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)

In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease). Consistent with this novel view, substantial evidences suggest that depressive illness is not a mere neurochemical disease, but is linked to gray matter atrophy due to the reduced number/size of neurons and glia in brain. Importantly, neurogenesis, that is, birth/maturation of functional new neurons, continues to occur throughout the lifetime in human adult brains (e.g., hippocampus); the neurogenesis is impaired by multiple not-fully defined factors (e.g., aging, chronic stress-induced increase of glucocorticoids, and excitotoxicity), accounting for brain atrophy in patients with depressive illness and neurodegenerative diseases. Chronic treatment of lithium, in agreement with the delayed-onset of mood-stabilizing effects of lithium, up-regulates cell survival molecules (e.g., Bcl-2, cyclic AMP-responsive element binding protein, brain-derived neurotrophic factor, Grp78, Hsp70, and beta-catenin), while down-regulating pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome c release, beta-amyloid peptide production, and tau hyperphosphorylation), thus preventing or even reversing neuronal cell death and neurogenesis retardation.
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PMID:Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. 1634 Jan 57

Multipotent stem/progenitor cells derived from human first trimester forebrain can be expanded as free-floating aggregates, so called neurospheres. These cells can differentiate into neurons, astrocytes and oligodendrocytes. In vitro differentiation protocols normally yield gamma-aminobutyric acid-immunoreactive neurons, whereas only few tyrosine hydroxylase (TH) expressing neurons are found. The present report describes conditions under which 4-10% of the cells in the culture become TH immunoreactive (ir) neurons within 24h. Factors including acidic fibroblast growth factor (aFGF) in combination with agents that increase intracellular cyclic AMP and activate protein kinase C, in addition to a substrate that promotes neuronal differentiation appear critical for efficient TH induction. The cells remain THir after trypsinization and replating, even when their subsequent culturing takes place in the absence of inducing factors. Consistent with a dopaminergic phenotype, mRNAs encoding aromatic acid decarboxylase, but not dopamine-beta-hydroxylase were detected by quantitative real time RT-PCR. Ten weeks after the cells had been grafted into the striatum of adult rats with unilateral nigrostriatal lesions, only very few of the surviving human neurons expressed TH. Our data suggest that a significant proportion of expandable human neural progenitors can differentiate into TH-expressing cells in vitro and that they could be useful for drug and gene discovery. Additional experiments, however, are required to improve the survival and phenotypic stability of these cells before they can be considered useful for cell replacement therapy in Parkinson's disease.
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PMID:Induction of dopaminergic neurons from growth factor expanded neural stem/progenitor cell cultures derived from human first trimester forebrain. 1702 82

Selegiline inhibits the activity of monoamine oxidase B, enhances the release of dopamine, blocks the uptake of dopamine, acts as a calmodulin antagonist, and enhances the level of cyclic AMP, which in turn protects dopaminergic neurons. It possesses cognition-enhancing functions, rejuvenates serum insulin-like growth factor I in aged rats, and enhances life expectancy in rodents. Selegiline possesses neurotrophic-like actions, and rescues axotomized motorneurons independent of monoamine oxidase B inhibition. It enhances the synthesis of nerve growth factor, protects dopaminergic neurons from glutamate-mediated neurotoxicity, and protects dopaminergic neurons from toxic factors present in the spinal fluid of parkinsonian patients, and the said effect may be mediated via elaborating brain derived neurotrophic factor. Selegiline increases the striatal superoxide dismutase, protects against peroxynitrite- and nitric oxide-induced apoptosis, and guards dopaminergic neurons from toxicity induced by glutathione depletion. It stimulates the biosynthesis of interleukin 1-beta and interleukin-6, is an immunoenhancing substance, possesses antiapoptotic actions, and is neuroprotectant in nature. Selegiline has been shown to be efficacious in Parkinson's disease, global ischemia, Gille de la Tourette syndrome, and narcolepsy. Its therapeutic efficacy in Alzheimer's disease remains uncertain. In Alzheimer's disease, short term studies of selegiline suggest a beneficial effect; whereas long term studies are less convincing.
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PMID:Therapeutic efficacy of selegiline in neurodegenerative disorders and neurological diseases. 1710 May 91

