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)

Parkinson's disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN-DBS. This supports the view that a clinically beneficial effect of STN-DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi.
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PMID:Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients. 1573 23

The biarylpropylsulfonamide class of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) potentiators represented by N-2-(4-(4-cyanophenol)phenol)propyl-2-propanesulfonamide (LY404187) and (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430) are positive, allosteric AMPA receptor activators, which enhance AMPA receptor-mediated neurotransmission by reducing desensitization of the ion channel. Although these compounds have efficacy in in vivo rodent models of cognition, depression, and Parkinson's disease, little is known about biochemical pathways activated by these agents. Given the well established regulation of the nitric oxide/cGMP pathway by excitatory neurotransmission, the current study characterized AMPA receptor potentiator-mediated cGMP response in mouse cerebellum. Acute treatment by both LY404187 and LY503430 [2.0, 5.0, or 10 mg/kg subcutaneously (s.c.)] elevated basal cerebellar cGMP levels in a dose-dependent manner. Pretreatment with the noncompetitive, allosteric AMPA receptor-selective antagonist 7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-monohydrochloride-(9CI) (GYKI 53655) [3.0 mg/kg intraperitoneally (i.p.)], completely blocked the effect of LY404187, demonstrating that activation of AMPA receptors induces cGMP levels. Interestingly, pretreatment with the N-methyl-d-aspartate (NMDA) open channel blocker dizocilpine (0.3 and 1.0 mg/kg i.p.) also abolished the AMPA receptor potentiator-mediated cGMP accumulation, indicating that activation of AMPA receptors leads to NMDA receptor-mediated transmission involved in cGMP regulation. Pharmacological augmentation of the endogenous glutamate tone via the alkaloid harmaline (20-60 mg/kg i.p.) synergized with AMPA potentiator activity and provided further direct evidence of in vivo allosteric activation of AMPA receptors by LY404187. The synergism between harmaline and LY404187 was specific, since cGMP accumulation induced by foot-shock stress was not augmented by the AMPA receptor potentiator. Taken together, these data indicate that the cGMP system may play an important role in pharmacological efficacy of the biarylpropylsulfonamide class of AMPA receptor potentiators.
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PMID:Pharmacological characterization of cGMP regulation by the biarylpropylsulfonamide class of positive, allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. 1680 62

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.
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PMID:Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's disease. 1681 81

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.
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PMID:Deep brain stimulation in Parkinson's disease patients: biochemical evidence. 1701 59

Nitric oxide (NO) is a short lived diatomic free radical species synthesized by nitric oxide synthases (NOS). The physiological roles of NO depend on its local concentrations as well as availability and the nature of downstream target molecules. At low nanomolar concentrations, activation of soluble guanylyl cyclase (sGC) is the major event initiated by NO. The resulting elevation in the intracellular cyclic GMP (cGMP) levels serves as signals for regulating diverse cellular and physiological processes. The participation of NO and cGMP in diverse physiological processes is made possible through cell type specific spatio-temporal regulation of NO and cGMP synthesis and signal diversity downstream of cGMP achieved through specific target selection. Thus cyclic GMP directly regulates the activities of its downstream effectors such as Protein Kinase G (PKG), Cyclic Nucleotide Gated channels (CNG) and Cyclic nucleotide phosphodiesterases, which in turn regulate the activities of a number of proteins that are involved in regulating diverse cellular and physiological processes. Localization and activity of the NO-cGMP signaling pathway components are regulated by G-protein coupled receptors, receptor and non receptor tyrosine kinases, phosphatases and other signaling molecules. NO also serves as a powerful paracrine factor. At micromolar concentrations, NO reacts with superoxide anion to form reactive peroxinitrite, thereby leading to the oxidation of important cellular proteins. Extensive research efforts over the past two decades have shown that NO is an important modulator of axon outgrowth and guidance, synaptic plasticity, neural precursor proliferation as well as neuronal survival. Excessive NO production as that evoked by inflammatory signals has been identified as one of the major causative reasons for the pathogenesis of a number of neurodegenerative diseases such as ALS, Alzheimers and Parkinson diseases. Regenerative therapies involving transplantation of embryonic stem cells (ES cells) and ES cell derived lineage committed neural precursor cells have recently shown promising results in animal models of Parkinson disease (PD). Recent studies from our laboratory have shown that a functional NO-cGMP signaling system is operative early during the differentiation of embryonic stem cells. The cell type specific, spatio-temporally regulated NO-cGMP signaling pathways are well suited for inductive signals to use them for important cell fate decision making and lineage commitment processes. We believe that manipulating the NO-cGMP signaling system will be an important tool for large scale generation of lineage committed precursor cells to be used for regenerative therapies.
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PMID:NO-cGMP signaling and regenerative medicine involving stem cells. 1704 68

