UMLS:C0030567 - FACTA Search

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)

Alterations in motor response that complicate levodopa treatment of Parkinson's disease appear to involve sensitization of striatal ionotropic glutamate receptors. Since protein kinase C (PKC)-mediated phosphorylation regulates glutamatergic receptors of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) subtype and has been linked to several forms of behavioral plasticity, activation of PKC signaling in striatal spiny neurons may also contribute to the motor plasticity changes associated with chronic levodopa therapy. To evaluate this possibility, we sought to augment PKC signaling by using Herpes Simplex Virus type 1 vectors (pHSVpkcDelta) to directly transfer the catalytic domain of the PKCbetaII gene into striatal neurons of parkinsonian rats. Microinjection of pHSVpkcDelta vectors lead to the persistent expression of PkcDelta (35% loss over 21 days) in medium spiny neurons together with an increase in serine 831 phosphorylation on AMPA receptor GluR1 subunits and hastened the appearance of the shortened response duration produced by chronic levodopa treatment (P<0.05). In pHSVpkcDelta-infected animals, intrastriatal injection of the PKC inhibitor NPC-15437 (1.0 microg) attenuated both the increased GluR1 phosphorylation (P<0.01) and the accelerated onset of the levodopa-induced response modifications (P<0.01). However, in rats that received levodopa treatment for 21 days without the gene transfer, intrastriatal NPC-15437 had no effect on the response shortening or on GluR1 S831 phosphorylation. The results suggest that an increase in PKC-mediated signaling, including, in part, phosphorylation of AMPA receptors, on striatal spiny neurons may be sufficient to promote the initial appearance, but not necessary the ultimate expression, of the levodopa-induced motor response changes occurring in a rodent model of the human motor complication syndrome.
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PMID:Gene transfer of constitutively active protein kinase C into striatal neurons accelerates onset of levodopa-induced motor response alterations in parkinsonian rats. 1269 33

In the present study, we attempted to address the modulation of the gene expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors in the neostriatum of the 6-hydroxydopamine (6-OHDA)-lesioned rat, an animal model of Parkinson's disease. After 2 weeks of lesion, reverse transcriptase-polymerase chain reactions (RT-PCRs) revealed significant reduction in GluR1 mRNA expression but a significant enhancement of NR1 mRNA expression in the striatal tissues of the lesioned side. No modulation in the mRNA expression of GluR2, GluR3, GluR4 and NR2B were found. Immunofluorescence with digital imaging analysis also demonstrated a significant reduction in GluR1 immunoreactivity in the lesioned neostriatum. Interestingly, the reduction in GluR1 immunoreactivity was primarily observed in presumed striatal medium spiny neurons but not in parvalbumin-labeled striatal GABAergic interneurons. Immunoreactivity for GluR2, GluR2/3, GluR4, NR1 and NR2B was unchanged in neurons of the neostriatum of the lesioned side. The present results indicate that there is an opposite trend in modulation in the gene expressions of GluR1 and NR1 in the neostriatum of 6-OHDA-lesioned rats after dopamine denervation. Modulation of GluR1 mRNA and immunoreactivity is likely to be limited in the striatal projection neurons. These findings have implications for the use of NMDA and AMPA receptor antagonists in the treatment of Parkinson's disease.
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PMID:Gene expression of glutamate receptors GluR1 and NR1 is differentially modulated in striatal neurons in rats after 6-hydroxydopamine lesion. 1289 51

