Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopaminergic neurons of the midbrain are the main source of dopamine (DA) in the brain. DA has been shown to be involved in the control of movements, the signaling of error in prediction of reward, motivation, and cognition. Cerebral DA depletion is the hallmark of Parkinson's disease (PD). Other pathological states have also been associated with DA dysfunction, such as schizophrenia, autism, and attention deficit hyperactivity disorder in children, as well as drug abuse. DA is closely associated with reward-seeking behaviors, such as approach, consumption, and addiction. Recent researches suggest that the firing of DA neurons is a motivational substance as a consequence of reward-anticipation. This hypothesis is based on the evidence that, when a reward is greater than expected, the firing of certain DA neurons increases, which consequently increases desire or motivation towards the reward.
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PMID:Dopamine, learning, and reward-seeking behavior. 1832 Jul 25

Modafinil is a wake-promoting agent that is pharmacologically different from other stimulants. It has been investigated in healthy volunteers, and in individuals with clinical disorders associated with excessive sleepiness, fatigue, impaired cognition and other symptoms. This review examines the use of modafinil in clinical practice based on the results of randomized, double-blind, placebo-controlled clinical trials available in the English language in the MEDLINE database. In sleep-deprived individuals, modafinil improves mood, fatigue, sleepiness and cognition to a similar extent as caffeine but has a longer duration of action. Evidence for improved cognition in non-sleep-deprived healthy volunteers is controversial.Modafinil improves excessive sleepiness and illness severity in all three disorders for which it has been approved by the US FDA, i.e. narcolepsy, shift-work sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure (CPAP). However, its effects on safety on the job and on morbidities associated with these disorders have not been ascertained. Continued use of CPAP in obstructive sleep apnoea is essential. Modafinil does not benefit cataplexy.In very small, short-term trials, modafinil improved excessive sleepiness in patients with myotonic dystrophy. It was efficacious in fairly large studies of attention deficit hyperactivity disorder (ADHD) in children and adolescents, and was as efficacious as methylphenidate in a small trial, but has not been approved by the FDA, in part because of its serious dermatological toxicity. In a trial of 21 non-concurrent subjects, with 2-week treatment periods, modafinil was as effective as dexamfetamine in adult ADHD. Modafinil was helpful for depressive symptoms in bipolar disorder in a trial that excluded patients with stimulant-induced mania. A single dose of modafinil may hasten recovery from general anaesthesia after day surgery. A single dose of modafinil improved the ability of emergency room physicians to attend didactic lectures after a night shift, but did not improve their ability to drive home and caused sleep disturbances subsequently.Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness and depression in patients with traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue and multiple sclerosis; however, it did not provide any benefit greater than placebo.Trials of modafinil for excessive sleepiness in Parkinson's disease, cocaine addiction and cognition in chronic fatigue syndrome provided inconsistent results; all studies had extremely small sample sizes. Modafinil cannot be recommended for these conditions until definitive data become available.Modafinil induces and inhibits several cytochrome P450 isoenzymes and has the potential for interacting with drugs from all classes. The modafinil dose should be reduced in the elderly and in patients with hepatic disease. Caution is needed in patients with severe renal insufficiency because of substantial increases in levels of modafinil acid. Common adverse events with modafinil include insomnia, headache, nausea, nervousness and hypertension. Decreased appetite, weight loss and serious dermatological have been reported with greater frequency in children and adolescents, probably due to the higher doses (based on bodyweight) used. Modafinil may have some abuse/addictive potential although no cases have been reported to date.
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PMID:Approved and investigational uses of modafinil : an evidence-based review. 1872 34

Methylphenidate (MPH) is a central nervous system stimulant derived from an amphetamine and acts as a potent inhibitor of catecholamine reuptake and increases dopamine levels in the brain. Methylphenidate is widely used for the treatment of children and adults with attention deficit hyperactivity disorder. Because the dopaminergic system is critical to the pathological process in Parkinson disease (PD), it has been suggested that MPH, which increases dopaminergic stimulation at the postsynaptic receptor level, may provide symptomatic relief in PD patients. This article reviews those studies that have evaluated the potential of MPH to treat the motor and cognitive aspects of PD, summarizes the evidence for clinical use in other neurological diseases, and briefly reviews the physiological mechanisms whereby MPH may bring about its therapeutic effects. Methylphenidate does seem to be useful for ameliorating cognitive, affective, and motor deficits in PD and in other neurological patients; however, additional studies are needed before MPH can be routinely prescribed as an adjunct therapy in these populations.
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PMID:Methylphenidate for the treatment of Parkinson disease and other neurological disorders. 1897 88

Executive dysfunction (ED) is a prominent and often disabling feature of cognitive impairment in Parkinson's disease (PD). Few studies have examined treatments. Given the role of noradrenergic pathology in ED, atomoxetine, a norepinephrine reuptake inhibitor indicated for attention deficit hyperactivity disorder (ADHD), may be a potential treatment for PD-related ED. Twelve patients with PD and disabling ED completed an 8-week pilot open-label, flexible dose (25-100 mg/day) trial of atomoxetine. On primary outcome measures, atomoxetine was associated with improved ED based on the Clinical Global Impression-Change Scale (75% positive response rate; 95% CI: 43-95%, P < 05) and behavioral measures of ED [Frontal Systems Behavior Scale (FrSBE) Executive Dysfunction and Connors Adult ADHD Rating Scale (CAARS) inattention/memory subscales]. Adverse effects included sleep and gastrointestinal disturbances and hypomania. Atomoxetine is tolerable in PD and may benefit clinical manifestations of ED, warranting further study in controlled trials.
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PMID:Atomoxetine for the treatment of executive dysfunction in Parkinson's disease: a pilot open-label study. 1902 77

