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)

NC mice, a model for atopic dermatitis, showed scratching behavior when kept under conventional environment. The scratching behavior of NC mice was suppressed by distraction or by the administration of naltrexone (1 mg/kg, s.c.), an opioid antagonist. These results suggest that such scratching behavior is itch-associated response. The itch-associated response of the NC mice was significantly suppressed by an intravenous injection of nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), but not D-NAME (10 mg/kg) and saline. Intracutaneous NO production in the rostral back, a region which the NC mice mainly scratched, was markedly increased as compared with the caudal back, a non-scratched region. The increased NO production in the rostral back of NC mice was decreased by the intravenous injection of L-NAME (10 mg/kg). These results suggest that NO and NO synthase are new target in the treatment of atopic pruritus.
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PMID:[Involvement of nitric oxide in itch-scratch response of NC mice]. 1062 49

We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 microM ET-1 (1.43 +/- 0.64 microM, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 +/- 0.38 microM) whilst that in the flare increased to reach a peak value of 2.28 +/- 0.61 microM at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52% at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ET(A)/ET(B) antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26%, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo.
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PMID:The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo. 1118 78

1 Substance P (SP) elicits itch and itch-associated responses in humans and mice, respectively. In mice, NK(1) tachykinin receptors are involved in SP-induced itch-associated responses, scratching, and mast cells do not play a critical role. The present study was conducted to elucidate the role of nitric oxide (NO) on SP-induced scratching in mice. 2 An intradermal injection of SP (100 nmol site(-1)) elicited scratching in mice, and it was suppressed by an intravenous injection of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), but not by its inactive enantiomer D-NAME. Intradermal injections of L-NAME (100 nmol site(-1)), another NOS inhibitor 7-nitroindazole (10 nmol site(-1)) and the NO scavenger haemoglobin (0.01-10 nmol site(-1)) also inhibited SP-induced scratching. 3 L-NAME (100 nmol site(-1)) did not affect scratching induced by an intradermal injection of 5-hydroxytryptamine (100 nmol site(-1)). 4 Intradermal injections of L-arginine (300 nmol site(-1)) and the NO donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3; 100 nmol site(-1)) increased scratching induced by SP. Intradermal injections of L-arginine (1-1000 nmol site(-1)) or NOR3 (1-100 nmol site(-1)) alone were without effects on scratching. 5 Intradermal injections of SP (10-100 nmol site(-1)) increased the intradermal concentration of NO in a dose-dependent manner in mice. An increase in NO levels induced by SP was inhibited by L-NAME and the NK(1) tachykinin receptor antagonist L-668,169, but not by the NK(2) tachykinin receptor antagonist L-659,877. 6 SP (1-10 micro M) elicited NO production in cultured human keratinocytes and the SP-induced NO production was inhibited by L-NAME and L-668,169. 7 We conclude that intradermal SP increases NO in the skin, possibly through the action on NK(1) tachykinin receptors on the epidermal keratinocytes and that NO enhances SP-induced itch-associated responses.
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PMID:Nitric oxide enhances substance P-induced itch-associated responses in mice. 1252 91

Different drugs from various pharmacological classes were compared for their ability to protect against the nasal effects of acute allergen challenge in a guinea pig model. In the model, sneezing and nose rubbing were recorded after an initial allergen challenge in guinea pigs previously sensitized to egg albumin. Four days later the same guinea pigs were re-challenged a second time when anesthetised. In these anaesthetized animals, nasal airway pressure, pulmonary inflation pressure and cellular infiltration into nasal lavage fluid were measured. The drug tested were autacoid antagonists (mepyramine--3mg/kg, cetirizine--3mg/kg and montelukast--10mg/kg), L-NAME (10 or 20mg/kg), heparin (20mg/kg) and dexamethasone (20mg/kg) given either intraperitoneally or intravenously; all were given shortly before challenge. Sneezing induced by allergen challenge was statistically significantly reduced by mepyramine, cetirizine and dexamethasone whereas only cetirizine reduced nose rubbing. Changes in nasal airway pressure due to allergen exposure were reduced by cetirizine, montelukast, L-NAME, and heparin, but not by mepyramine, nor dexamethasone. In the presence of L-NAME, nasal airway pressure actually changed in the opposite direction. Cellular infiltration, as assessed by cytometry in nasal lavage fluid 60min after acute allergen challenge, was reduced by montelukast and heparin but not by antihistamines, L-NAME nor dexamethasone. This pattern of effects of the drugs, given by doses and routes previously described in the literature as being effective was not completely consistent with expected responses. The lack of effect of dexamethasone probably reflects the fact that it was given acutely whereas in the clinic chronic administration is used. The two antihistamines were not identical in their actions, presumably reflecting the fact that cetirizine has therapeutic actions not entirely confined to blockade of H1 receptors. Montelukast has not been reported to have major effects on sneezing and itching in the clinic but reduces nasal obstruction (lower nasal airway pressure or nasal patency). Montelukast's effects on cellular infiltration indicate the possible involvement of leukotrienes. Heparin has actions on inflammatory cell infiltration. This could explain its profile of reducing both cellular infiltration, and increased nasal airway pressure.
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PMID:Differential responses to various classes of drugs in a model of allergic rhinitis in guinea pigs. 1790 20