In animal models of Parkinson's disease, a supersensitive response to dopamine (DA) is associated with a switch in the coupling of striatal DA D1 receptors from a cyclic AMP/protein kinase A signaling pathway to one involving extracellular signal-regulated kinase/mitogen-associated protein kinase. In this study, we found that generation of organotypic striatal cultures, with concomitant loss of DA innervation, led to a downregulation in preprotachykinin-A gene expression, which was reinstated by D1 receptor activation in an extracellular signal-regulated kinase/mitogen-associated protein kinase-dependent manner. These data demonstrate that acute organotypic slice cultures recapitulate important changes in D1 receptor-mediated signal transduction seen in DA-denervated animals, providing a valuable model system to study denervation effects on DA signaling and striatal gene expression.
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PMID:D1 receptor regulation of preprotachykinin-A gene by extracellular signal-regulated kinase pathway in striatal cultures. 1818 6

Neuronal burst firing in the subthalamic nucleus (STN) is one of the hallmarks of dopamine depletion in Parkinson's disease. Here, we have determined the postsynaptic effects of dopamine in the STN and the functional consequences of dopamine receptor modulation on burst firing in vitro. STN cells displayed regular spiking activity at a rate of 7.9+/-0.5 Hz. Application of dopamine (30 microM) induced membrane depolarisations accompanied by an increase in firing rate of mean 12.0+/-0.6 Hz in all 69 cells. The dopamine effect was mimicked by the dopamine D1/D5 receptor agonist SKF38393 (10 microM, 17 cells) and the dopamine D2-like receptor agonist quinpirole (10 microM, 35 cells), partly reduced by D1/D5 antagonist SCH23390 (2 microM, seven cells), but unaffected by the D2 antagonists sulpiride (10 microM, seven cells) or eticlopride (10 microM, six cells). Using voltage ramps, dopamine induced an inward current of 69+/-9.4 pA at a holding potential of -60 mV (n=17). This current was accompanied by an increase in input conductance of 1.55+/-0.35 nS which reversed at -30.6+/-2.3 mV, an effect mimicked by SKF38393 (10 microM, nine cells). Similar responses were observed when measuring instantaneous current evoked by voltage steps and in the presence of the I(h) blocker, ZD7288, indicating effects independent of I(h). The increase in conductance was blocked by SCH23390 (2 microM, n=4), mimicked by the activator of adenylyl cyclase forskolin (10 microM, n=7) and blocked by H-89, an inhibitor of cyclic AMP dependent protein kinase A (10 microM, n=6). These results indicate that the dopamine depolarisation is in part mediated by D1/D5 receptor mediated activation of a cyclic-nucleotide gated (CNG) non-specific cation conductance. This conductance contributes to the membrane depolarisation that changes STN neuronal bursting to more regular activity by significantly increasing burst duration and number of spikes per burst.
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PMID:Depolarisation and suppression of burst firing activity in the mouse subthalamic nucleus by dopamine D1/D5 receptor activation of a cyclic-nucleotide gated non-specific cation conductance. 1854 95

Salsolinol, an endogenous neurotoxin, is known to be involved in the neuropathy of Parkinson's disease and chronic alcoholism. In these diseases, increased thrombotic events are also commonly reported, yet the mechanism underlying remains poorly understood. Here we report that salsolinol can enhance agonist-induced platelet aggregation and granular secretion, which is essential in the thrombus formation. In rat and human platelets, agonist-induced platelet aggregation was significantly increased by salsolinol in a concentration-dependent manner. Agonist-induced granular secretions of serotonin and concomitant P-selectin expression were also augmented by salsolinol. alpha2-adrenergic blockers attenuated the salsolinol-enhanced aggregation and the inhibition of cyclic AMP generation was found, suggesting the involvement of alpha2-adrenergic receptor-mediated pathways in these events. In accord with the in-vitro results, in an arterial and venous thrombosis model in vivo in the rat, salsolinol shortened vessel occlusion time and increased thrombus formation, respectively. In conclusion, we demonstrated that salsolinol can enhance agonist-induced aggregation and granular secretion in platelets through alpha2-adrenergic receptor activation, which resulted in the increased thrombus formation in vivo. These results suggest that salsolinol-enhanced platelet aggregation could be a possible contributing factor to the thrombotic events observed in Parkinson's disease and alcoholism.
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PMID:Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation. 1861 38