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson's disease, and Huntington's disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.
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PMID:Pharmacological treatment effects on eye movement control. 1902 66

Phosphodiesterases (PDEs) represent important cornerstones of cGMP signaling in various tissues. Since the discovery of PDE activity in 1962, it has become clear that the functional characteristics of PDEs and their role in cyclic nucleotide signaling are fairly complex. On the one hand, members of the PDE family responsible for the hydrolysis of cGMP affect cellular responses by shaping cGMP signals derived from the activation of soluble cytosolic and/or membrane bound particulate guanylyl cyclases. Conversely, PDEs may function as downstream effectors in the cGMP signaling cascade. To make things even more sophisticated, cGMP modulates the activity of several PDEs either directly, by binding to a regulatory domain, or indirectly, through phosphorylation, and the result can be either inhibition or stimulation of the enzyme, depending on the subtype. Furthermore, cross-talk between cGMP and cAMP signaling is achieved by cGMP-dependent modulation of PDEs hydrolyzing cAMP and vice versa. Mammals possess at least 21 PDE genes and often express a set of PDEs in a tissue- and differentiation-dependent manner. Given these premises, it is still a challenging task to elucidate the physiological function(s) of individual PDE genes. The present chapter focuses on the role of PDEs as regulators of neuronal functions. Useful information regarding this topic has been gained by studying (1) the expression pattern of PDEs in the CNS, (2) the association of PDEs with specific macromolecular signaling complexes and (3) the phenotypes associated with mutations or ablation of PDE genes in man, mice and fruit flies, respectively. PDEs degrading cGMP and/or being regulated by cGMP have been implicated in cognition and learning, Parkinson's disease, attention deficit hyperactivity disorder, psychosis and depression. Correspondingly, modulators of PDEs have become attractive tools for treatment of these disorders of CNS function.
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PMID:Phosphodiesterases in the central nervous system. 1908 26

The neural circuit connecting the cerebral cortex and the basal ganglia mediates a variety of brain functions including voluntary movement, motor learning, and reinforcement learning. These functions are dependent on midbrain dopamine systems that innervate the prefrontal cortex and the striatum. The pathogenesis of certain neurological and neuropsychiatric diseases involves the dysfunction of these dopamin systems; some of these diseases include Parkinson's disease, schizophrenia, and attention deficit hyperactivity disorder. To understand the physiology and pathology of brain functions, the mechanisms of neural circuitry that controls behaviors should be studied. Immunotoxin-mediated cell targeting is an approach employed in transgenic animals to eliminated specific neuronal types from a neuronal circuitry. This approach has been used to study the neural circuit mechanism in the central and peripheral nervous systems. Here, we describe the use of immunotoxin-mediated cell targeting for studying the neural circuitry that underlies the motor behavior demonstrated in response to systemic dopamine stimulation; further, we propose the potential mechanism that controls direct and indirect striatal pathway-dependent behavior.
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PMID:[Functional analysis of the roles of direct and indirect pathways by using immunotoxin-mediated cell targeting approach]. 1937 11

Restless legs syndrome (RLS) is characterized by paraesthesias-dysesthesias and motor restlessness worsening at rest-in the evening, with at least temporary relief by activity. Its etiology is unknown, though it could be secondary to various conditions. It is well known, however, that dopamine plays a crucial role in the pathophysiology of RLS, as dopaminergic agonists achieve marked improvement. Pramipexole is a nonergoline compound with selectivity for D3 dopamine receptors. This drug is very effective in the treatment of idiopathic and secondary RLS and in treatment-resistant patients, as shown by double-blind, placebo-controlled studies in adults. In children, studies are much more limited, and RLS is often misdiagnosed as "growing pain" or attention deficit hyperactivity disorder. Pramipexole has been successful in open studies, eliminating clinical symptoms. This medication has the advantage of being free of the frequently encountered problems seen with ergot derivatives. The side-effects are limited, particularly at the dosages usually prescribed for RLS treatment: They are much lower than in Parkinson's disease, and inappropriate sleepiness and sleep attacks, particularly while driving, or compulsive behavior have not been seen. Compared with the adverse reactions of levodopa, including tolerance, rebound, and augmentation phenomena in RLS, which led to usage of dopamine agonists as first line of treatment for RLS, pramipexole has had one of the best profiles. Augmentation can still be noted with the drug, but after longer usage time compared with many other dopamine agonists. Although excessive daytime sleepiness has been noted, sleep attacks have not been encountered in RLS patients treated with pramipexole.
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PMID:Pramipexole: new use for an old drug - the potential use of pramipexole in the treatment of restless legs syndrome. 1941 89

Intraindividual variability (IIV) reflects lawful but transient within-person changes in performance. Increased IIV in cognition shares systematic associations with numerous conditions characterized by alterations in dopamine (DA) neuromodulation (e.g., old age, ADHD, schizophrenia, and Parkinson's disease). In a group of normal middle-aged adults, we examined links between PET-derived measures of D2 receptor binding in striatum, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and hippocampus (HC) and IIV for tasks assessing recognition memory and executive functioning. An index of IIV, the intraindividual standard deviation (ISD), was computed across successful response latency trials for each cognitive outcome. Lower D2 binding in OC, ACC, and HC, but not striatum, was associated with increasing ISDs for the memory and executive measures. Consistent with neurocomputational models, the present findings suggest a role for extrastriatal DA neurotransmission in modulating variability in cognitive functioning.
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PMID:Extrastriatal dopamine D2 receptor binding modulates intraindividual variability in episodic recognition and executive functioning. 1952 93

Dopamine signaling is involved in a number of brain pathways, and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo- and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine-based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control.
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PMID:Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals. 1967 Mar 15


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