Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
Add more filters










Publication year range
1.
Asian-Australas J Anim Sci ; 28(11): 1545-50, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26580277

ABSTRACT

c-MYC (v-myelocytomatosis viral oncogene homologue) is a transcription factor that plays important role in many biological process including cell growth and differentiation, such as myogenesis and adipogenesis. In this study, we aimed to detect MYC gene polymorphisms, their genotype frequencies and to determine associations between these polymorphisms and meat quality traits in Berkshire pigs. We identified a single nucleotide polymorphism (SNP) in intron 2 of MYC gene by Sanger sequencing, i.e., g.3350G>C (rs321898326), that is only found in Berkshire pigs, but not in other breeds including Duroc, Landrace, and Yorkshire pigs that were used in this study. Genotypes of total 378 Berkshire pigs (138 sows and 240 boars) were determined using Hha I restriction enzyme digestion after polymerase chain reaction. Observed allele frequencies of GG, GC, and CC genotypes were 0.399, 0.508, and 0.093 respectively. Statistical analysis indicated that the g.3350G>C polymorphism was significantly associated with pH45min and cooking loss (p<0.05), suggesting that g.3350G>C SNP can be used for pre-selection of pH45min and cooking loss traits in Berkshire pigs.

2.
Genet Mol Res ; 12(1): 731-7, 2013 Mar 13.
Article in English | MEDLINE | ID: mdl-23546956

ABSTRACT

Phospholipid transfer protein (PLTP) regulates high-density lipoprotein metabolism. The gene encoding PLTP is located on bovine chromosome 13. The objective of this study was to identify single nucleotide polymorphisms (SNPs) in the Hanwoo (Bos taurus coreanae) PLTP gene to detect novel mutations affecting economically important traits. Five SNPs were identified in the coding region (C7368T, G7453A, C9888T, and C9905T) and intron (A1750G). G7453A changes amino acid 362 of PLTP from alanine to threonine, and C9888T changes amino acid 491 of PLTP from proline to serine. Statistical analyses revealed that the G7453A and C9888T polymorphisms in the PLTP gene were significantly associated with marbling score (P < 0.05). The relationship between haplotype and economic traits was analyzed and found to be significantly associated with marbling score (P < 0.05). The results suggest that PLTP polymorphisms might be an important genetic influence on economic traits in Hanwoo.


Subject(s)
Cattle/genetics , Meat/standards , Phospholipid Transfer Proteins/genetics , Polymorphism, Single Nucleotide , Amino Acid Substitution , Animals , Exons/genetics , Gene Frequency , Genotype , Haplotypes , Introns/genetics , Republic of Korea
3.
Neuropharmacology ; 52(2): 515-26, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17116309

ABSTRACT

The contribution of striatal protein kinase C (PKC) isoform changes in levodopa (L-DOPA) induced motor response complications in parkinsonian rats was investigated and the ability of tamoxifen, an antiestrogen with a partial PKC antagonist property, to prevent these response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats as well as in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated cynomologous monkeys was studied. Following treatment of adult male rats with L-DOPA twice daily for 3 weeks, protein levels of left (lesioned) and right (intact) striatal PKC isoforms were measured. Western blot analysis showed increased protein expression of both the novel PKC epsilon isoform and the atypical PKC lambda isoform ipsilateral to the lesion (174+/-17% for epsilon, 140+/-9% for lambda, of intact striatum in 6-OHDA lesioned plus chronic L-DOPA treated animals) in acute L-DOPA treated rats. No enhancement was observed in PKC immunoreactivity for other isoforms. Tamoxifen (5.0 mg/kg p.o.) significantly attenuated the L-DOPA induced augmentation of protein expression of PKC epsilon and PKC lambda, but had no effect on immunoreactivity for other PKC isoforms. In chronic L-DOPA treated parkinsonian rats, tamoxifen prevented (5.0 mg/kg p.o.) as well as ameliorated (5.0 mg/kg p.o.) the characteristic shortening in duration of motor response to L-DOPA challenge. In MPTP lesioned primates, similar to the ameliorative effect seen in rats, tamoxifen (1 and 3 mg/kg p.o) reduced the appearance of L-DOPA induced dyskinesia by 61% and 55% respectively (p<0.05). These results suggest that changes in specific striatal PKC isoforms contribute to the pathogenesis of L-DOPA induced motor complications and further that drugs able to selectively inhibit these signaling kinases might provide adjunctive benefit in the treatment of Parkinson's disease.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/drug therapy , Levodopa/adverse effects , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Disease Models, Animal , Drug Administration Schedule , Drug Interactions , Dyskinesia, Drug-Induced/etiology , Haplorhini , Male , Models, Biological , Nerve Tissue Proteins/metabolism , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Protein Kinase C/metabolism , Rats , Rats, Sprague-Dawley , Time Factors
4.
Exp Neurol ; 196(2): 422-9, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16203001