Human embryonic stem cells hold considerable potential for cell-based treatments of a variety of degenerative diseases, including diabetes, ischemic heart failure, and Parkinson's disease. However, advancing research to provide clinical-grade product requires scale-up to therapeutic quantities of stem cells and their differentiated progeny. Most human embryonic stem cell culture platforms require direct support by a fibroblast feeder layer or indirect support using fibroblast conditioned medium. Accordingly, large numbers of clinically compliant fibroblasts will be requisite for stem cell production. Published platforms for feeder production are insufficient for stem cell scale-up, being costly to operate and requiring considerable effort to prepare, maintain and harvest. Here we describe the expansion of cGMP-grade, FDA-approved human foreskin fibroblasts using cGMP-grade reagents and polystyrene-based cationic trimethyl ammonium-coated microcarriers in spinner flasks. Fibroblasts attach rapidly to the microcarriers (T(1/2)=75 min), and expand with a maximum doubling time of 22.5h. Importantly, microcarrier-expanded fibroblasts and their conditioned medium support pluripotent stem cell growth through >5 passages, enabling extended self-renewal and expansion while retaining full differentiation potential. In summary, the method described is an economical and cGMP-compliant means of producing human fibroblast cells in support of cGMP human embryonic stem cell culture.
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PMID:Efficient expansion of clinical-grade human fibroblasts on microcarriers: cells suitable for ex vivo expansion of clinical-grade hESCs. 1826 18

The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson's disease.
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PMID:Effects of sildenafil on nigrostriatal dopamine neurons in a murine model of Parkinson's disease. 1878 Sep 70

Excessive production of nitric oxide (NO) by microglia is at least in part responsible for the pathogenesis of various neurodegenerative disorders including Parkinson disease, but at the same time NO may also play a distinct role as a signaling molecule such as an activator of soluble guanylyl cyclase. Here we investigated potential roles of the NO-soluble guanylyl cyclase-cyclic GMP signaling pathway in the regulation of dopaminergic neurodegeneration. Activation of microglia by interferon-gamma (IFN-gamma) followed by lipopolysaccharide (LPS) caused dopaminergic cell death in rat midbrain slice cultures, which was dependent on NO production. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, as well as KT5823, an inhibitor of cyclic GMP-dependent protein kinase, exacerbated dopaminergic cell death induced by IFN-gamma/LPS. Conversely, 8-bromo-cyclic GMP attenuated IFN-gamma/LPS cytotoxicity on dopaminergic neurons. Notably, although heme oxygenase-1 (HO-1) was expressed prominently in cells other than dopaminergic neurons in control cultures, robust expression of HO-1 was induced in surviving dopaminergic neurons challenged with IFN-gamma/LPS. ODQ and KT5823 decreased, whereas 8-bromo-cyclic GMP increased, the number of dopaminergic neurons expressing HO-1 after IFN-gamma/LPS challenge, without parallel changes in HO-1 expression in other cell populations. An NO donor 3-(4-morpholinyl)sydnonimine hydrochloride also induced HO-1 expression in dopaminergic neurons, which was abolished by ODQ and augmented by 8-bromo-cyclic GMP. Moreover, IFN-gamma/LPS-induced dopaminergic cell death was augmented by zinc protoporphyrin IX, an HO-1 inhibitor. The NO donor cytotoxicity on dopaminergic neurons was also augmented by ODQ and zinc protoporphyrin IX. These results indicate that the NO-cyclic GMP signaling pathway promotes the induction of HO-1 specifically in dopaminergic neurons, which acts as an endogenous protective system to limit inflammatory degeneration of this cell population.
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PMID:Nitric oxide-cyclic GMP signaling pathway limits inflammatory degeneration of midbrain dopaminergic neurons: cell type-specific regulation of heme oxygenase-1 expression. 1899 44

