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)

Embryonic stem (ES) cells have the ability to replicate themselves and differentiate into various mature cells. Recently, dopaminergic neurons were efficiently induced from ES cells using mouse stromal cells (PA6 cells) as a feeder cell layer. This simple procedure seems to be very efficient to obtain dopamine-releasing cells for future clinical cell transplantation treatment of Parkinson's disease. In this study, we prepared stock solutions containing neural inducing factors (NIFs) by washing PA6 cells with phosphate-buffered saline containing heparin. ES cells grew successfully in culture media supplemented with 33 v/v% NIFs stock solution, and the rate of neural differentiation of ES cell progeny increased with increasing heparin concentration in the culture media. In addition, NIFs-immobilized surfaces were prepared by exposing polyethyleneimine-modified surfaces to NIFs stock solutions. The NIFs-immobilized culture dish effectively supported cell growth as the culture medium supplemented with NIFs stock did, but its induction effect to dopaminergic neurons from ES cells was much smaller than free NIFs. NIFs stock solutions have two different activities. One can stimulate cell growth and the other induces differentiation of ES cells to the neural fate when heparin existed. The former factors were effectively immobilized on the culture dish, but those that induce differentiation may not be. Further optimization is required.
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PMID:Collection of neural inducing factors from PA6 cells using heparin solution and their immobilization on plastic culture dishes for the induction of neurons from embryonic stem cells. 1587 80

Pyridoxal-5-phosphate, the biological active form of pyridoxine, is a cofactor for dopa-decarboxylase (DDC) enzyme. Pyridoxine may augment the conversion of levodopa to dopamine in the periphery and therefore decrease availability of levodopa to the brain. However, this effect can be negated in the presence of a DDC inhibitor, which potentiates plasma levodopa level. A single nucleotide polymorphism at the nucleotide 1947 in the catechol-O-methyltransferase (COMT) gene encodes the high (COMT(H)) and low activity (COMT(L)) forms of the enzyme. In this study, we examined the effect of the COMT(L) allele on the clinical response to pyridoxine in Parkinson's disease (PD) patients. PD patients who were on stable and optimized dose of levodopa were included in this study. Their mean motor and activities of living score improved after high dose pyridoxine (P = 0.09, P = 0.04), and worsened after a washout period (P = 0.005, P = 0.001). Using a multivariate model, the presence of the COMT(L) allele predicted response to pyridoxine, with the best outcome observed in COMT(L/L) homozygotes. Our observational study suggests that the status the functional COMT(L) variant may be potentially useful to select PD patients for high dose pyridoxine therapy.
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PMID:Functional COMT variant predicts response to high dose pyridoxine in Parkinson's disease. 1596 67

Pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI), are structurally related endogenous peptides widely expressed in the central and peripheral nervous system and showing rich profile of biological activities. They act as neurotransmitters, neuromodulators and neurotrophic factors. Recently, their neuroprotective potential has been revealed in numerous in vitro and in vivo models. Thus, PACAP and VIP protected the cells from neurotoxic effects of ethanol, hydrogen peroxide (H2O2, beta-amyloid and glycoprotein 120 (gp120). Moreover, PACAP showed neuroprotection against glutamate, human prion protein fragment 106-126 [PrP(106-126)] and C2-ceramide. Both peptides reduced brain damage after ischemia and ameliorated neurological deficits in a model of Parkinson's disease. Neuroprotective potential of PHI has not been thoroughly investigated yet, but several results obtained in the last years do not exclude it. The mechanism underlying neuroprotective properties of PACAP seems to involve activation of adenylyl cyclase (AC) --> cyclic adenosine 3',5'-mono-phosphate (cAMP) --> protein kinase A (PKA) and mitogen-activated protein (MAP) kinase pathways, and inhibition of caspase-3. PACAP can also, yet indirectly, stimulate astrocytes to release neuroprotective factors, such as regulated upon activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein 1 (MIP-1) chemokines. Neuroprotective activity of VIP seems to involve an indirect mechanism requiring astrocytes. VIP-stimulated astrocytes secrete neuroprotective proteins, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP), as well as a number of cytokines. However, in the activated microglia, VIP and PACAP are capable of inhibiting the production of inflammatory mediators which can lead to neurodegenerative processes within the brain. In conclusion, studies carried out on the central nervous system have shown that PACAP, VIP, and likely PHI, are endowed with a neuroprotective potential, which renders them (or their derivatives) promising therapeutic agents in several psychoneurological disorders linked to neurodegeneration.
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PMID:Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. 1598 13

