Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies suggest that nitric oxide (NO.) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO. is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO-), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7 NI. Our results suggest that NO. plays a role in MPTP neurotoxicity as well as novel therapeutic strategies for Parkinson's disease.
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PMID:Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. 753 Feb 97

The present study was undertaken to investigate whether the relatively selective neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), protects against methamphetamine (METH)-induced neurotoxicity. Male Swiss Webster mice received the following treatments (i.p.; q 3 h x 3): (a) vehicle/saline, (b) 7-NI (25 mg/kg)/saline, (c) vehicle/METH (5 mg/kg), and (d) 7-NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (a) and (b) received two vehicle injections, and groups (c) and (d) received two 7-NI injections (25 mg/kg, each). Administration of vehicle/METH resulted in 68, 44, and 55% decreases in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid, respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared with control values. Treatment with 7-NI (group d) provided full protection against the depletion of dopamine and its metabolites and the loss of dopamine transporter binding sites. Administration of 7-NI/saline (group b) affected neither the tissue concentration of dopamine and its metabolites nor the binding parameters of [3H] mazindol compared with control values. 7-NI had no significant effect on animals' body temperature, and it did not affect METH-induced hyperthermia. These findings indicate a role for nitric oxide in methamphetamine-induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.
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PMID:The neuronal nitric oxide synthase inhibitor, 7-nitroindazole, protects against methamphetamine-induced neurotoxicity in vivo. 885 65

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
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PMID:The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. 930 87

Oxidative stress may contribute to nigral cell death in Parkinson's disease based on postmortem investigations showing increased iron levels, decreased levels of reduced glutathione (GSH), and impaired mitochondrial function. This leads to oxidative damage because lipid peroxidation is increased in substantia nigra and there is a widespread increase in protein and DNA oxidation in the brain in Parkinson's disease. Nitric oxide (NO) may be one of the free radical species involved in nigral degeneration. NO is involved in the production of hydroxyl radicals resulting from MPP+-induced dopamine efflux in striatum. Mice treated with the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole show reduced toxicity to MPTP and knock-out mice lacking neuronal NOS show decreased MPTP susceptibility. In primates, 7-nitroindazole inhibits MPTP toxicity but this remains controversial because no protection is afforded by the nonspecific NOS inhibitor, L-NAME. Indeed, in Parkinson's disease itself, there is little evidence for nitric oxide's involvement in nigral pathology. A susceptibility factor for the development of Parkinson's disease may involve isoforms of cytochrome P450, some of which are found in the brain. CYP2EI, which is associated with free radical production and the formation of endogenous toxins, is selectively localized in nigral dopamine-containing cells. CYP2E1 metabolizes n-hexane leading to the formation of its neurotoxic metabolite 2,5-hexanedione which may explain cases of solvent-induced parkinsonism. Oxidative processes clearly contribute to the pathology of Parkinson's disease but are probably secondary to some other primary unidentified cause, presumably genetic or environmental. Nevertheless, their involvement may allow therapeutic intervention in the cascade of events associated with the progression of Parkinson's disease.
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PMID:Oxidative mechanisms in nigral cell death in Parkinson's disease. 961 15

Methamphetamine (METH) is one of the major drugs of abuse that is postulated to cause neurotoxicity by depleting dopamine (DA) and its metabolites, high-affinity DA uptake sites, and the activity of tyrosine hydroxylase. The present study was undertaken to investigate whether the relatively selective, neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), protects against METH-induced neurotoxicity. Male Swiss Webster mice received the following injections intraperitoneally (i.p.) 3 times (every 3 hr): (i) vehicle/saline, (ii) 7-NI (25 mg/kg)/saline, (iii) vehicle/METH (5 mg/kg), and (iv) 7-NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (i) and (iii) received two vehicle injections and groups (ii) and (iv) received two 7-NI injections (25 mg/kg each). The administration of vehicle/METH resulted in 68, 44 and 55% decreases in the concentration of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared to control values. The treatment with 7-NI (group iv) provided a full protection against the depletion of DA and its metabolites, and the loss of dopamine transporter binding sites. Multiple injection of METH caused a significant decrease in the concentration of serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA). Treatment with 7-NI partially blocked the depletion of 5-HT and completely blocked the reduction in 5-HIAA levels. The administration of 7-NI/saline (group ii) affected neither the tissue concentration of DA, 5-HT and their metabolites (DOPAC, HVA and 5-HIAA) nor the binding parameters of [3H]-mazindol compared to control (vehicle/saline) values. 7-NI had no significant effect on the animals' body temperature, and it did not affect METH-induced hyperthermia. These findings indicate a role for nitric oxide in METH-induced neurotoxicity and also suggest that blockage of NOS may be beneficial for the management of Parkinson's disease.
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PMID:Effects of 7-nitroindazole, an NOS inhibitor on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in mice. 966 70

