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)

Selective agonists for D1-like and D2-like dopamine receptors can interact synergistically to enhance each other's actions on locomotion and behavior in experimental animals. Clinically, the combination of the D2 agonist bromocriptine with L-dopa (which has pronounced D1 effects) is a highly effective treatment for Parkinson's disease. The mechanisms underlying this important receptor interaction are poorly understood and are the subject of intense study in vitro. In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway, D1-selective (but not D2-selective) dopamine agonists produce a marked increase in expression of the immediate-early gene c-fos in the striatum ipsilateral to the 6-OHDA lesion. In the experiments reported here, we have used this in vivo model to explore the possibility that combinations of D1-selective and D2-selective agonists might have effects on c-fos transcription that are different from those exhibited by D1 or D2 agonists administered alone. We examined the effects of the D1-selective agonist SKF-38393 and the D2-selective agonist quinpirole (LY 171555) on the expression of Fos-like protein and c-fos mRNA in the caudoputamen and made parallel behavioral observations in the same animals. A low dose of SKF-38393 produced little contraversive rotation and little induction of Fos-like immunoreactivity in the striatum. A low dose of quinpirole elicited contralateral rotation but little or no induction of Fos-like immunoreactivity in the caudoputamen; there was, however, induction of Fos in the globus pallidus ipsilateral to the 6-OHDA lesion. Combination of the low dose of SKF-38393 and quinpirole produced a synergistic effect on rotation and elicited, in the dopamine-depleted caudoputamen, a striking pattern of Fos-like protein expression in which Fos-positive neurons were concentrated in striosomes and in the dorsolateral caudoputamen. Northern blot analysis showed that c-fos mRNA was expressed following combined agonist treatment but was not detectable after the single-agonist treatments. Both the contraversive rotation and the induction of Fos-like immunoreactivity were blocked by the preadministration of the D1-preferring antagonist SCH-23390 and the D2-selective antagonist raclopride in combination. Pretreatment with the glutamate NMDA receptor antagonist MK-801 also blocked the induction of Fos-like immunoreactivity, and it reversed the rotation. These findings suggest a D1/D2 synergistic mechanism that involves the participation of D1-responsive striatonigral and D2-responsive striatopallidal output pathways, and that is sensitive to glutamatergic modulation.
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PMID:D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease. 135 13

Excitotoxic cell death is hypothesized to contribute to numerous neuropathologic conditions, including hypoxic/ischemic encephalopathy, hypoglycemia, Parkinson's disease, and Huntington's disease. Neuronal death from excitotoxic lesions has been shown to be an active process, with activation of immediate early gene transcription, resulting in secondary changes in gene expression. Another feature of neurotoxic cell death that has been examined is the presence of DNA fragmentation, which presumably indicates impending nuclear disintegration. A technique has been described for labeling fragmented DNA in situ, allowing precise determination of the anatomic and temporal distribution of neurons after an excitotoxic lesion. To investigate this phenomenon, we performed in situ nick translation on brain tissue from rats that have undergone stereotaxically placed intrastriatal quinolinic acid injections. Furthermore, in these same animals we analyzed the expression of c-fos mRNA to compare the time course and regional distribution of DNA fragmentation with immediate early gene activation after an excitotoxic lesion. Our analysis indicates that c-fos expression increases soon after quinolinic acid injection, is widespread in rat brain, but is effectively absent by 24 h postinjection. DNA fragmentation, however, is limited to striatum and is maximal at 24 h after injection. These results demonstrate the sensitivity of in situ nick translation for the detection of regional neuropathology and illustrate the temporal and spatial relationship of c-fos expression to excitotoxic neuronal death.
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PMID:DNA fragmentation and immediate early gene expression in rat striatum following quinolinic acid administration. 764 26

