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)

Removal of the superior colliculus (SC) in neonatal Wistar rats results in a rapid loss of retinal ganglion cells (RGCs). There is an early twofold increase in RGC death 4-8 hr postlesion (PL) followed by a later 10-11-fold increase in pyknosis about 24 hr PL. We have now used neurotrophic factors (BDNF, NT-4/5, NT-3, NGF, LIF), glutamate receptor antagonists (MK-801, DNQX, CNQX), an antioxidant (N-ace-tyl-L-cysteine), and an NOS inhibitor (L-NAME) to determine whether the early and late phases of lesion-induced RGC death involved similar or different mechanisms. Normal and pyknotic nuclei of tectally projecting RGCs were visualized by injecting the left s.c. of 2 d old rats with diamidino yellow (DY). Two days later the injection site was removed. In most rats, right eyes were injected with factors immediately after the s.c. ablation. Rats were perfused either 6 or 24 hr PL. In the latter group a second intravitreal injection of the appropriate factor was sometimes made 12 hr PL. NT- 4/5 and BDNF significantly decreased RGC pyknosis 6 and 24 hr PL, whereas NT-3 was only protective 6 hr PL. LIF slightly reduced RGC death 24 hr PL, but NGF had no influence on RGC survival at either time point. NT-4/5 also reduced the rate of naturally occurring RGC death. MK-801, DNQX, CNQX, N-acetylcysteine, and L-NAME all prevented the early lesion-induced increase in RGC death but had no significant effect on RGC death measured 24 hr PL; none of these factors significantly reduced the rate of naturally occuring RGC death. Cycloheximide, shown previously to reduce RGC pyknosis 24 hr PL, did not prevent RGC death 6 hr PL. The data indicate that there are at least two mechanisms involved in RGC death after neonatal target ablation. The early increase is related to excitotoxic effects mediated by glutamate receptors and involves NOS and the production of free radicals. We found no evidence that RGC death measured 24 hr PL is dependent on these processes, but the later death does require protein synthesis and, most likely, the activation of an endogenous suicide program. NT-4/5 and BDNF protected RGCs from both types of lesion-induced death.
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PMID:At least two mechanisms are involved in the death of retinal ganglion cells following target ablation in neonatal rats. 861 49

Primary cultures of rat embryonic motor neurons deprived of brain-derived neurotrophic factor (BDNF) induce neuronal nitric oxide synthase (NOS) within 18 hr. Subsequently, >60% of the neurons undergo apoptosis between 18 and 24 hr after plating. Nitro-L-arginine and nitro-L-arginine methyl ester (L-NAME) prevented motor neuron death induced by trophic factor deprivation. Exogenous generation of nitric oxide at concentrations lower than 100 nM overcame the protection by L-NAME. Manganese tetrakis (4-benzoyl acid) porphyrin, a cell-permeant superoxide scavenger, also prevented nitric oxide-dependent motor neuron death. Motor neurons cultured without trophic support rapidly became immunoreactive for nitrotyrosine when compared with motor neurons incubated with BDNF, L-NAME, or manganese TBAP. Our results suggest that peroxynitrite, a strong oxidant formed by the reaction of NO and superoxide, plays an important role in the induction of apoptosis in motor neurons deprived of trophic factors and that BDNF supports motor neuron survival in part by preventing neuronal NOS expression.
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PMID:Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation. 943 14

Trophic factor deprivation induces neuronal nitric oxide synthase (NOS) and apoptosis of rat embryonic motor neurons in culture. We report here that motor neurons constitutively express endothelial NOS that helps support the survival of motor neurons cultured with brain-derived neurotrophic factor (BDNF) by activating the nitric oxide-dependent soluble guanylate cyclase. Exposure of BDNF-treated motor neurons to nitro-L-arginine methyl ester (L-NAME) decreased cell survival 40-50% 24 hr after plating. Both low steady-state concentrations of exogenous nitric oxide (<0.1 microM) and cGMP analogs protected BDNF-treated motor neurons from death induced by L-NAME. Equivalent concentrations of cAMP analogs did not affect cell survival. Inhibition of nitric oxide-sensitive guanylate cyclase with 2 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the survival of BDNF-treated motor neurons by 35%. cGMP analogs also protected from ODQ-induced motor neuron death, whereas exogenous nitric oxide did not. In all cases, cell death was prevented with caspase inhibitors. Our results suggest that nitric oxide-stimulated cGMP synthesis helps to prevent apoptosis in BDNF-treated motor neurons.
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PMID:Nitric oxide-dependent production of cGMP supports the survival of rat embryonic motor neurons cultured with brain-derived neurotrophic factor. 957 Aug 1