Phosphodiesterases (PDEs) represent important cornerstones of cGMP signaling in various tissues. Since the discovery of PDE activity in 1962, it has become clear that the functional characteristics of PDEs and their role in cyclic nucleotide signaling are fairly complex. On the one hand, members of the PDE family responsible for the hydrolysis of cGMP affect cellular responses by shaping cGMP signals derived from the activation of soluble cytosolic and/or membrane bound particulate guanylyl cyclases. Conversely, PDEs may function as downstream effectors in the cGMP signaling cascade. To make things even more sophisticated, cGMP modulates the activity of several PDEs either directly, by binding to a regulatory domain, or indirectly, through phosphorylation, and the result can be either inhibition or stimulation of the enzyme, depending on the subtype. Furthermore, cross-talk between cGMP and cAMP signaling is achieved by cGMP-dependent modulation of PDEs hydrolyzing cAMP and vice versa. Mammals possess at least 21 PDE genes and often express a set of PDEs in a tissue- and differentiation-dependent manner. Given these premises, it is still a challenging task to elucidate the physiological function(s) of individual PDE genes. The present chapter focuses on the role of PDEs as regulators of neuronal functions. Useful information regarding this topic has been gained by studying (1) the expression pattern of PDEs in the CNS, (2) the association of PDEs with specific macromolecular signaling complexes and (3) the phenotypes associated with mutations or ablation of PDE genes in man, mice and fruit flies, respectively. PDEs degrading cGMP and/or being regulated by cGMP have been implicated in cognition and learning, Parkinson's disease, attention deficit hyperactivity disorder, psychosis and depression. Correspondingly, modulators of PDEs have become attractive tools for treatment of these disorders of CNS function.
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PMID:Phosphodiesterases in the central nervous system. 1908 26

Proteosomal degradation of proteins is one of the major mechanisms of intracellular protein turnover. Failure of the proteosome to degrade misfolded protein is implicated in the accumulation of alpha-synuclein in Parkinson's disease (PD). Heme oxygenase-1 (HO-1), an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor) is expressed in response to various stressors. HO-1 is up-regulated in PD- and Alzheimer's disease-affected neural tissues. In this study, we found that HO-1 over-expression engenders dose-dependent decreases in alpha-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of alpha-synuclein was restored. Likewise, treatment of HO-1 over-expressing cells with the HO-1 inhibitor, tin mesoporphyrin, the iron chelator deferoxamine or antagonist of CO-dependent cGMP activation, methylene blue, mitigated the HO-1-induced reduction in alpha-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of alpha-synuclein was almost completely restored. In contrast to the effect on alpha-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated alpha-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of alpha-synuclein (WT) but not that of A30P. Our results suggest that HO-1, which is expressed when neurons are exposed to toxic stimuli capable of inducing protein misfolding, triggers proteosomal degradation of proteins and prevents intracellular accumulation of protein aggregates and inclusions. Resistance to HO-1 induced proteosomal degradation may render the familial PD-associated A30P mutation prone to toxic intracellular aggregation.
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PMID:The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. 1945 84


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