmembrane potential K+ can also indirectly attenuate neural activity through effects upon levels of the endogenously-synthesised free radical, nitric oxide (NO). Stimulation of the release of NO by K+ has been observed using a variety of cell preparations, which include endothelium, smooth muscle, adrenal medulla, hypothalamus and cerebellum. Importantly, a growing number of studies now report that an increase in the production of NO is associated with analgesia through a modulation of nociceptive input and a downregulation of sensitised nociceptors, most likely achieved through an increase in intraneural content of cGMP. The clinical role of a K+-evoked liberation of NO as a principal mechanism in the management of dentine hypersensitivity is supported by recent findings which include: (1) the localisation of NADPH-diaphorase activity and inducible nitric oxide synthase (iNOS) immunoreactivity within odontoblasts, their processes in dentine, and the subodontoblast layer of the pulp; (2) iNOS causes a sustained release of large (nanomolar) amounts of NO; (3) NO is freely diffusible and capable of displaying remarkably potent effector actions at distant target cells; (4) the actions of NO may be enhanced by endogenous carrier molecules such as S-nitrosothiols; (5) the synthesis of NO can be evoked by concentrations of K+ ion far less (i.e. <1 mM) than those required for direct inhibitory effects upon neural activity.
Pain 1996 Nov
PMID:The enigma of potassium ion in the management of dentine hypersensitivity: is nitric oxide the elusive second messenger? 925 93

Nitric oxide (NO) is a neuronal messenger that it is thought to be involved in the nociceptive transmission modulation. The activity of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) was shown to be identical to NOS activity in the brain. Since the periaqueductal gray matter (PAG) plays an important role in pain perception and antinociception this study was carried out to monitor the expression of NADPH-d in PAG after nociceptive visceral stimulation. Our data showed that the noxious visceral stimulation significantly increased NADPH-d positive neurons and that these neurons were localized in the ventrolateral areas of the PAG. These findings suggest that NO in the PAG may play a role in pain modulation and antinociception.
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PMID:Induction of NADPH-diaphorase activity in the rat periaqueductal gray matter after nociceptive visceral stimulation. 963 Jul 10

The present study was undertaken to examine the involvement of descending pain modulatory systems from the brainstem rostral ventromedial medulla (RVM) in modulating visceral hyperalgesia produced by intracolonic instillation of zymosan. Three hours after intracolonic zymosan, the visceromotor response (VMR) to noxious colorectal distension (CRD, 80 mmHg, 20s) was increased significantly. This hyperalgesia was attenuated in a dose-dependent manner by the selective NMDA receptor antagonist APV (10-30 fmol, 1 microl) microinjected into the RVM. The hyperalgesia was also attenuated by intra-RVM administration of the nitric oxide synthase (NOS) inhibitor L-NAME. In support, there was a significant increase in the number of cells in the RVM labeled for NADPH diaphorase (NADPH-d) or neuronal NOS (nNOS) in zymosan-treated rats. In contrast to the effects of APV and L-NAME, administration of the non-NMDA receptor antagonist DNQX into the RVM further enhanced the already facilitated VMR to CRD in zymosan-treated rats. Taken together, these data suggest that zymosan-produced visceral hyperalgesia is influenced by two descending pain modulatory systems: a facilitatory system mediated by activation of NMDA receptors in the RVM and production of nitric oxide, and an inhibitory system mediated by activity at non-NMDA receptors in the RVM. The unmasking of one system by selective blockade of the other suggests simultaneous activation of both by colonic inflammation.
Pain 1998 Oct
PMID:Role of glutamate receptors and nitric oxide in the rostral ventromedial medulla in visceral hyperalgesia. 982 12

The substantia gelatinosa of the spinal cord (lamina II) is the major site of integration for nociceptive information. Activation of NMDA glutamate receptor, production of nitric oxide (NO), and enhanced release of substance P and calcitonin gene-related peptide (CGRP) from primary afferents are key events in pain perception and central hyperexcitability. By combining reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry for NO-producing neurons with immunogold labeling for substance P, CGRP, and glutamate, we show that (1) NO-producing neurons in lamina IIi are islet cells; (2) these neurons rarely form synapses onto peptide-immunoreactive profiles; and (3) NADPH diaphorase-positive dendrites are often in close spatial relationship with peptide-containing terminals and are observed at the periphery of type II glomeruli showing glutamate-immunoreactive central endings. By means of confocal fluorescent microscopy in acute spinal cord slices loaded with the Ca2+ indicator Indo-1, we also demonstrate that (1) NMDA evokes a substantial [Ca2+]i increase in a subpopulation of neurons in laminae I-II, with morphological features similar to those of islet cells; (2) a different neuronal population in laminae I-IIo, unresponsive to NMDA, displays a significant [Ca2+]i increase after slice perfusion with either substance P and the NO donor 3morpholinosydnonimine (SIN-1); and (3) the responses to both substance P and SIN-1 are either abolished or significantly inhibited by the NK1 receptor antagonist sendide. These results provide compelling evidence that glutamate released at type II glomeruli triggers the production of NO in islet cells within lamina IIi after NMDA receptor activation. The release of substance P from primary afferents triggered by newly synthesized NO may play a crucial role in the cellular mechanism leading to spinal hyperexcitability and increased pain perception.
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PMID:Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. 985 75