Expression of the immediate early gene c-fos increases acutely following neuronal depolarization. c-fos and Fos protein have been widely used to investigate basal ganglia responses to changes in dopaminergic neurotransmission. Increased dopaminergic input to D1 receptors increases Fos synthesis in striatal neurons. The role of D2 receptors in regulating Fos activity has been more difficult to establish. Because dopamine is believed to excite striatal neurons via D1 receptors and inhibit them via D2 receptors, we hypothesized that acute dopamine depletion would increase Fos activity in basal ganglia circuits normally inhibited by dopaminergic input to D2 receptors. Rats were perfused after a single dose of the dopamine-depleting drug reserpine. The brains of rats perfused 3 h after reserpine displayed numerous Fos-like immunoreactive nuclei in the striatum, entopeduncular nucleus, nucleus accumbens shell, and ventral pallidum, and sparse Fos-like immunoreactive nuclei in the globus pallidus and nucleus accumbens core. Few or no Fos-like immunoreactive nuclei were seen following perfusion 30 min, 60 min, and 24 h after reserpine. In the 3-h paradigm, pretreatment with the selective D1 antagonist SCH 23390 did not change the pattern of Fos-like immunoreactivity; pretreatment with the selective D2 agonist quinpirole completely blocked increased Fos synthesis. Acute dopamine depletion, therefore, increases Fos activity in the basal ganglia by disinhibiting D2 circuits. These results support the parallel pathway model of basal ganglia function, and show that Fos can be used to investigate the role of D2 receptors in striatal function. The findings suggest anatomic correlates for the clinical effects of acute dopamine depletion in drug therapy and advanced Parkinson's disease in humans.
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PMID:Reserpine increases Fos activity in the rat basal ganglia via a quinpirole-sensitive mechanism. 791 58

The expression of proenkephalin (PENK), prodynorphin (PDYN) and c-fos genes was studied in the striatum of C57B1/6 mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP), which are used as a rodent model of Parkinson's disease (PD). Two weeks after systemic administration of MPTP (2 x 40 mg/kg, s.c. 18h apart), the lesion of the substantia nigra (SN) could be visualised by loss of the nigral tyrosine hydroxylase (TH) mRNA hybridization signal and by a 91% decrease in striatal dopamine levels. The levels of PENK and PDYN mRNAs were not significantly changed in the striatum of the lesioned mice, as compared to non-treated controls. The induction of the immediate early gene c-fos by the dopamine D2 receptor antagonist haloperidol was not altered, while the selective D1 receptor agonist SKF 38393 failed to induce c-fos in the striatum of MPTP-treated mice. These results are in contrast to the data concerning rats with the 6-hydroxydopamine (6-OHDA) lesion of the SN, which serve as another rodent model of PD. In the striata of 6-OHDA-lesioned rats, PENK gene is upregulated, PDYN gene is down-regulated and the induction of c-fos gene by D2 receptor antagonists is abolished, whereas selective D1 receptor agonists induce c-fos gene, which does not occur in non-lesioned rats. We presume that the lack of influence of the MPTP lesion in mice on the striatal gene expression was mainly caused by insufficient dopamine depletion in the striatum, which could not be increased in this model. The importance of the changes observed in 6-OHDA-lesioned rats has been discussed in the context of the mouse and primate MPTP models of PD.
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PMID:The expression of proenkephalin and prodynorphin genes and the induction of c-fos gene by dopaminergic drugs are not altered in the straitum of MPTP-treated mice. 852

The efficacy of L-dihydroxyphenylalanine (L-DOPA) in ameliorating the symptoms of Parkinson's disease (PD) is attributed to its conversion to dopamine (DA) by the enzyme aromatic L-amino-acid decarboxylase (AADC) in the striatum. Although the site of this conversion in the DA-denervated striatum has yet to be identified, it has been proposed that L-DOPA could be converted to DA at non-dopaminergic sites containing AADC. In the present study, we used immunocytochemical techniques to examine the localization of AADC and DA in the striatum of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopaminergic projection. In the DA-denervated striatum, we observed AADC-immunoreactive (-IR) cells with morphological characteristics similar to a class of small aspiny interneuron. Although usually obscured by a dense plexus of AADC-IR fibers, these cells could also occasionally be detected in the intact striatum. Acute administration of L-DOPA to DA-denervated animals elicited contralateral rotational behavior as well as a pronounced c-fos protein immunoreactivity in the striatum ipsilateral to the lesion. Following acute administration of L-DOPA, but not after acute saline, DA-IR cells were detected in the denervated striatum. These DA-IR cells are similar in morphology and were found in the same location as the AADC-IR cells. These results strongly suggest the existence of a class of AADC-containing striatal cells that can form DA from exogenous L-DOPA in the rat. In the DA deafferented striatum, DA produced by these cells from exogenous L-DOPA could be released to exert physiological effects on DA receptive tissue. It is possible that similar cells could contribute to the efficacy of L-DOPA in the treatment of Parkinson's disease.
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PMID:Aromatic L-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenous L-DOPA to dopamine. 875 Sep 61