ABSTRACT

AMPA and NMDA receptors, abundantly expressed on striatal medium spiny neurons, have been implicated in the regulation of corticostriatal synaptic efficacy. To evaluate the contribution of both glutamate receptor types to the pathogenesis of motor response alterations associated with dopaminergic treatment, we studied the ability of the selective AMPA receptor antagonist GYKI-47261 and the selective NMDA receptor antagonists, MK-801 and amantadine, to mitigate these syndromes in rodent and primate models of Parkinson's disease. The effects of GYKI-47261 and amantadine (or MK-801), alone and in combination, were compared for their ability to modify dyskinesias induced by levodopa. In rats, simultaneous administration of subthreshold doses of AMPA and NMDA receptor antagonists completely normalized the wearing-off response to acute levodopa challenge produced by chronic levodopa treatment (P < 0.05). In primates, the glutamate antagonists GYKI-47261 and amantadine, co-administered at low doses (failing to alter dyskinesia scores), reduced levodopa-induced dyskinesias by 51% (P < 0.05). The simultaneous AMPA and NMDA receptor blockade acts to provide a substantially greater reduction in the response alterations induced by levodopa than inhibition of either of these receptors alone. The results suggest that mechanisms mediated by both ionotropic glutamate receptors make an independent contribution to the pathogenesis of these motor response changes and further that a combination of both drug types may provide relief from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone.


Subject(s)
Dopamine Agents/adverse effects , Levodopa/adverse effects , Parkinson Disease, Secondary/chemically induced , Receptors, AMPA/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Amantadine/pharmacology , Animals , Antiparkinson Agents/pharmacology , Behavior, Animal , Benzazepines/pharmacology , Benzodiazepines/pharmacology , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacology , Haplorhini , Male , Motor Activity/drug effects , Parkinson Disease, Secondary/drug therapy , Quinpirole/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, AMPA/antagonists & inhibitors , Receptors, Glutamate/physiology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Rotarod Performance Test/methods , Time Factors
5.
Neuropharmacology ; 47(2): 184-94, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15223297

ABSTRACT

Sensitization of NMDA receptors containing the NR2B subunit has been increasingly associated with various forms of synaptic plasticity, including those implicated in the pathogenesis of extrapyramidal motor dysfunction. To determine whether activation of NR2B containing receptors contributes to the development and maintenance of levodopa-induced response changes in parkinsonian animals, we evaluated the effects of the selective NR2B antagonist CP-101,606 on these response alterations in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Three weeks of twice-daily levodopa treatment decreased the duration of the rotational response to acute levodopa challenge. The response alteration was associated with an increase in GluR1 (S831) phosphorylation in medium spiny neurons of the dorsolateral striatum. Both the attenuated rotational response and augmented GluR1 phosphorylation were decreased by CP-101,606 treatment. These CP-101,606 effects were observed when the compound was administered either at the end of chronic levodopa treatment (ameliorative effect) or together with the twice-daily levodopa treatment for 3 weeks (preventive effect). Furthermore, concurrent administration of CP-101,606 with levodopa potentiated the ability of levodopa challenge to reverse the 6-OHDA lesion-induced contralateral forelimb movement deficit as measured in a drag test. These results suggest that activation of NR2B subunit containing NMDA receptors contributes to both the development and maintenance of levodopa-induced motor response alterations, through a mechanism that involves an increase in GluR1 phosphorylation in striatal spiny neurons.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Levodopa/antagonists & inhibitors , Parkinson Disease, Secondary/drug therapy , Piperidines/pharmacology , Receptors, N-Methyl-D-Aspartate/drug effects , Animals , Functional Laterality/physiology , Levodopa/pharmacology , Locomotion/drug effects , Male , Neostriatum/drug effects , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Phosphorylation , Rats , Rats, Sprague-Dawley , Receptors, AMPA/metabolism , Rotation , Serine/metabolism , Stereotyped Behavior/drug effects , Sympathectomy, Chemical
6.
Exp Neurol ; 184(1): 285-94, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14637099