A significant loss of dopamine was found in rat striatal slices incubated with 1-methyl-4-phenylpyridinium ion (MPP+) at a concentration of 2 microM or higher. The addition of 7-nitroindazole, a specific inhibitor of neuronal nitric oxide synthase (nNOS), prevented this effect on dopamine when the concentration of MPP+ was between 2-5 microM, but not at higher concentrations. This protection was reproduced with other less specific NOS-inhibitors, such as nitro-arginine and nitro-arginine methylester. 7-nitroindazole did not protect against the dopamine depletion caused by the non-specific mitochondrial chain blocker rotenone. Neither MPP- nor rotenone significantly increased the nitrite concentration in striatal slices, measured as an index of nitric oxide production. The basal production of nitric oxide may be enough to trigger the dopamine depletion at very low concentrations of MPP+, probably acting synergistically with cytosolic calcium increase. Higher concentrations of MPP+ are toxic by themselves without the mediation of nitric oxide. The inhibition of nNOS may protect against dopamine loss at early stages of a neurodegenerative process, and it could then be considered in the treatment or prevention of neurodegenerative human processes such as Parkinson's disease.
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PMID:7-Nitroindazole prevents dopamine depletion caused by low concentrations of MPP+ in rat striatal slices. 969 40

Nitric oxide (NO) is a unique biological messenger molecule which mediates diverse physiologic roles. NO mediates blood vessel relaxation by endothelium, immune activity of macrophages and neurotransmission of central and peripheral neurons. NO is produced from three NO Synthase (NOS) isoforms: Neuronal NOS (nNOS), endothelial NOS, and inducible NOS (iNOS). In the central nervous system, NO may play important roles in neurotransmitter release, neurotransmitter reuptake, neurodevelopment, synaptic plasticity, and regulation of gene expression. However, excessive production of NO following a pathologic insult can lead to neurotoxicity. NO plays a role in mediating neurotoxicity associated with a variety of neurologic disorders, including stroke, Parkinson's Disease, and HIV dementia.
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PMID:Nitric oxide in neurodegeneration. 993 44

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.
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PMID:Nitric oxide synthases: targets for therapeutic strategies in neurological diseases. 1044 86

Modern molecular biology has revealed vast numbers of large and complex proteins and genes that regulate body function. By contrast, discoveries over the past ten years indicate that crucial features of neuronal communication, blood vessel modulation and immune response are mediated by a remarkably simple chemical, nitric oxide (NO). Endogenous NO is generated from arginine by a family of three distinct calmodulin- dependent NO synthase (NOS) enzymes. NOS from endothelial cells (eNOS) and neurons (nNOS) are both constitutively expressed enzymes, whose activities are stimulated by increases in intracellular calcium. Immune functions for NO are mediated by a calcium-independent inducible NOS (iNOS). Expression of iNOS protein requires transcriptional activation, which is mediated by specific combinations of cytokines. All three NOS use NADPH as an electron donor and employ five enzyme cofactors to catalyze a five-electron oxidation of arginine to NO with stoichiometric formation of citrulline. The highest levels of NO throughout the body are found in neurons, where NO functions as a unique messenger molecule. In the autonomic nervous system NO functions NO functions as a major non-adrenergic non-cholinergic (NANC) neurotransmitter. This NANC pathway plays a particularly important role in producing relaxation of smooth muscle in the cerebral circulation and the gastrointestinal, urogenital and respiratory tracts. Dysregulation of NOS activity in autonomic nerves plays a major role in diverse pathophysiological conditions including migraine headache, hypertrophic pyloric stenosis and male impotence. In the brain, NO functions as a neuromodulator and appears to mediate aspects of learning and memory. Although endogenous NO was originally appreciated as a mediator of smooth muscle relaxation, NO also plays a major role in skeletal muscle. Physiologically muscle-derived NO regulates skeletal muscle contractility and exercise-induced glucose uptake. nNOS occurs at the plasma membrane of skeletal muscle which facilitates diffusion of NO to the vasculature to regulate muscle perfusion. nNOS protein occurs in the dystrophin complex in skeletal muscle and NO may therefore participate in the pathophysiology of muscular dystrophy. NO signalling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signalling is largely regulated at the level of NO biosynthesis. Acute control of nNOS activity is mediated by allosteric enzyme regulation, by posttranslational modification and by subcellular targeting of the enzyme. nNOS protein levels are also dynamically regulated by changes in gene transcription, and this affords long-lasting changes in tissue NO levels. While NO normally functions as a physiological neuronal mediator, excess production of NO mediates brain injury. Overactivation of glutamate receptors associated with cerebral ischemia and other excitotoxic processes results in massive release of NO. As a free radical, NO is inherently reactive and mediates cellular toxicity by damaging critical metabolic enzymes and by reacting with superoxide to form an even more potent oxidant, peroxynitrite. Through these mechanisms, NO appears to play a major role in the pathophysiology of stroke, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
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PMID:Endogenous nitric oxide synthesis: biological functions and pathophysiology. 1063 Jun 82

Previous work showed that several relatively specific inhibitors of neuronal nitric oxide synthase (nNOS) produce protection against MPTP induced dopaminergic toxicity. We examined whether a highly specific novel inhibitor of nNOS, ARRI 7338, could also protect against MPTP toxicity. ARR17338 produced dose-dependent significant protection against MPTP induced depletion of dopamine and protected against MPTP induced depletions of tyrosine hydroxylase immunostained neurons in the substantia nigra. These results provide further evidence that inhibitors of nNOS may be useful for the treatment of Parkinson's disease.
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PMID:Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity. 1081 4


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