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)

Growing evidence indicates that aldehydic products of lipid peroxidation play an important role in the pathophysiology of neurodegenerative disorders such as Parkinson's disease. In the present study, modulation of D1-like receptor binding and function by saturated alkanals and unsaturated alkenals, 4-hydroxynonenal (4-HNE) and trans-2-nonenal (nonenal), was examined in rat striatal membranes. The 4-HNE and nonenal were most effective in modulating both the specific D1-like receptor binding and function as measured by adenylate cyclase activation. Inactivation of receptor binding and the depression of adenylate cyclase activity were partially prevented by protection of the D1/D5-receptor with the agonist (R)-SKF 38393 or the specific antagonist SCH 23390. 4-HNE inhibited adenylate cyclase activation by Gpp (NH)p and forskolin, indicating the modulation of Gsalpha and the catalytic subunit of adenylate cyclase, respectively. Our data suggests that aldehydic products of lipid peroxidation can directly modulate the binding and functional properties of D1/D5 receptors, as well as effector proteins within their signaling pathway.
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PMID:Modulation of D1-like dopamine receptor function by aldehydic products of lipid peroxidation. 1264 68

Behavioral and microdialysis studies have been performed on antagonistic A(2A)/D(2) interactions in animal models of Parkinson's Disease. The behavioral analysis involved studies on locomotor activity in reserpinized mice, haloperidol-induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis studies were indirectly performed on the striatopallidal GABA neurons by studying extracellular glutamate levels in the striatum and globus pallidus of the awake freely moving rat. The striatum was perfused with A(2A) and/or D(2) agonists via reverse microdialysis. The results show that the A(2A) antagonists SCH58261 and KF17837 can increase locomotor activity in reserpinized mice and produce contralateral rotational behavior only after administration of subthreshold doses of l-DOPA or the D(2) like agonist quinpirole. Furthermore, antagonizing the A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D(2) heterodimers where A(2A) R inhibits the D(2) R transduction and D(2) inhibits the adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that the A(2A) agonist CGS21680 striatally coperfused with the D(2) agonist quinpirole more potently counteract the D(2) agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A(2A)/D(2) interaction. In the DA denervated but not in the control striatum the A(2A) agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A(2A) R located on the striatal glutamate terminals, where also D(2) like R exist, here probably as D(4). Thus, the signaling of this A(2A) R may be set free by the loss of D(4) tone on the AC activated by A(2A) in this postulated A(2A)/D(4) heteromer on the glutamate terminals. Taken together, the results indicate that the antiparkinsonian actions of A(2A) antagonists probably are produced by blockade of A(2A) R in the A(2A)/D(2) heterodimers mainly located in the striatopallidal GABA neurons.
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PMID:Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease. 1519 5

Dual probe microdialysis was used to study A2A/D2 receptor interactions in the striato-pallidal GABA pathway in a model of Parkinson's Disease. The A2A agonist CGS21680 and/or the D2-like agonist quinpirole were perfused via reverse microdialysis into the DA denervated striatum and the effects on globus pallidus (GP) extracellular GABA levels were evaluated. CGS21680 alone produced in the DA denervated striatum a transient rise of GP GABA levels. Quinpirole perfused alone into the DA denervated striatum reduced GP GABA levels, which was not only counteracted by coperfused CGS21680, but led to an enhancement of the GABA levels, which was larger than that seen with CGS21680 alone. These results may reflect existence not only of antagonistic A2A/D2 interactions but also of the appearance of D2/A2A interactions increasing the A2A signaling at the level of the adenylate cyclase. Such actions diminish the therapeutic efficacy of L-dopa and D2 agonists. L-dopa induced dyskinesias could be caused by changes in the balance of A2A/D2 heteromers vs A2A homomers expressed at the surface membrane, where A2A homomers dominate with abnormal increases in A2A signaling. This may lead to stabilization of abnormal receptor mosaics (high order hetero-oligomers) leading to formation of abnormal motor programs contributing to dyskinesia development.
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PMID:Experimental studies and theoretical aspects on A2A/D2 receptor interactions in a model of Parkinson's disease. Relevance for L-dopa induced dyskinesias. 1676 81