ABSTRACT

Adenosine A(2A) receptors, abundantly expressed on striatal medium spiny neurons, appear to activate signaling cascades implicated in the regulation of coexpressed ionotropic glutamatergic receptors. To evaluate the contribution of adenosinergic mechanisms to the pathogenesis of the response alterations induced by dopaminergic treatment, we studied the ability of the selective adenosine A(2A) receptor antagonist KW-6002 to prevent as well as palliate these syndromes in rodent and primate models of Parkinson's disease. In rats, KW-6002 reversed the shortened motor response produced by chronic levodopa treatment while reducing levodopa-induced hyperphosphorylation at S845 residues on AMPA receptor GluR1 subunits. In primates, KW-6002 evidenced modest antiparkinsonian activity when given alone. Once-daily coadministration of KW-6002 with apomorphine prevented the development of dyskinesias, which appeared in control animals 7-10 days after initiating apomorphine treatment. Animals initially given apomorphine plus KW-6002 for 3 weeks did not begin to manifest apomorphine-induced dyskinesias until 10-12 days after discontinuing the A(2A) antagonist. These results suggest that KW-6002 can attenuate the induction as well as the expression of motor response alterations to chronic dopaminergic stimulation in parkinsonian animals, possibly by blocking A(2A) receptor-stimulated signaling pathways. Our findings strengthen the rationale for developing A(2A) antagonists as an early treatment strategy for Parkinson's disease.


Subject(s)
Adenosine A2 Receptor Antagonists , Dopamine Agonists/toxicity , Parkinson Disease, Secondary/physiopathology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/antagonists & inhibitors , Animals , Antiparkinson Agents/therapeutic use , Apomorphine/toxicity , Denervation , Dyskinesia, Drug-Induced/pathology , Dyskinesia, Drug-Induced/prevention & control , Levodopa/therapeutic use , Macaca fascicularis , Male , Neurons/pathology , Oxidopamine/antagonists & inhibitors , Oxidopamine/toxicity , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/pathology , Phosphorylation , Purines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, AMPA/metabolism , Receptors, Dopamine D1/agonists , Receptors, Dopamine D2/agonists , Sympatholytics/antagonists & inhibitors , Sympatholytics/toxicity
7.
Amino Acids ; 23(1-3): 133-9, 2002.
Article in English | MEDLINE | ID: mdl-12373527

ABSTRACT

Chronically administered levodopa to Parkinson's disease (PD) patients ultimately produces alterations in motor response. Similarly, in 6-hydroxydopamine lesioned hemi-parkinsonian rats, chronic twice-daily administration of levodopa progressively shortens the duration of contralateral turning, an index of, the wearing-off fluctuations that occur in parkinsonian patients. The pathogenesis of these response alterations involves, in part, upregulation of corticostriatal glutamatergic synaptic transmission. Changes involving kinase and phosphatase signaling pathways within striatal dopaminoceptive medium-spiny neurons now appear to contribute to increased synaptic efficacy of glutamatergic receptors in these neurons. Glutamate-mediated striatal sensitization subsequently modifies basal ganglia output in ways that favor the appearance of parkinsonian motor complications. At the molecular level, transcriptional activation of striatal CREB and cdk5 may contribute to the persistent expression of these levodopa-induced response alterations. Conceivably, a safer and more effective therapy for PD can be provided by drugs that target signaling proteins within striatal spiny neurons or those that interact extracellularly with non-dopaminergic receptors such as AMPA and NMDA, adenosine, adrenergic, opioid, and serotonergic.


Subject(s)
Corpus Striatum/physiopathology , Dyskinesia, Drug-Induced/etiology , Glutamic Acid/metabolism , Parkinson Disease/complications , Parkinson Disease/physiopathology , Animals , Antiparkinson Agents/adverse effects , Antiparkinson Agents/therapeutic use , Corpus Striatum/metabolism , Humans , Levodopa/adverse effects , Levodopa/therapeutic use , Motor Activity/physiology , Parkinson Disease/drug therapy , Receptors, Cell Surface/metabolism
8.
Neurology ; 57(10): 1829-34, 2001 Nov 27.
Article in English | MEDLINE | ID: mdl-11723272