CNS gene transfer could provide new approaches to the modelling of neurodegenerative diseases and devising potential therapies. One such disorder is Parkinson's disease (PD), in which dysfunction of several different metabolic processes has been implicated. Here we review the literature on gene transfer systems based on herpes simplex virus type 1 (HSV-1) and non-viral polyethyleneimine (PEI) and calcium phosphate nanoparticle methods. We also assess the usefulness of various CNS gene delivery methods and present some of our own data to exemplify such usefulness. Our data result from vectors stereotaxically introduced to the substantia nigra (SN) of adult rats and evaluated 1 week and/or 1 month post injection using histochemical methods to assess recombinant ss-galactosidase enzyme activity. Gene transfer using PEI or calcium phosphate-mediated transfections was observed for both methods and PEI was comparable to that of HSV-1 amplicon. Our data show that the amplicon delivery was markedly increased when packaged with a helper virus and was similar to the expression profile achieved with a full-size replication-defective HSV-1 recombinant (8117/43). We also examine whether PEI or HSV-1 amplicon-mediated gene transfer could facilitate assessment of the biological effects induced by a dominant negative FGF receptor-1 mutant to model the reduced FGF signalling thought to occur in Parkinson's disease.
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PMID:Assessment of viral and non-viral gene transfer into adult rat brains using HSV-1, calcium phosphate and PEI-based methods. 1622 47

The dopamine-D2-agonist pramipexole (PPX) was tested for blocking mitochondrial permeability transition (PT) in order to give a possible explanation for its neuroprotective effect seen in PPX-treated Parkinson's disease patients. Patch-clamp techniques for studying single-channel currents in the inner mitochondrial membrane and large-amplitude swelling of energized mitochondria were used to study PPX action on the permeability transition pore (PTP), a key player in the mitochondrial route of the apoptotic cascade. Identity of the PTP was proven by measuring the concentration-response relation for cyclosporin A-blockade (IC50=26 nM). PPX inhibits the PTP reversibly with an IC50 of 500 nM, which is close to the values determined earlier as plasma concentrations after PPX medication in patients. Interaction of PPX with the PTP is further supported by demonstrating that it abolished Ca2+-triggered swelling in functionally intact mitochondria. Blockade of the PTP by PPX was attenuated by increasing concentrations of inorganic phosphate and by acidification. We suggest that PPX could exert part of its neuroprotective effect by inhibition of the PTP and thus, probably, blocking of the mitochondrial pathway of the apoptosis cascade.
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PMID:Patch clamp reveals powerful blockade of the mitochondrial permeability transition pore by the D2-receptor agonist pramipexole. 1640 57

Dysfunction of dopamine neurons has been implicated in several neuropsychiatric disorders, including Parkinson's disease, addiction, bipolar disorder and depression. Recent elucidation of gene expression profiles in dopamine neuron subpopulations has shed light on the function of different groups of dopamine neurons in the CNS and on their dysfunction in disease states. In particular, concerted differences in gene expression appear to underlie the unique properties of distinct dopamine neurons. Specifically, dopamine neurons in the substantia nigra (SN), which are prone to degenerate in Parkinson's disease, express high levels of transcripts related to energy metabolism, mitochondria and phosphate signalling pathways. In contrast, ventral tegmental area (VTA) dopamine neurons prominently express genes related to synaptic plasticity and neuropeptides, suggesting intriguing mechanisms for the involvement of VTA dysfunction in addiction and mood disorders. As new functions of dopaminergic neurotransmission become clearer, continued exploration of the transcriptional neuroanatomy of these unique neurons will be vital for producing targeted, selective, and effective therapeutic agents.
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PMID:Gene expression profiles of brain dopamine neurons and relevance to neuropsychiatric disease. 1674 Jun 10