The diffusible factors, nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) are both suggested to be intercellular messengers that have similar synaptic activities and developmental influences in the brain. In the present study, we have analysed their mutual regulation with respect to their production in rodent neocortical neurons. Some of the cultured rat neocortical neurons exhibited immunoreactivity for both neuronal NO synthase (NOS) and the BDNF receptor trkB. Neuronal NOS appeared to be activated autonomously and produced NO in culture as monitored by nitrite accumulation. Inhibition of the endogenous NO production in culture by a NOS inhibitor, NG-monomethyl-L-arginine (NMMA), enhanced basal expression of BDNF mRNA and protein. Similarly, cerebroventricular administration of another NOS inhibitor, N-omega-nitro-L-arginine methylester (L-NAME), but not D-NAME or saline, increased BDNF content in the neocortex. In the opposite direction, however, BDNF appeared to function as a positive regulator for NO synthesis. Addition of BDNF upregulated the neuronal NOS expression as well as NO production in neocortical culture. In agreement, BDNF knock-out mice exhibited significant impairment of neuronal NOS expression in the neocortex. Taken together, these observations suggest that the trans-synaptic signalling molecules, NO and BDNF, influence the production of each other and mutually regulate the strength of their intercellular communications.
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PMID:Mutual regulation between the intercellular messengers nitric oxide and brain-derived neurotrophic factor in rodent neocortical neurons. 1021 9

The present study examined the effect of treatment with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) together with peripheral nerve (PN) graft or brain-derived neurotrophic factor (BDNF) on the survival of CN neurons at the L1 level of the spinal cord following hemisection at T11. In control animals 41% of CN neurons survived 15 days after the hemisection, and 48% of these expressed NOS. Treatment with either PN graft implantation or continuous infusion of BDNF increased the survival rate of CN neurons to 70%; 70% of these expressed NOS. Combined L-NAME and PN graft or L-NAME and BDNF improved the rescue rate up to 94%, but only approximately 33% expressed NOS. Our results suggest that the expression of NOS might adversely influence the neuroprotective function of neurotrophic factors on injured CN neurons in the spinal cord.
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PMID:Additive effect of NOS inhibitor and neurotrophic factors on the survival of injured Clarke's neurons. 1057 71

In order to find a way to develop a new treatment for inner ear disorders, the effects of a nitric oxide synthase (NOS) inhibitor [N-nitro-L-arginine methylester (L-NAME)] and a neurotrophin [brain-derived neurotrophic factor (BDNF)] were investigated. The effect of L-NAME and BDNF on gentamicin-induced vestibular hair cell damage was investigated by using the in vitro LIVE/DEAD system. Both L-NAME and BDNF individually reduced the vestibular hair cell damage caused by gentamicin but the combination of L-NAME and BDNF was more successful in preventing damage. It is therefore suggested that treatment with a combination of an NOS inhibitor and a neurotrophin will help us to treat inner ear disorders.
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PMID:Brain-derived neurotrophic factor and nitric oxide synthase inhibitor protect the vestibular organ against gentamicin ototoxicity. 1187 87

Gentamicin-induced production of reactive oxygen species (ROS) and of nitric oxide (NO) in the vestibular end organs of the guinea pig was investigated by applying two new fluorescence indicators, 4,5-diaminofluorescein diacetate for direct detection of NO and dihydrotetramethylrosamine for ROS. The vestibular sensory cells produced both NO and ROS after exposure to gentamicin. A nonspecific inhibitor of NO synthase, L-NAME, inhibited the production of NO but did not appear to affect the production of ROS following exposure to gentamicin. In contrast, a radical scavenger, D-methionine, or the neurotrophin BDNF suppressed the production of ROS, in turn stimulating NO production. These findings could indicate that both NO and ROS play an important role in aminoglycoside ototoxicity.
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PMID:Simultaneous detection of both nitric oxide and reactive oxygen species in guinea pig vestibular sensory cells. 1202 7