Glial cell line-derived neurotrophic factor (GDNF) is a highly selective neurotrophic factor for midbrain dopaminergic neurons and might thus be of potential use in the therapy of Parkinson's disease. In this study, we present evidence that the survival-promoting action of GDNF on dopaminergic neurons requires the concurrent activation of cAMP-dependent signaling pathways. In serum-free low density cultures of the dissociated embryonic day 15 mesencephalon, dopaminergic neurons undergo constant cell death as evidenced by a 90% reduction in tyrosine hydroxylase-immunoreactive (TH-IR) cell numbers between days 1 and 9 of cultivation. This decline was not affected by GDNF (5 ng/ml) within the initial 3 days of cultivation, but was in part attenuated with prolonged treatment. In contrast, stimulation of 3-day-old mesencephalic cultures with GDNF induced c-fos expression in 73% of all TH-IR neurons, indicative for the early presence of efficient signal-transduction coupling in these neurons. Combined treatment of mesencephalic cultures with dibutyryl cyclic AMP (dbcAMP; 100 microM) and GDNF accelerated the onset of the survival effects of GDNF on dopaminergic neurons, resulting in a 1.5-fold increase in the number of surviving TH-IR neurons at 3 days in vitro. In addition, activation of cAMP-dependent signal pathways significantly potentiated the survival-promoting effects of GDNF on dopaminergic neurons in older cultures. dbcAMP alone had no effect on dopaminergic cell survival. Taken together, our findings suggest that the action of GDNF on midbrain dopaminergic neurons is modulated by other extracellular signals.
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PMID:Effects of glial cell line-derived neurotrophic factor (GDNF) on dopaminergic neurons require concurrent activation of cAMP-dependent signaling pathways. 885 92

1. Previous experiments have suggested a potential atypical antipsychotic activity of the ergoline derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2 = 1.11) and a moderate affinity to D1 receptors. In vivo experiments showed antagonism of dopamine and 5-hydroxytryptamine (5-HT) receptor-linked behaviours. 2. In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6-hydroxydopamine (6-OHDA), were used to determine the effects of LEK-8829 on turning behaviour and on striatal c-fos mRNA levels. 3. The administration of LEK-8829 induced a long lasting contralateral turning behaviour that was dose-dependent. It was found that the specific D1 receptor antagonist SCH-23390 but not the D2 receptor antagonist haloperidol or 5-HT1A antagonist pindolol, dose-dependently inhibited the turning behaviour induced by LEK-8829. 4. In an attempt to clarify the D1:D2 receptor interactions involved in the action of LEK-8829 in the 6OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH-23390 pretreatment on striatal c-fos mRNA expression induced either by LEK-8829 or by the typical antipsychotic haloperidol. 5. LEK-8829 induced a bilateral striatal c-fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH-23390. In contrast, haloperidol-induced striatal c-fos mRNA expression was limited to the innervated striatum and was not blocked by SCH-23390. 6. Our data demonstrate an intrinsic activity of LEK-8829 on D1 receptors that is potentiated in the dopamine-depleted striatum. We conclude, therefore, that the putative atypical antipsychotic LEK-8829 may prove useful as an experimental tool for the study of D1:D2 receptor interactions and could have beneficial effects in the treatment of drug-induced psychosis in patients with Parkinson's disease.
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PMID:The D1 receptor-mediated effects of the ergoline derivative LEK-8829 in rats with unilateral 6-hydroxydopamine lesions. 893 22