Cholestasis is a major systemic disorder associated with distressing pruritus (itch). Nitric oxide (NO) is a neurotransmitter, assumed to be involved in pruritus. Based on over-production of NO in cholestatic liver diseases, this project aimed to investigate involvement of NO in cholestasis-related itch in mice. To achieve this, cholestasis was induced by bile duct ligation (BDL). Our results showed that BDL mice elicited significant itch on fifth and seventh day after the procedure. This scratching behavior was inhibited by intraperitoneal (IP) treatment of mice with non-selective NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME; 3mg/kg) and inducible NOS (iNOS) inhibitor aminoguanidine (AG; 100mg/kg). The inhibitory effects of l-NAME and AG were reversed by pretreatment with l-arginine (100mg/kg). Administration of l-NAME, AG and l-arginine per se, in BDL and SHAM mice did not produce scratching behaviors. In addition, intradermal injection of l-arginine at dose of 300 nmol/site significantly increased itch in BDL mice. Furthermore, nitrite levels in skin and serum of BDL animals significantly increased after 7 d of operation and administration of NOS inhibitors decreased this enhancement. l-arginine injection reversed the effects of NOS inhibitors on reduction of nitrite levels in the skin and serum of BDL mice. Finally, cutaneous iNOS expression increased in BDL mice 7 d after surgery. Taken together, our study showed for the first time that BDL, as a model of acute cholestasis in rodents, induces NO over-production by activating NOS enzymes, especially iNOS, which contribute to pruritus.
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PMID:Evidence for the involvement of nitric oxide in cholestasis-induced itch associated response in mice. 2780 97

Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scrat-ching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior.
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PMID:Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice. 2811 97

Chloroquine (CQ) induces histamine-independent itch in human and mice. We recently reported the role of intradermal nitric oxide (NO)/cyclic guanosine monophosphate pathway in CQ-evoked scratching in mice. Chloroquine stimulates neuronal nitric oxide synthase (nNOS) activity to over-producing NO in the skin. Sumatriptan, a 5-hydroxytryptamine 1b/1d receptors (5-HTR1b/1d) agonist, is involved in pain and used to treat migraine and cluster headaches. According to previous studies, sumatriptan inhibits NOS activity. Thus, we aimed to investigate the effect of sumatriptan on CQ-induced scratching. We used the rostral back model of itch. Chloroquine was injected intradermally into the rostral back of NMRI mice, and the scratching behavior was evaluated by measuring the number of bouts over 30 min. We evaluated the effect of sumatriptan and combination of sumatriptan and a non-selective NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), on the scratching behavior. Additionally, the changes of skin, hippocampus, and cortical nitrite level after different treatments were studied. Intraperitoneal and intradermal sumatriptan attenuates CQ-induced itch which reversed by GR-127935, the selective 5-HTR1b and 5-HTR1d antagonist. Co-administration of subeffective doses of sumatriptan and L-NAME significantly decreases the scratching behavior. Intradermal injection of CQ significantly increases the intradermal nitrite levels while it does not have any significant effects on hippocampal or cortical nitrite concentrations. Likewise, the effective doses of intraperitoneal and intradermal sumatriptan significantly reduce intradermal nitrite levels. We concluded that sumatriptan suppresses CQ-induced itch most likely by activating 5-HT1b/1d receptors. This effect probably mediates through NO pathway.
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PMID:Pharmacological evidence of involvement of nitric oxide pathway in anti-pruritic effects of sumatriptan in chloroquine-induced scratching in mice. 2881 20

It is well established that extracellular proteins that negatively regulate T cell function, such as Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), can be effectively targeted to enhance cancer immunotherapies and Chimeric Antigen Receptor T cells (CAR-T cells). Intracellular proteins that inhibit T cell receptor (TCR) signal transduction, though less well studied, are also potentially useful therapeutic targets to enhance T cell activity against tumor. Four major classes of enzymes that attenuate TCR signaling include E3 ubiquitin kinases such as the Casitas B-lineage lymphoma proteins (Cbl-b and c-Cbl), and Itchy (Itch), inhibitory tyrosine phosphatases, such as Src homology region 2 domain-containing phosphatases (SHP-1 and SHP-2), inhibitory protein kinases, such as C-terminal Src kinase (Csk), and inhibitory lipid kinases such as Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase (SHIP) and Diacylglycerol kinases (DGKs). This review describes the mechanism of action of eighteen intracellular inhibitory regulatory proteins in T cells within these four classes, and assesses their potential value as clinical targets to enhance the anti-tumor activity of endogenous T cells and CAR-T cells.
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PMID:Beyond the Cell Surface: Targeting Intracellular Negative Regulators to Enhance T cell Anti-Tumor Activity. 3175 21