ABSTRACT

BACKGROUND: Serotoninergic transmission in the basal ganglia is known to influence dopaminergic mechanisms and motor function. OBJECTIVE: To evaluate the possibility that serotoninergic 5-HT1A autoreceptors (by regulating the release of serotonin as well as dopamine formed from exogenous levodopa) affect the response alterations complicating levodopa treatment of PD. METHODS: The 5-HT1A receptor agonist sarizotan (EMD128130) was systemically administered alone and together with levodopa to parkinsonian rats and nonhuman primates. RESULTS: In 6-hydroxydopamine-lesioned rats, sarizotan (2.5 mg/kg PO) had no effect on the acute rotational response to levodopa but did attenuate the shortening in motor response duration induced by chronic levodopa treatment. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, sarizotan (2 mg/kg PO) alone had no effect on parkinsonian severity or on the antiparkinsonian response to levodopa. In contrast, the same dose of sarizotan reduced levodopa-induced choreiform dyskinesias by 91 +/- 5.9%. In both species, the motoric effects of sarizotan were blocked by the selective 5-HT1A antagonist WAY100635 (0.1 mg/kg SC), indicating that the observed sarizotan responses were probably mediated at the 5-HT1A autoreceptor. CONCLUSION: Pharmaceuticals acting to stimulate 5-HT1A receptors could prove useful in the treatment of the motor response complications in parkinsonian patients.


Subject(s)
Antiparkinson Agents/pharmacology , Motor Skills/drug effects , Parkinsonian Disorders/physiopathology , Receptors, Serotonin/drug effects , Stereotyped Behavior/drug effects , Animals , Corpus Striatum/drug effects , Corpus Striatum/physiopathology , Dose-Response Relationship, Drug , Female , Levodopa/pharmacology , Macaca fascicularis , Male , Motor Skills/physiology , Organic Chemicals , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/physiology , Receptors, Serotonin, 5-HT1 , Species Specificity , Stereotyped Behavior/physiology , Substantia Nigra/drug effects , Substantia Nigra/physiopathology
10.
Cancer Res ; 61(15): 5741-8, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11479210

ABSTRACT

The cell surface molecules controlling apoptosis in cortical neurons are largely unknown. A monoclonal antibody was derived that induces cultured neocortical neurons to undergo apoptosis. A Fab fragment of the antibody, however, lacked the ability to induce cell death. The antigen was purified, and characterized by compositional analysis, fast atom bombardment (FAB) mass spectrometry, sequential exoglycosidase treatments, methylation analysis, and (1)H-nuclear magnetic resonance spectroscopy, proving to be isoglobotetraosylceramide (IsoGb4). IsoGb4 has been shown previously to be a metastasis marker, antibodies against which block metastases in a mammary adenocarcinoma model (S. A. Carlsen et al., Cancer Res., 53: 2906-2911, 1993). Addition of the purified antigen to cells lacking this glycolipid demonstrated that it is capable of functioning as a portable apoptosis-transducing molecule. Intracellular ceramide levels were increased after the treatment with the apoptosis-inducing antibody, but the membrane sphingomyelin level remained unchanged. Fumonisin B1 inhibited both the ceramide increase and the apoptosis induced via IsoGb4, which indicated that the ceramide synthase pathway is likely to be involved in apoptosis induction by IsoGb4.


Subject(s)
Antibodies, Monoclonal/metabolism , Antigens, Surface/metabolism , Apoptosis/physiology , Globosides/metabolism , Neurons/cytology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antigens, Surface/immunology , Antigens, Surface/isolation & purification , Apoptosis/immunology , Carbohydrate Sequence , Cell Transformation, Neoplastic , Globosides/immunology , Globosides/isolation & purification , HeLa Cells , Humans , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Neurons/immunology , Neurons/metabolism , Signal Transduction/physiology
11.
Curr Opin Microbiol ; 4(3): 237-45, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11378473

ABSTRACT

During the past year, a series of studies have provided new perspectives about genetic diversity in Helicobacter pylori. The results illustrate how the current revolution in genomics and proteomics is being used to understand how this organism co-evolves with its host. The approaches should have broad applications to other host-bacterium relationships.