A2A receptor is highly coexpressed with enkephalin and D2 receptor in striatopallidal neurons. A2A antagonists acutely enhance motor behavior in animal models of Parkinson's disease (PD) and are therefore considered potential PD therapeutic agents. Analysis of gene expression regulation using pharmacologic tools or A2A receptor-deficient mice (A2A-/-) shows that the A2A receptor positively and tonically controls the expression of enkephalin and immediate early genes in striatopallidal neurons. Because this regulation strictly mirrors the effect of D2 receptor, these data strongly support the hypothesis that A2A antagonists reduce the activity of striatopallidal neurons in models of PD. However, analysis of A2A-/- mice suggests additional effects of A2A receptor in the control of striatal physiology. Unexpectedly, these animals exhibited a reduction in exploratory activity and a 50% reduction in substance P expression. This was associated with a 45% decrease in the striatal extracellular dopamine concentration, suggesting that chronic absence of A2A receptor results in a functional hypodopaminergic state in the striatum. The A2A receptor controls inhibitory synaptic transmission negatively in the striatum and positively in the globus pallidus; this further supports the efficacy of A2A antagonists in reducing the activity of striatopallidal neurons in PD. The A2A receptor does not modulate basal alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-mediated excitatory corticoaccumbal synaptic transmission during normal physiologic conditions. However, genetic inactivation or pharmacologic blockade of the A2A receptor significantly reduced long-term potentiation (LTP) at this synapse. Therefore, this receptor is implicated in the induction of corticoaccumbal LTP, an effect that could be related to its involvement in long-term behavioral sensitization to repeated dopaminergic treatment.
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PMID:A2A receptor and striatal cellular functions: regulation of gene expression, currents, and synaptic transmission. 1466 2

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A2A antagonist for use in the management of Parkinson's disease (PD) illustrates approaches to some of the relevant issues. Adenosine A2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent L-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose L-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose L-dopa with fewer dyskinesias than produced by optimal-dose L-dopa alone. KW6002 also safely prolonged the efficacy half-time of L-dopa. The results suggest that drugs capable of selectively blocking adenosine A2A receptors could confer therapeutic benefit to L-dopa-treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.
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PMID:Translating A2A antagonist KW6002 from animal models to parkinsonian patients. 1466 22

Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.
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PMID:Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease. 1497 5

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.
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PMID:AMPA receptor potentiators for the treatment of CNS disorders. 1518 Apr 79

Kainate receptors (KARs) are widely expressed the basal ganglia. In this study, we used electron microscopic immunocytochemistry and whole-cell recording techniques to examine the localization and function of KARs in the rat globus pallidus (GP). Dendrites were the most common immunoreactive elements, while terminals forming symmetric or asymmetric synapses and unmyelinated axons comprised most of the presynaptic labeling. To determine whether synaptically released glutamate activates KARs, we recorded excitatory postsynaptic currents (EPSCs) in the GP following single-pulse stimulation of the internal capsule. 4-(8-Methyl-9H-1,3-dioxolo[4,5 h]{2,3}benzodiazepine-5-yl)-benzenamine hydrochloride (GYKI 52466, 100 microm), an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, reduced but did not completely block evoked EPSCs. The remaining EPSC component was mediated through activation of KARs because it was abolished by 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), an AMPA/KAR antagonist. The rise time (10-90%) and decay time constant (tau) for those EPSCs were longer than those of AMPA-mediated EPSCs recorded before GYKI 52466 application. KAR activation inhibited EPSCs. This inhibition was associated with a significant increase in paired-pulse facilitation ratio, suggesting a presynaptic action of KAR. KAR inhibition of EPSCs was blocked by the G-protein inhibitor, N-ethylmaleimide (NEM), or the protein kinase C (PKC) inhibitor calphostin C. Our results demonstrate that KAR activation has dual effects on glutamatergic transmission in the rat GP: (1) it mediates small-amplitude EPSCs; and (2) it reduces glutamatergic synaptic transmission through a presynaptic G-protein coupled, PKC-dependent, metabotropic mechanism. These findings provide evidence for the multifarious functions of KARs in regulating synaptic transmission, and open up the possibility for the development of pharmacotherapies to reduce the hyperactive subthalamofugal projection in Parkinson's disease.
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PMID:Localization and function of pre- and postsynaptic kainate receptors in the rat globus pallidus. 1642 Apr 45