Both nitric oxide (NO) and prostaglandins (PG) and their associated enzymes nitric oxide synthases (NOS) and cyclooxygenases (COX) (specifically COX-2) have been implicated in the development of hyperalgesia. This study examined the effects of naturally occurring chronic inflammation, chronic mastitis, on spinal nociceptive processing in sheep and focused on potential alterations in spinal PG and NO signaling pathways. Mechanical withdrawal thresholds were significantly lower in animals suffering from chronic inflammation (n=6) compared to control animals (n=6). Hyperalgesia was restricted to the side contralateral to the inflammation (decrease from ipsilateral side: hindlimb 33.2+/-5%, forelimb 19.4+/-5%). Neuronal NOS-immunoreactivity was significantly reduced bilaterally in lumbar and cervical spinal cord throughout laminae I-III (decrease 18.4+/-5% and 16.9+/-4%, respectively) and in lamina X (decrease 29.1+/-6% and 17.1+/-4%, respectively) in mastitic animals relative to control animals. No difference was detected in eNOS or iNOS-immunoreactivity or in NADPH-diaphorase staining, a marker of dynamically active NOS. RT-PCR failed to detect any change in levels of nNOS, eNOS, iNOS, COX-1 or COX-2 mRNAs. However, a marked increase in the PGE receptor, EP(3) (but not EP(2)) mRNA was detected in ipsilateral spinal cord tissue from animals with chronic inflammation. This increase in EP(3) receptor expression indicates that spinal PGs are important in the spinal response to chronic peripheral inflammation. Contralateral mechanical hyperalgesia may not be directly linked to changes in spinal EP(3) receptor mRNA expression, however, the bilateral changes in nNOS suggest that this pathway may contribute to the adaptive behavioural response observed.
Pain 2000 Jun
PMID:The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation. 1081 61

Glucocorticoids (GC) provide neuroprotection and early recovery after spinal cord injury (SCI). While several mechanisms were proposed to account for these effects, limited information exists regarding GC actions in sensory areas of the spinal cord. Presently, we studied the time course of Fos expression, and reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemical staining to monitor neuronal responses to SCI with or without GC treatment. Rats with sham-operation or transection at the thoracic level (T7-T8) received vehicle or 5 mg/kg of the GC dexamethasone (DEX) at 5 min post-lesion and were sacrificed 2 or 4 h after surgery. Another group of SCI rats received vehicle or intensive DEX treatment (5 min, 6 h, 18 h and 46 h post-lesion) and were sacrificed 48 h after surgery. The number of NADPH-d positive neurons or Fos immunoreactive nuclei was studied by computer-assisted image analysis in superficial dorsal horn (Laminae I-III) and central canal area (Lamina X) below the lesion. While constitutive Fos immunoreactive nuclei were sparse in controls, SCI increased Fos expression at 2 and 4 h after injury. DEX treatment significantly enhanced the number of Fos positive nuclei in Laminae I-III by 4 h after transection, although the response was not maintained by intensive steroid treatment when tested at 48 h after SCI. NADPH-d positive neurons in Laminae I-III increased at 2 and 4 h after SCI while a delayed increased was found in central canal area (Lamina X). DEX treatment decreased NADPH-d positive neurons to sham-operated levels at all time points examined. Thus, while GC stimulation of Fos suggests activation of neurons involved in sympathetic outflow and/or pain, down-regulation of NADPH-d indicates attenuation of nociceptive outflow, considering the role of enzyme-derived nitric oxide in pain-related mechanisms. Differential hormonal effects on these molecules agree with their localization in different cell populations.
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PMID:Glucocorticoid effects on Fos immunoreactivity and NADPH-diaphorase histochemical staining following spinal cord injury. 1153 30


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