Subject(s)
Bacterial Proteins/genetics , Helicobacter pylori/genetics , Proteome , Genetic Variation , Genome, Bacterial , Oligonucleotide Array Sequence Analysis
12.
Methods Mol Med ; 62: 247-53, 2001.
Article in English | MEDLINE | ID: mdl-21318780

ABSTRACT

The cardinal signs of Parkinson's disease (PD) reflect striatal dopamine depletion due to the progressive degeneration of neurons arising from the substantia nigra. Initially, treatment with the dopamine precursor levodopa ordinarily confers substantial clinical benefit. Later, however, increasing difficulties arise mainly due to the appearance of motor response fluctuations and dyskinesias complicating the treatment of late-stage PD (1-6). Available evidence suggests that standard dopaminomimetic treatment regimens promote the intermittent activation of striatal dopaminergic receptors, which under normal conditions operate mainly tonically (7), and that this nonphysiologic stimulation favors the appearance of the motor fluctuations and dyskinesias (8).

13.
Trends Neurosci ; 23(10 Suppl): S86-91, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11052225

ABSTRACT

Characteristic changes involving interactions between dopamine and glutamate in striatal medium spiny neurons now appear to contribute to symptom production in Parkinson's disease (PD). The balance between kinase and phosphatase signaling modifies the phosphorylation state of glutamate receptors and thus their synaptic strength. Sensitization of spiny-neuron NMDA and AMPA receptors alters cortical glutamatergic input to the striatum and modifies striatal GABAergic output, and thus motor function. Conceivably, the pharmacological targeting of spiny-neuron mechanisms modified in PD will provide a safer and more effective therapy.


Subject(s)
Antiparkinson Agents/pharmacology , Corpus Striatum/metabolism , Dopamine/metabolism , Glutamic Acid/metabolism , Levodopa/pharmacology , Neurons, Efferent/metabolism , Parkinsonian Disorders/metabolism , Animals , Humans , Models, Neurological , Neurons, Efferent/ultrastructure , Phosphotransferases/metabolism , Receptors, Dopamine/metabolism , Receptors, Glutamate/metabolism , Signal Transduction
14.
J Neurol ; 247 Suppl 2: II36-42, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10991664

ABSTRACT

Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson's disease, and their prevention or reversal could prove useful in the treatment of this disorder.


Subject(s)
Antiparkinson Agents/pharmacology , Central Nervous System/drug effects , Dyskinesias/drug therapy , Parkinson Disease/drug therapy , Receptors, Glutamate/drug effects , Animals , Central Nervous System/pathology , Central Nervous System/physiopathology , Dyskinesias/physiopathology , Humans , Parkinson Disease/physiopathology , Receptors, Glutamate/metabolism
15.
Ann Neurol ; 47(4 Suppl 1): S122-9; discussion S129-30, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10762139

ABSTRACT

Recent studies suggest that motor dysfunction associated with the chronic nonphysiologic stimulation of dopaminergic receptors on striatal spiny neurons alters the sensitivity of nearby glutamatergic receptors, especially those of the N-methyl-D-aspartate (NMDA) subtype. Lesioning the nigrostriatal dopamine system of rats or nonhuman primates induces parkinsonian signs; subsequent once- or twice-daily treatment with levodopa produces many of the features of the human motor complication syndrome. Some drugs that block NMDA receptors palliate parkinsonian signs in these animal models, as well as in patients with Parkinson's disease. Certain NMDA receptor antagonists injected into the striatum or given systemically also have the ability to act palliatively or prophylactically to alleviate levodopa-induced response alterations. These observations support the view that sensitization of striatal NMDA receptors contributes to the pathogenesis of motor dysfunction in Parkinson's disease. Since protein phosphorylation serves as an important regulatory mechanism for NMDA receptors, differential increases in the phosphorylation state of tyrosine and serine residues, observed as a result of nigrostriatal system destruction as well as response alteration induction, could account for the apparent augmentation in synaptic efficacy. Current evidence thus suggests that the intermittent stimulation of dopaminergic receptors activates signal transduction pathways in striatal neurons, which augment phosphorylation of NMDA receptors and thus their sensitivity to cortical glutamatergic input. As a result, striatal output changes in ways that favor the appearance of parkinsonian signs and motor complications.