Parkinson's disease (PD) is characterized by a selective loss of dopamine-producing neurons in the substantia nigra (SN), which in turn results in dopamine depletion in the striatum, and the presence of neuronal cytoplasmic inclusions known as Lewy bodies (LBs). Alpha-synuclein is a presynaptic protein that accumulates abnormally in LBs and is seen predominantly in cases of dementia with LBs. Although the central role of alpha-synuclein in neurodegeneration has been previously demonstrated by the discovery of missense alpha-synuclein mutations in familial PD, the specific mechanism by which alpha-synuclein contributes to these diseases remains unclear. In the present study, we examined whether alpha-synuclein affects the downstream signaling of dopamine D2 receptor (D2R). In CHO cells stably transfected with D2Rs, alpha-synuclein enhanced dopamine D2-agonist-mediated inhibition of adenylate cyclase, which consequently affected its downstream cAMP-responsive element (CRE)-mediated gene transcription, while C-terminal deletion mutant of alpha-synuclein did not. Our study suggests that the alpha-synuclein enhances the dopamine-mediated intracellular signaling pathways by D2R, thus provide a possible mechanism in presynaptic regulation of the synaptic homeostasis in the dopaminergic neurotransmission.
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PMID:Alpha-synuclein enhances dopamine D2 receptor signaling. 1708 19

Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.
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PMID:Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress. 1859 41

This study investigated the proteomic changes at different time points in the precipitated pellets of rat spinal cords after applying complete spinal cord transection. By two-dimensional electrophoresis, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry, MALDI-TOF/TOF and peptide mass fingerprinting analysis, 44 proteins were identified, most of which are membrane and/or organellar proteins. They are mainly involved in metabolic processes (75%), developmental processes (30%), or responses to stimuli (30%), playing negative or positive roles. In particular, decreases of pyruvate dehydrogenase beta, aconitase 2, fumarate hydratase 1, and ATP synthase subunit 6 can lead to ATP depletion by crippling tricarboxylic acid cycle and oxidative phosphorylation. Decreases of several antioxidant proteins such as catalase, peroxiredoxin 1, Parkinson disease 7, and stress-induced phosphoprotein 1 can contribute to the secondary injury of spinal cord. Decreases of development-related 3-phosphoglycerate dehydrogenase and stathmin 1 may be not propitious for spinal cord regeneration. On the other hand, increases of isocitrate dehydrogenase 3 alpha/gamma and glutamate dehydrogenase 1 can help compensate the impaired energy metabolism. Increases of sirtuin 2, crystallin alpha B (CRYAB), and heat shock 27-kDa protein 1 can help resist stresses induced by injury. Increases of adenylate cyclase-associated protein 1 and galactose binding lectin 3 can help regeneration by replaying their roles in neural development. To our knowledge, this is the first case of characterization of the proteomic changes seen in the precipitated fraction of injured spinal cord. Most of the identified proteins were found for the first time to be differentially expressed after spinal cord injury, which may provide new clues about the molecular mechanisms of spinal cord injury and repair.
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PMID:Proteomic profiling of the insoluble pellets of the transected rat spinal cord. 1911 13

Vasoactive neuropeptides (VNs) such as pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, as well as immune and nociception modulators. They have key roles in blood vessels in the central nervous system (CNS) including maintaining functional integrity of the blood brain barrier (BBB) and blood spinal barrier (BSB). VNs are potent activators of adenylate cyclase and thus also have a key role in cyclic AMP production affecting regulatory T cell and other immune functions. Virchow-Robin spaces (VRSs) are perivascular compartments surrounding small vessels within the CNS and contain VNs. Autoimmunity of VNs or VN receptors may affect BBB and VRS function and, therefore, may contribute to the aetiology of neurological-related conditions including multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. VN autoimmunity will likely affect CNS and immunological homeostasis. Various pharmacological and immunological treatments including phosphodiesterase inhibitors and plasmapheresis may be indicated.
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PMID:Postulated role of vasoactive neuropeptide-related immunopathology of the blood brain barrier and Virchow-Robin spaces in the aetiology of neurological-related conditions. 1922 45

Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes, such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators or inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson's disease), can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies have suggested that both right-sided and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit, which is widely expressed in a variety of tissues, including liver, lung, heart, and coronary and pulmonary arteries; it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review, the authors discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy, with an emphasis on echocardiographic diagnosis.
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PMID:Role of serotoninergic pathways in drug-induced valvular heart disease and diagnostic features by echocardiography. 1955 85

Neuropsychiatric symptoms occur in a number of neurological fatigue-related conditions including multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and chronic fatigue syndrome (CFS). These conditions have been attributed variably to neuroinflammatory and neurodegenerative processes. While autoimmune pathology, at least in part, has long been suspected in these conditions proof has been elusive. Autoimmune pathomechanisms affecting the blood-brain barrier (BBB) or blood-spinal barrier (BSB) may predispose the BBB/BSB to 'leakiness' and be a precursor to additional autoimmune events resulting in neuroinflammatory or neurodegenerative processes. The aim of the paper is to postulate immunopathology of the cerebrospinal perivascular compartment involving certain vasoactive neuropeptides, specifically pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), in the etiology of certain neuropsychiatric fatigue-related conditions such as MS, ALS, PD, and CFS. Vasoactive neuropeptides (VNs) such as PACAP and VIP have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, and immune and nociception modulators. PACAP and VIP are widely distributed in the central nervous system (CNS) and have key roles in CNS blood vessels including maintaining functional integrity of the BBB and BSB. Autoimmunity affecting these VNs would likely have a detrimental effect on BBB and BSB functioning arguably predisposing to further pathological processes. Virchow-Robin spaces (VRS) are perivascular compartments surrounding small vessels within the CNS which contribute to the BBB and BSB integrity and contain PACAP and VIP receptors. Autoimmunity of these receptors would likely affect BBB and VRS function and therefore may contribute to the etiology of these conditions by affecting CNS and immunological homeostasis, including promoting neuropsychological symptomatology. PACAP and VIP, as potent activators of adenylate cyclase (AC), have a key role in cyclic adenosine monophosphate (cAMP) production affecting regulatory T cell (Treg) and other immune functions. Phosphodiesterase enzymes (PDEs) catalyze cAMP and PDE inhibitors (PDEIs) maintain cAMP levels and have proven and well known therapeutic benefit in animal models such as experimental allergic encephalomyelitis (EAE). Therefore PDEIs may have a role in therapy for certain neuropsychiatric fatigue-related conditions.
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PMID:Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment? 1955 3

Dopamine agonists directly activate dopamine receptors, bypassing the presynaptic synthesis of dopamine. There are two main classes of dopamine receptors: the D1 class linked to the enzyme adenyl cyclase and the D2 coupled to G-proteins that inhibit adenyl cyclase. Dopamine agonists are effective as monotherapy in early Parkinson's disease and as an adjunctive treatment to levodopa in the advanced stages of the disease. Dopamine agonists are increasingly used early, particularly in young-onset Parkinson's disease due to their levodopa-sparing effects and putative role as neuroprotective agents. The potential neuroprotective property of agonists has been the focus of research and debate in recent years. This review summarizes the use of dopamine agonists in Parkinson's disease and reviews the laboratory, clinical and functional imaging evidence of neuroprotection in this class of drug and discusses the clinical implications of their use in Parkinson's disease management.
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PMID:Dopamine agonists and their role in Parkinson's disease treatment. 1981 Aug 83


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