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)

Nitric oxide (*NO)-mediated toxicity has been involved in neurodegenerative diseases, including Parkinson's disease (PD). We have recently reported an increase of about 50% in *NO production rate in PMA-activated polymorphonuclear leukocytes (PMN) from either newly diagnosed or chronically treated PD patients. As humoral factors in sera from PD patients could inhibit cell dopaminergic activity, the aim of this study was to determine whether a plasma circulating factor from PD patients could modify *NO metabolism in PMN from healthy control subjects. To this purpose, we determined simultaneously the maximal production rate of *NO and hydrogen peroxide (H2O2) of PMA-activated PMN isolated from healthy control subjects in the presence of aliquots of plasma of PD patients. The results showed that, after 30 min incubation, plasma from newly diagnosed (n=4) or from L-Dopa chronically treated (n=7) PD patients enhanced *NO release in neutrophils isolated from healthy controls by about 50% and 47% respectively, with respect to non-parkinsonian control plasma (n = 10); in the same condition, H2O2 production did not differ among the groups. These data suggest that an overproduction of *NO related to plasma circulating factors, already detected at initial stages of the disease, participates in the pathophysiology of Parkinson's disease.
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PMID:Circulating plasma factors in Parkinson's disease enhance nitric oxide release of normal human neutrophils. 1042 50

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

Inflammatory reaction is thought to be an important contributor to neuronal damage in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and the parkinsonism dementia complex of Guam. Among the toxic agents released in brain tissues by activated cells, we focus attention in this review on peroxynitrite, the product of the reaction between nitric oxide (NO) and superoxide. Peroxynitrite is a strong oxidizing and nitrating agent which can react with all classes of biomolecules. In the CNS it can be generated by microglial cells activated by pro-inflammatory cytokines or beta-amyloid peptide (beta-A) and by neurons in three different situations: hyperactivity of glutamate neurotransmission, mitochondrial dysfunction and depletion of L-arginine or tetrahydrobiopterin. The first two situations correspond to cellular responses to an initial neuronal injury and the peroxynitrite formed only exacerbates the inflammatory process, whereas in the third situation the peroxynitrite generated directly contributes to the initiation of the neurodegenerative process.
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PMID:Neurodegenerative disorders: the role of peroxynitrite. 1052 72

Altered glial function in the substantia nigra in Parkinson's disease may lead to the release of toxic substances that cause dopaminergic cell death or increase neuronal vulnerability to neurotoxins. To investigate this concept, we examined the effects of subjecting astrocytes to lipopolysaccharide (LPS)-induced activation alone or combined with L-buthionine-[S,R]-sulfoximine-induced glutathione depletion or inhibition of complex I activity by 1-methyl-4-phenylpyridinium (MPP+) on the viability of primary ventral mesencephalic neurones or susceptibility to MPP+ and 6-hydroxydopamine (6-OHDA) in co-cultures. LPS-activated astrocytes caused neuronal death in a time-dependent manner, but glutathione-depleted or complex I-inhibited astrocytes had no effect on neuronal viability. The neurotoxicity of LPS-activated astrocytes was inhibited by the inducible nitric oxide synthase inhibitor aminoguanidine, by the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and by reduced glutathione (GSH). MPP+-induced neuronal death was greater in ventral mesencephalic cultures previously cultured with LPS-activated, glutathione-depleted, or complex I-inhibited astrocytes compared with co-cultures containing normal astrocytes. The increased neuronal susceptibility to MPP+ caused by LPS-activated or complex I-inhibited astrocytes and glutathione-depleted astrocytes was inhibited by the NMDA/glutamate antagonist MK-801 and by GSH, respectively. Neuronal death caused by 6-OHDA was increased in ventral mesencephalic cultures previously cultured with LPS-activated and glutathione-depleted, but not complex I-inhibited astrocytes, compared with co-cultures containing normal astrocytes. Treatment of co-cultures with GSH prevented the increased neuronal susceptibility to 6-OHDA. These findings suggest that glial dysfunction may cause neuronal death or render neurones susceptible to toxic insults via a mechanism involving the release of free radicals and glutamate. Such a mechanism may play a role in the development or progression of nigrostriatal degeneration in Parkinson's disease.
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PMID:Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures. 1058 7

Glutamate and reactive oxygen species including nitric oxide (NO) and superoxide anion (O2.-) have been postulated to play pivotal roles in the pathogenesis of the neuronal cell loss that is associated with several neurological disease states including Parkinson's disease and amyotrophic lateral sclerosis. In mesencephalic cultures, nondopaminergic neurons but not dopaminergic neurons are susceptible to NO cytotoxicity, although both types of neurons are damaged by glutamate. Methylphenylpyridium ion (MPP+) selectively enhances glutamate and NO cytotoxicity against dopaminergic neurons of mesencephalic cultures. It is suggested that glutathione plays an important role in the expression of NO-mediated glutamate cytotoxicity in dopaminergic neurons. In cultured spinal neurons, glutamate coadministered with the glutamate transporter inhibitor selectively damages motor neurons. Motor neurons are injured by NO, whereas nonmotor neurons are protected by NO through the guanylyl cyclase-cGMP cascade. It is suggested that selective motor neuronal death caused by chronic low-level exposure to glutamate is mediated by the formation of NO in nonmotor neurons. It is possible that neurotoxicity induced by NO and O2.- associated with neurodegenerative disorders is regulated by intracellular defense systems such as glutathione and cGMP.
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PMID:[Neuronal response to radical stress]. 1062 40