Subject(s)
Corpus Striatum/physiopathology , Motor Neurons/physiology , Parkinson Disease, Secondary/physiopathology , Parkinson Disease/etiology , Parkinson Disease/physiopathology , Animals , Dopamine Agents/adverse effects , Humans , Levodopa/adverse effects , Motor Neurons/drug effects , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/etiology
16.
Brain Res ; 853(2): 174-85, 2000 Jan 24.
Article in English | MEDLINE | ID: mdl-10640615

ABSTRACT

Both excitotoxicity and altered trophic factor support have been implicated in the pathogenesis of Alzheimer's disease. To determine whether stimulation of p75, the low-affinity receptor for nerve growth factor, contributes to the excitotoxin-induced apoptotic death of cholinergic neurons, we examined the effect of unilateral kainic acid (KA; PBS vehicle, 1.25, 2.5 and 5.0 nmol) administration into rat basal forebrain on neuronal loss and p75 expression. KA (2. 5 nmol) destroyed 43% of Nissl-stained neurons and 70% of choline acetyltransferase (ChAT)-positive neurons 5 days after injection. Agarose gel electrophoresis revealed that KA (2.5 nmol) induced local internucleosomal DNA fragmentation after 6-48 h. Immunohistochemical analysis further showed that KA (2.5 nmol) augmented p75 immunoreactivity at a time when terminal transferase-mediated deoxyuridine trophosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive nuclei were increased. Many fragmented nuclei were co-labeled with ChAT antibody. The chronic administration of anti-rat p75 or the protein synthesis inhibitor, cycloheximide, but not anti-human p75, substantially reduced the KA-induced destruction of cholinergic neurons and the induction of internucleosomal DNA fragmentation. Anti-rat p75, but not cycloheximide, also reversed the spatial memory impairment produced by KA. These findings suggest that overexpression of p75 contributes to the excitotoxin-induced death of rat basal forebrain cholinergic neurons by an apoptotic-like mechanism.


Subject(s)
Acetylcholine/metabolism , Kainic Acid/pharmacology , Neurons/drug effects , Neurotoxins/pharmacology , Prosencephalon/drug effects , Receptor, Nerve Growth Factor/biosynthesis , Animals , Antibodies/pharmacology , Apoptosis/drug effects , Behavior, Animal/drug effects , Cell Count/drug effects , Cell Death/drug effects , Choline O-Acetyltransferase/metabolism , Cycloheximide/pharmacology , DNA Fragmentation/drug effects , Kainic Acid/administration & dosage , Male , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Microinjections , Neurons/pathology , Neuroprotective Agents/pharmacology , Prosencephalon/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Nerve Growth Factor/antagonists & inhibitors
17.
Brain Res ; 821(2): 433-42, 1999 Mar 13.
Article in English | MEDLINE | ID: mdl-10064831

ABSTRACT

Sensitization of striatal N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathogenesis of the response alterations associated with dopaminomimetic treatment of parkinsonian animals and patients. To determine whether serine phosphorylation of NMDA receptor subunits by activation of Ca2+/calmodulin-dependent protein-kinase II (CaMKII) contributes to this process, we examined the effects of unilateral nigrostriatal ablation with 6-hydroxydopamine and subsequent treatment with levodopa, SKF 38393 (D1-preferring dopamine agonist), or quinpirole (D2-preferring agonist) on motor responses and phosphorylation states. Three weeks of twice-daily levodopa administration to rats shortened the duration of their rotational response to levodopa or SKF 38393 challenge, but prolonged the duration of quinpirole-induced rotation. At the same time, levodopa treatment elevated serine phosphorylation of striatal NR2A (p<0.02), but not that of NR2B subunits, without associated changes in subunit protein levels. Chronic treatment with SKF 38393 increased NR2A (p<0.0001) but decreased NR2B (p<0.004) serine phosphorylation. In contrast, chronic quinpirole treatment had no effect on NR2A but increased NR2B phosphorylation (p<0.0001). The acute intrastriatal injection of the CaMKII inhibitor KN93 (1.0 micrograms) not only normalized the levodopa-induced motor response alterations but also attenuated the D1 and D2 receptor-mediated serine phosphorylation of NR2A and NR2B subunits, respectively (p<0.02). These results suggest that a CaMKII-mediated rise in serine phosphorylation of NMDA receptor subunits induced by intermittent stimulation of D1 or D2 dopaminergic receptors contributes to the apparent enhancement in striatal NMDA receptor sensitivity and thus to the dopaminergic response plasticity in levodopa-treated parkinsonian rats.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Corpus Striatum/chemistry , Dopamine Agonists/pharmacology , Dopamine/physiology , Nerve Degeneration/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Antibodies , Antiparkinson Agents/pharmacology , Benzylamines/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Corpus Striatum/cytology , Corpus Striatum/metabolism , Enzyme Inhibitors/pharmacology , Levodopa/pharmacology , Male , Motor Neurons/chemistry , Motor Neurons/enzymology , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/metabolism , Phosphorylation , Phosphoserine/analysis , Phosphoserine/immunology , Phosphoserine/metabolism , Rats , Rats, Sprague-Dawley , Serine/metabolism , Sulfonamides/pharmacology , Sympatholytics
18.
Brain Res ; 813(1): 150-9, 1998 Nov 30.
Article in English | MEDLINE | ID: mdl-9824689