The aim of this study is to investigate the changes of the pupil's light reflex (PLR) and mobility in Parkinson's disease (PD) patients with and without cognitive disorder. Twenty two (22) patients (ten males, twelve females, mean age: 72.7+/-7.3 years) with identified PD entered the study. The patients were examined with the Mini Mental State Examination (MMSE), the Wechsler II Memory Scale (WMS II) and the Hamilton Depression Scale (HAM-D17). Eleven (11) patients (five males, six females, mean age: 72.09+/-7.06 years) were free of any cognitive deficits and eleven (11) patients (five males, six females, mean age: 73.36+/-7.55 years) had cognitive disorder according to the aforementioned scales. None of the patients satisfied the DSM-IV-TR criteria for depression or anxiety disorder. The patients underwent a pupillometric study in both eyes with single flash stimuli of 24.6 candelas/m(2) intensity and 20 ms duration. The pupillometric parameters that were studied were: Latency for the onset of Constriction (T1), Baseline Pupil Radius (R1), Minimum Pupil Radius after the pupil reaction to light (R2), Amplitude (AMP, R1-R2), Time for maximum Miosis (T2), Maximum Constriction Velocity (VCmax) and Maximum Constriction Acceleration (ACmax). The pupillometric findings of each group were compared to those of an age and sex matched group of eleven healthy subjects. Furthermore, a comparison between the findings of the two groups was conducted. ACmax and VCmax were significantly lower in patients without (PD) and with coexisting cognitive impairment (PDC) compared to normal subjects (NC) (p<0.001). Patients with cognitive impairment (PDC) had significantly lower levels of ACmax, VCmax and AMP than patients without cognitive deficits (PD). Cognitive impairment in PD, which mainly reflects a central cholinergic deficit, may be a crucial pathogenetic factor for the decrease in the aforementioned pupillometric parameters. VCmax and ACmax can be considered as the most sensitive indicators of this central cholinergic deficiency.
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PMID:Pupillometric findings in patients with Parkinson's disease and cognitive disorder. 1904 1

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

Human embryonic stem (hES) cell differentiation into dopamine neurons is considered a promising strategy for cell replacement therapy in Parkinson's disease, yet the functional properties of hES cell-derived dopamine neurons remain poorly defined. The objective of this study was to characterize intracellular calcium (Ca(2+)) and sub-plasma membrane cyclic AMP-signaling properties in hES cell-derived dopamine neurons. We found that hES cell-derived dopamine neurons and neural progenitors raised Ca(2+) from intra- and extracellular compartments in response to depolarization, glutamate, ATP, and dopamine D(2) receptor activation, while undifferentiated hES cells only mobilized Ca(2+) from intracellular stores in response to ATP and D(2) receptor-induced activation. Interestingly, we also found that hES cell-derived dopamine neurons in addition to primary ventral midbrain dopamine neurons were more prone to release Ca(2+) from intracellular stores than non-dopamine neurons following treatment with the neuropeptide neurotensin. Furthermore, hES cell-derived dopamine neurons showed cAMP elevations in response to forskolin and 3-isobutyl-methylxanthine, similar to primary dopamine neurons. Taken together, these results unravel the temporal sequence by which hES cells acquire Ca(2+) and cAMP signaling competence during dopamine differentiation.
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PMID:Ca2+ and cAMP signaling in human embryonic stem cell-derived dopamine neurons. 2004 54

Autosomal-dominant striatal degeneration (ADSD) is an autosomal-dominant movement disorder affecting the striatal part of the basal ganglia. ADSD is characterized by bradykinesia, dysarthria, and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. Using genetic linkage analysis, we have mapped the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. A maximum LOD score of 4.1 (Theta = 0) was obtained at marker D5S1962. Here we show that ADSD is caused by a complex frameshift mutation (c.94G>C+c.95delT) in the phosphodiesterase 8B (PDE8B) gene, which results in a loss of enzymatic phosphodiesterase activity. We found that PDE8B is highly expressed in the brain, especially in the putamen, which is affected by ADSD. PDE8B degrades cyclic AMP, a second messenger implied in dopamine signaling. Dopamine is one of the main neurotransmitters involved in movement control and is deficient in Parkinson disease. We believe that the functional analysis of PDE8B will help to further elucidate the pathomechanism of ADSD as well as contribute to a better understanding of movement disorders.
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PMID:Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. 2008 14


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