Evidence from several studies suggests that the progressive degeneration of dopaminergic (DA) neurones of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) may in part be due to excessive release of glutamate from subthalamic projections onto nigral DA neurones. Previous in vitro studies have demonstrated that selective activation of Group III metabotropic glutamate receptors (mGluR) negatively modulates excitatory transmission in the SNc and is neuroprotective against glutamate-mediated toxicity. Consistent with this, we have reported preliminary data indicating that the selective group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) can also protect the nigrostriatal system against 6-hydroxydopamine (6-OHDA) toxicity in vivo. We have now extended these preliminary studies in this model and report here that both acute and subchronic intranigral injections of l-AP4 provide significant protection of the nigrostriatal system against 6-OHDA toxicity. This neuroprotection displays a bell-shaped profile with a clear concentration-dependent relationship. In contrast, when administered to animals 7 days post-6-OHDA lesioning, l-AP4 significantly protects the functionality but not the integrity of the nigrostriatal system. We further demonstrate that neuroprotection by l-AP4 in vivo is reversed by coadministration of the selective Group III mGluR antagonist (RS)-alpha-methylserine-O-phosphate, confirming a receptor-mediated mechanism of action. These data provide further compelling evidence that selective activation of Group III mGluR is neuroprotective in an in vivo experimental model of PD, a finding that may have important implications for the future treatment of this disease.
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PMID:Selective activation of group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutryic acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo. 1701 6

A real-time quantitative PCR approach was used to quantify mRNA levels corresponding to the neuropeptides enkephalin, dynorphin, and the 67-kDa isoform of glutamic acid decarboxylase (GAD67) in the human putamen from young and aged individuals as well as from aged patients affected by Parkinson's disease (PD). cDNA-specific primers were designed to amplify GAD67, proenkephalin (pENK), prodynorphin (pDYN), and the housekeeping genes glyceraldehydes-3-phosphate dehydrogenase (GAPDH) and guanine nucleotide binding protein, beta-peptide 2-like I (GNB2LI). GAPDH and GNB2LI mRNA levels were similarly expressed among the groups and were therefore used as endogenous reference genes. Normalized data showed that mRNA levels for both pENK and pDYN were reduced in the putamen of aged controls and aged individuals affected by PD, compared with young controls. In addition, we showed that GAD67 mRNA levels did not change during aging and PD. Further analyses showed no differences in mRNA levels, for pENK, pDYN, or GAD67 mRNA, between PD patients and aged matched controls. These findings contrast with animal models of parkinsonism, for which expression of pDYN, pENK, and GAD67 mRNA has been reported to change after striatal dopamine denervation. Compensatory mechanisms and regional differences within the human putamen as well as the severity index of the disease, clinical diagnosis, and response to phalmacological therapy are possible reasons for these results. The present study suggests that alteration of neuropeptide pathways in the human putamen may be involved in the functional deterioration of parts of the extrapyramidal system during aging.
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PMID:Alterations in prodynorphin, proenkephalin, and GAD67 mRNA levels in the aged human putamen: correlation with Parkinson's disease. 1720 88

Leucine-rich repeat kinase 2 (LRRK2), a product of a causative gene for the autosomal-dominant form of familial Parkinson's disease (PARK8), harbors a Ras-like small GTP binding protein-like (ROC) domain besides the kinase domain, although the relationship between these two functional domains remains elusive. Here we show by thin-layer chromatographic analysis that LRRK2 stably binds GTP but lacks a GTPase activity in HEK293 and Neuro-2a cells. A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling. The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase. These data suggest that binding of GTP to the ROC domain regulates the kinase activity of LRRK2 as well as its phosphorylation by other kinase(s).
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PMID:GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. 1726 Sep 67

Unlike traditional, tracer-based methods of molecular imaging, magnetic resonance spectroscopy (MRS) is based on the behavior of specific nuclei within a magnetic field and the general principle that the resonant frequency depends on the nucleus' immediate chemical environment. Most clinical MRS research has concentrated on the metabolites visible with proton spectroscopy and measured in specified tissue volumes in the brain. This methodology has been applied in various neurodegenerative disorders, most frequently utilizing measures of N-acetylaspartate as a neuronal marker. At short echo times, additional compounds can be quantified, including myo-inositol, a putative marker for neuroglia, the excitatory neurotransmitter glutamate and its metabolic counterpart glutamine, and the inhibitory neurotransmitter gamma-aminobutyric acid. 31P-MRS can be used to study high-energy phosphate metabolites, providing an in vivo assessment of tissue bioenergetic status. This review discusses the application of these techniques to patients with neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.
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PMID:MR spectroscopy in neurodegenerative disease. 1727 31


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