Recent evidence has linked striatal amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor function to the adverse effects of long-term dopaminergic treatment in Parkinson's disease. The phosphorylation of AMPA subunit, GluR1, reflects AMPA receptor activity. To determine whether serine phosphorylation of GluR1 subunit by activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) contributes to the process, we examined the effects of unilateral nigrostriatal depletion with 6-hydroxydopamine and subsequent L: -dopa treatment on motor responses and phosphorylation states. Three weeks of L: -dopa administration to rats shortened the duration of the rotational response. We found a significant reduction in the abundance of both phosphorylated GluR1 at serine-831 site (pGluR1S831) and GluR1 in the cell plasma membrane of lesioned striatum. Chronic treatment of lesioned rats with L: -dopa markedly upregulated the phosphorylation of GluR1 in lesioned striatum with a concomitant normalization of the plasma membrane GluR1 abundance, which lasted at least 1 day after withdrawal of chronic L: -dopa treatment. Our immunostaining data showed that these changes were confined to parvalbumin-positive neurons where GluR1 subunits are exclusively expressed. Both the altered motor response duration and the degree of pGluR1S831 were attenuated by the intrastriatal administration of CaMKII inhibitor KN-93. These findings suggest that activation of CaMKII contributes to both development and maintenance of motor response duration alterations, through a mechanism that involves an increase in pGluR1S831 within parvalbumin-positive neurons.
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PMID:Changes in subcellular distribution and phosphorylation of GluR1 in lesioned striatum of 6-hydroxydopamine-lesioned and l-dopa-treated rats. 1705 70

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission and play a key role in synaptic plasticity in the mammalian central nervous system (CNS). In recent years several classes of AMPA receptor potentiators have been reported in the literature, including pyrrolidones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and biarylpropylsulfonamides (LY392098, LY404187, LY450108, LY451395 and LY503430). Clinical and preclinical data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. However, recent evidence has shown that in addition to modulating fast synaptic plasticity and memory processes, AMPA receptor potentiators alter downstream signalling pathways and may thereby have utility in other CNS disorders. The present review summarises studies into the effects of AMPA receptor potentiators (with a focus on the biarylpropylsulfonamides) in rodent models of depression and Parkinson's disease.
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PMID:AMPA receptor potentiators: application for depression and Parkinson's disease. 1750 4

Deprenyl, used clinically in Parkinson's disease, has multiple pharmacological effects which make it a good candidate to treat neurotoxicity. Thus, we investigated deprenyl's ability to attenuate methamphetamine-induced dopamine neurotoxicity. We also examined deprenyl's effect in changing markers associated with psychostimulant sensitization. A potential therapeutic effect on either pathological domain would be a boon in developing novel treatments for methamphetamine abuse. Adult male Sprague-Dawley rats were split into 6 groups. Three groups received a 7-day saline minipump with saline, 0.05 or 0.25 mg/kg SC deprenyl injections given for 10 days before, during and 5 days after the 7-day saline minipump implant. Similarly, 3 groups received methamphetamine pumps (25 mg/kg/day) with escalating daily injections of methamphetamine (0-6 mg/kg) in addition to the minipump treatment. These rats also received saline, 0.05 or 0.25 mg/kg deprenyl injections given before, during and the 7-day minipump treatment. Rats were killed on day 28 of withdrawal and brain samples taken. HPLC analysis for dopamine and 3,4-Dihydroxy-Phenylacetic Acid (DOPAC) revealed a loss of dopamine in the caudate and accumbens which was partially reversed by high dose deprenyl. Tyrosine hydroxylase immunostaining in the midbrain was unaffected by methamphetamine, suggesting that dopamine neurotoxicity was localized to the caudate. Western blot analysis of the caudate after methamphetamine revealed little change in Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) GluR1 or N-Methyl-d-Aspartate (NMDA) NR2B subunits, or their phosphorylation state. However, methamphetamine increased levels of GluR1 and its phosphorylation state in the prefrontal cortex (PFC), and these increases were attenuated by deprenyl. Methamphetamine also increased levels of PFC NR2B subunit, but these increases were not attenuated by deprenyl. We suggest that deprenyl may be effective in reducing the neurotoxic effects of methamphetamine and may also attenuate changes in prefrontal AMPA receptor function, presumably more associated with addiction rather than neurotoxicity.
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PMID:Deprenyl treatment attenuates long-term pre- and post-synaptic changes evoked by chronic methamphetamine. 1765 30

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