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

Striatal neurones receive myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide and adenosine. All these neurotransmitter systems interact each other and with voltage-dependent conductances to regulate the efficacy of the synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurones on this converging information dictates the final output of the striatum to the other basal ganglia structures. Recent morphological, immunohistochemical and electrophysiological findings demonstrated that the striatum also contains different interneurones, whose role in physiological and pathological conditions represents an intriguing challenge in these years. The use of the in vitro brain slice preparation has allowed not only the detailed investigation of the direct pre- and postsynaptic electrophysiological actions of several neurotransmitters in striatal neurones, but also the understanding of their role in two different forms of corticostriatal synaptic plasticity, long-term depression and long-term potentiation. These long-lasting changes in the efficacy of excitatory transmission have been proposed to represent the cellular basis of some forms of motor learning and are altered in animal models of human basal ganglia disorders, such as Parkinson's disease. The striatum also expresses high sensitivity to hypoxic-aglycemic insults. During these pathological conditions, striatal synaptic transmission is altered depending on presynaptic inhibition of transmitter release and opposite membrane potential changes occur in projection neurones and in cholinergic interneurones. These ionic mechanisms might partially explain the selective neuronal vulnerability observed in the striatum during global ischemia and Huntington's disease.
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PMID:Synaptic transmission in the striatum: from plasticity to neurodegeneration. 1072 75

In addition to its cofactor activities for aromatic L-amino acid hydroxylases and nitric oxide synthase (NOS), 6R-tetrahydrobiopterin (6R-BH(4)) shows diverse actions on neurons. Dopamine release from the rat striatum or PC12 cells was stimulated by 6R-BH(4). The action of 6R-BH(4) was independent of its cofactor activities and stereospecific. Ca(2+) channels in rat brain and PC12 cells were activated by 6R-BH(4) via cAMP-protein kinase A pathway. Membrane potential of PC12 cells was deplorized by 6R-BH(4). Thus, it is assumed that 6R-BH(4) acts on its specific action site (possibly outside of the cell membrane) to stimulate dopamine release by activating Ca(2+) channels. Apoptosis induced by depletion of serum and nerve growth factor in PC12 cells was prevented by 6R-BH(4). The cell surviving effect of 6R-BH(4) was also mediated by activation of Ca(2+) channels and cAMP-protein kinase A pathway. However, since 6R-BH(4) did not activate mitogen activated protein kinase, it did not support neuronal differentiation. Nitric oxide (NO)-induced cell death was prevented by 6R-BH(4) in PC12 cells. NOS activity was not changed by exogenous 6R-BH(4), but NO metabolites in culture medium were decreased by 6R-BH(4). When endogenous 6R-BH(4) was reduced by inhibition of biosynthesis, cell death was induced in PC12 cells. Superoxide is observed to be generated during autoxidation of 6R-BH(4). Superoxide producing system mimicked the cell protective action of 6R-BH(4) against NO toxicity. Thus, it is considered that 6R-BH(4) protects PC12 cells against NO toxicity by generating superoxide during its autoxidation. These results raised the possibility that 6R-BH(4) is a self-protective factor against NO toxicity in NO producing neurons. Our findings indicate that 6R-BH(4) regulates neuronal activities in the brain and that 6R-BH(4) can be a promising drug for neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.
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PMID:The role of 6R-tetrahydrobiopterin in the nervous system. 1072 82

Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is a hallmark of Parkinson's disease and inflammation and oxidative stress are closely associated with the pathogenesis of degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, resident immune cells of the brain, to release proinflammatory and neurotoxic factors tumor necrosis factor-alpha, interleukin-1beta, nitric oxide, and superoxide and subsequently caused damage to midbrain neurons, including dopaminergic neurons. The LPS-induced degeneration of the midbrain neurons was significantly reduced by cotreatment with naloxone, an opioid receptor antagonist. This study focused on understanding the mechanism of action for the protective effect of naloxone on dopaminergic neurons because of relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency. Naloxone inhibited LPS-induced activation of microglia and release of proinflammatory factors, and inhibition of microglia generation of superoxide free radical best correlated with the neuroprotective effect of naloxone isomers. To further delineate the site of action, naloxone was found to partially inhibit the binding of [(3)H]LPS to cell membranes, whereas it failed to prevent damage to dopaminergic neurons by peroxynitrite, a product of nitric oxide and superoxide. These results suggest that naloxone at least in part interferes with the binding of LPS to cell membranes to inhibit microglia activation and protect dopaminergic neurons as well as other neurons in the midbrain cultures from inflammatory damage.
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PMID:Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. 1077 35

MPTP produces clinical, biochemical, and neuropathologic changes reminiscent of those that occur in idiopathic Parkinson's disease (PD). In the present study we show that MPTP treatment led to activation of microglia in the substantia nigra pars compacta (SNpc), which was associated and colocalized with an increase in inducible nitric oxide synthase (iNOS) expression. In iNOS-deficient mice the increase of iNOS expression but not the activation of microglia was blocked. Dopaminergic SNpc neurons of iNOS-deficient mice were almost completely protected from MPTP toxicity in a chronic paradigm of MPTP toxicity. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites did not differ between iNOS-deficient mice and their wild-type littermates, this protection was not associated with a preservation of nigrostriatal terminals. Our results suggest that iNOS-derived nitric oxide produced in microglia plays an important role in the death of dopaminergic neurons but that other mechanisms contribute to the loss of dopaminergic terminals in MPTP neurotoxicity. We conclude that inhibition of iNOS may be a promising target for the treatment of PD.
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PMID:Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. 1080 Sep 68


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