Neuronal death is a prominent neuropathological component of fetal alcohol syndrome (FAS). Identification of molecular agents and pathways that can ameliorate alcohol-induced cell loss offers possible therapeutic strategies for FAS and potential insight into its pathogenesis. This study investigated the effects of growth factors on cellular survival in alcohol-exposed cerebellar granule cell (CGC) cultures and examined the role of the nitric oxide (NO)-cGMP-PKG (cGMP-dependent protein kinase) pathway in the cell survival-promoting effects of these growth factors. Primary CGC cultures were exposed to 0 or 400 mg/dl ethanol, accompanied by either no growth factor or 30 ng/ml fibroblast growth factor-2 (FGF-2), nerve growth factor (NGF), insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF) or epidermal growth factor (EGF). Viable neurons were quantified after 1 day of exposure. Two distinct types of cell survival-promoting effects of growth factors were detectable: (1) a neurotrophic effect, in which the growth factors diminished the background death of neurons that occurred in alcohol-free cultures; and (2) a neuroprotective effect, in which the growth factors diminished alcohol-induced cell death. The various growth factors differed markedly in their patterns of cell survival promotion. While BDNF and FGF-2 exerted both a neurotrophic and a neuroprotective effect, IGF-1 had only a neurotrophic effect and did not protect against alcohol toxicity, and NGF had only a neuroprotective effect and did not diminish background cell death. EGF had neither a neurotrophic nor a neuroprotective effect. In order to determine the role of the NO-cGMP-PKG pathway in the cell survival-promoting effects mediated by growth factors, cultures were exposed to one of several pharmacological inhibitors of the pathway, including NAME, LY83583 and PKG inhibitor. The cell survival-promoting effects of FGF-2, NGF and IGF-1 were all substantially reduced by each of the pathway inhibitors. In contrast, neither the neurotrophic nor the neuroprotective effects of BDNF were altered by any of the pathway inhibitors. Thus, growth factors differ in their patterns of neurotrophic and neuroprotective effects, and they differ in their reliance on the NO-cGMP-PKG pathway. While FGF-2, NGF and IGF-1 all signal their survival-promoting effects through the NO-cGMP-PKG pathway, BDNF does not rely upon this pathway for signal transduction in CGC cultures.
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PMID:FGF-2, NGF and IGF-1, but not BDNF, utilize a nitric oxide pathway to signal neurotrophic and neuroprotective effects against alcohol toxicity in cerebellar granule cell cultures. 1252 73

Previous studies have shown that running exercise, either alone or in combination with antidepressant treatment, results in increased hippocampal BDNF levels. Nitric oxide (NO) is an important signaling molecule that has neuronal survival-promoting properties and has been shown to play an important role in plasticity associated with activating interventions. Herein, we administered the NO synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in conjunction with the monoamine oxidase inhibitor (MAOI) antidepressant, tranylcypromine, and voluntary wheel-running exercise to determine whether the enhancement in full-length BDNF mRNA occurring with these interventions is dependent upon NO synthesis. Our results demonstrate that both chronic exercise and chronic exercise-plus-tranylcypromine lead to enhanced hippocampal BDNF mRNA and protein expression. NOS inhibition prevents this effect of chronic exercise, but only partly prevents the effects of the exercise/antidepressant combination. Thus, the robust enhancement in BDNF mRNA occurring with exercise appears to be NO synthesis-dependent, but the intervention including antidepressant may enhance BDNF expression through alternative intracellular mechanisms. In addition, because exercise and antidepressants have both been shown to activate survival-promoting genes, we evaluated the levels of hippocampal phosphatidylinositol 3' kinase (PI-3K), an important signaling molecule within a principal neuronal survival-promoting intracellular pathway. Like BDNF mRNA and protein, exercise increases the expression of PI-3K, whereas concomitant NOS inhibition prevents this increase in PI-3K immunoreactivity above control levels. Our results are discussed in light of possible overlapping, but distinct intracellular pathways activated by exercise and antidepressant treatment to bring about enhancements in BDNF expression and other survival-promoting effects. These findings further demonstrate the potential therapeutic potential of chronic exercise to supplement pharmacotherapeutic treatment of mood disorders.
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PMID:Nitric oxide synthesis is required for exercise-induced increases in hippocampal BDNF and phosphatidylinositol 3' kinase expression. 1637 31

Much evidence has gathered that nitric oxide (NO) signaling, via cGMP-dependent mechanisms, may activate pro-survival pathways in hippocampal neurons and inhibit apoptosis. Past research has revealed that the enhancement of monoaminergic neurotransmission via exercise or treatment with antidepressant medications leads to an enhanced expression of brain-derived neurotrophic factor (BDNF). In isolated hippocampal neurons, norepinephrine (NE) application also increases the immunoreactivity of BDNF and several pro-survival signaling molecules. The data herein support the possibility that NO signaling plays an important role in enhancing neurotrophin expression and activation of the pro-survival phosphatidylinositol 3' kinase (PI-3K) pathway stimulated by NE. In isolated hippocampal neurons, the NO donor, sodium nitroprusside, increases BDNF, PI-3K, and phospho-ERK1 immunoreactivity. Specific inhibitors of the NO system suggest that NE-induced increases in hippocampal BDNF and the PI-3K pathway, but not stimulation of the MAPK pathway, depend upon NO signaling. In addition, inhibiting cGMP suggest that the effects of NE on BDNF immunoreactivity and Akt phosphorylation are also cGMP-dependent. Finally, the application of l-NAME to hippocampal neurons increases cell death. This is the first study of its kind demonstrating the involvement of NE-induced pro-survival signaling in three distinct signaling pathways: PI-3K, MAPK, and NO/cGMP. Possible mechanisms are discussed in light of the results.
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PMID:Nitric oxide signaling participates in norepinephrine-induced activity of neuronal intracellular survival pathways. 1791 60


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