In order to investigate the role of adenosine A2A receptor blockade on dopamine-mediated motor responses, contralateral turning behaviour and expression of the early-gene c-fos was evaluated in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. SCH 58261, (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1 , 5-c]pyrimidine) a potent and selective antagonist of adenosine A2A receptors (5 mg/kg i.p.), induced a 70-fold increase in the contralateral turning behaviour induced by a low dose (2 mg/kg i.p.) of the dopamine precursor L-DOPA (L-3, 4-dihydroxyphenylalanine). Expression of c-fos as measured by Fos-like immunoreactivity after SCH 58261 plus L-DOPA was also potentiated as compared with L-DOPA alone, both in striatum and globus pallidus of the 6-hydroxydopamine-lesioned side of the brain. SCH 58261 induced a less marked potentiation (7-fold) of turning behaviour induced by dopamine D2 receptor stimulation with quinpirole, while Fos-like immunoreactivity in the striatum and globus pallidus was not affected. Previous studies have shown that SCH 58261 strongly potentiated dopamine D1 receptor-mediated responses. The results of the present study therefore indicate that the positive interaction between SCH 58261 and L-DOPA, in 6-hydroxydopamine-lesioned rats, is mainly due to an interaction with dopamine D1 receptors. The data also suggest that adenosine A2A receptor antagonists might be useful for potentiating the effects of L-DOPA in Parkinson's disease.
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PMID:Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats. 906 81

Parkinson's disease (PD) is characterized by the relatively selective and progressive loss of dopaminergic neurons in the substantia nigra. During the early stages of PD, there are marked compensatory changes in the dopaminergic system, although little is known of how these responses are orchestrated. Since the induction of cellular immediate-early genes (cIEG) has been linked to adaptive responses in the nervous system, we examined their expression in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of PD. MPTP elicited an induction of c-fos, fosB, Delta-fosB and c-jun mRNAs in the striatum that persisted for 24 h. There was a parallel increase in AP-1-like DNA binding activity for up to 7 days post-treatment. At 7 days, AP-1 complexes were specifically supershifted with antisera to FosB and JunD. Immunoblotting of MPTP-treated striata with a FosB-specific antiserum revealed elevated levels of approximately 35 and approximately 46 kDa cross-reactive proteins. Only the 35 kDa protein was increased at 7 days. Thus, the persistent AP-1 complex seen in the MPTP-treated striatum is composed of JunD and a 35 kDa FosB-related protein, possibly Delta-FosB. In situ hybridization revealed elevated expression of fosB and Delta-fosB in the MPTP-treated brain. Expression of both transcripts was highest in ventral striatum, nucleus accumbens and other terminal fields of the mesolimbic system, such as the olfactory tubercle and Islands of Calleja. Thus, the increased fosB expression accompanying MPTP treatment was predominantly associated with dopaminergic pathways. Since FosB was expressed in both vulnerable and spared neuronal populations, we suggest that Delta-FosB-JunD heterodimers play a role in the adaptive response to MPTP neurotoxicity.
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PMID:MPTP-Parkinsonism is accompanied by persistent expression of a delta-FosB-like protein in dopaminergic pathways. 947 80

Reactive oxygen species (ROS) play an important role in the pathogenesis of many human diseases, including the acute respiratory distress syndrome, Parkinson's disease, pulmonary fibrosis, and Alzheimer's disease. In mammalian cells, several genes known to be induced during the immediate early response to growth factors, including the protooncogenes c-fos and c-myc, have also been shown to be induced by ROS. We show that members of the STAT family of transcription factors, including STAT1 and STAT3, are activated in fibroblasts and A-431 carcinoma cells in response to H2O2. This activation occurs within 5 min, can be inhibited by antioxidants, and does not require protein synthesis. STAT activation in these cell lines is oxidant specific and does not occur in response to superoxide- or nitric oxide-generating stimuli. Buthionine sulfoximine, which depletes intracellular glutathione, also activates the STAT pathway. Moreover, H2O2 stimulates the activity of the known STAT kinases JAK2 and TYK2. Activation of STATs by platelet-derived growth factor (PDGF) is significantly inhibited by N-acetyl-L-cysteine and diphenylene iodonium, indicating that ROS production contributes to STAT activation in response to PDGF. These findings indicate that the JAK-STAT pathway responds to intracellular ROS and that PDGF uses ROS as a second messenger to regulate STAT activation.
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PMID:Activation of the JAK-STAT pathway by reactive oxygen species. 984 26


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