ABSTRACT

Sensitization of striatal N-methyl-D-aspartate receptors (NMDAR) has been linked to events leading to the motor response changes associated with the administration of dopaminomimetics to parkinsonian animals and patients. To determine whether tyrosine phosphorylation of NMDAR subunits contributes to the apparent long-term enhancement in synaptic efficacy of these receptors, we examined the effect of unilateral nigrostriatal dopamine system ablation with 6-hydroxydopamine followed by twice-daily treatment with l-DOPA on the phosphorylation state of rat striatal NR2A and NR2B subunits. Three weeks of intermittent l-DOPA administration produced a shortening in the duration of the rotational response to dopaminergic challenge and other changes mimicking those occurring in patients with Parkinson's disease. Concurrently, tyrosine phosphorylation of NR2A and especially of NR2B subunits increased ipsilateral to the lesion (20+/-5% and 46+/-7% of intact striatum, respectively; p<0.01) without attendant changes in subunit protein levels. Selective blockade of NR2B subunits with ACEA 10-1244, but not of NR2A subunits with MDL 100,453, reversed the l-DOPA-induced response alterations. The intrastriatal injection of a tyrosine kinase inhibitor, genistein, at a dose (2.0 microg) that normalized the response shortening, attenuated the NR2A and NR2B phosphorylation increase by about 12% and 24%, respectively (p<0.01). Taken together, these results suggest that augmented tyrosine phosphorylation of NR2B subunits, alone or in combination with the smaller rise in NR2A subunit phosphorylation, contributes to the apparent enhancement in striatal NMDAR sensitivity and thus to the plastic alterations in dopaminergic responses in l-DOPA-treated parkinsonian rats.


Subject(s)
Corpus Striatum/drug effects , Dopamine Agents/pharmacology , Dopamine/physiology , Peptide Fragments/metabolism , Protein-Tyrosine Kinases/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Corpus Striatum/metabolism , Denervation , Immunohistochemistry , Levodopa/pharmacology , Male , Phosphorylation , Psychomotor Performance/drug effects , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/chemistry
19.
Neurology ; 51(2 Suppl 2): S30-5, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9711978

ABSTRACT

Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD.


Subject(s)
Corpus Striatum/physiopathology , Dopamine/metabolism , Parkinson Disease/physiopathology , Receptors, Dopamine/metabolism , Corpus Striatum/metabolism , Humans , Parkinson Disease/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism
20.
Neurosci Lett ; 228(1): 5-8, 1997 May 30.
Article in English | MEDLINE | ID: mdl-9197274

ABSTRACT

Chronically administered levodopa, the standard treatment for Parkinson's disease, is ultimately associated with disabling alterations in motor response. To evaluate the possible contribution of striatal cAMP-dependent protein kinase A (PKA) signaling pathways to these response modifications, the acute effects of a PKA inhibitor, Rp-cAMPS, on motor response changes attending chronic, twice-daily administration of levodopa were measured in 6-hydroxydopamine lesioned hemi-parkinsonian rats. A single intrastriatal injection of Rp-cAMPS (2.5 or 25 microg) attenuated both the shortened duration and augmented intensity of levodopa-induced turning in a dose dependent manner. Rp-cAMPS completely normalized motor responses to a dopamine D1 agonist (SKF 38392), but had no effect on those to a dopamine D2 agonist (quinpirole). These results suggest that D1 receptor-mediated PKA activation may contribute to the development of the altered motor responses associated with chronic levodopa treatment.


Subject(s)
Antiparkinson Agents/pharmacology , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP/analogs & derivatives , Dopamine Agents/pharmacology , Enzyme Inhibitors/pharmacology , Levodopa/pharmacology , Motor Activity/drug effects , Parkinson Disease/physiopathology , Thionucleotides/pharmacology , Animals , Cyclic AMP/pharmacology , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Male , Quinpirole/pharmacology , Rats , Rats, Sprague-Dawley , Reaction Time , Receptors, Dopamine D1/agonists , Receptors, Dopamine D2/agonists , Rotation , Stereotyped Behavior/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...