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)

Amantadine is an effective drug for treatment of both, Parkinson's disease and viral infections. Side effects of amantadine include anemia, which may limit its therapeutic use. The cause of amantatine induced anemia is ill defined. At least in theory, the anemia could partially result from suicidal erythrocyte death or eryptosis, which accelerates the clearance of circulating erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Triggers of erythrocyte membrane scrambling include an increase of cytosolic Ca2+ concentration ([Ca2+]i) resulting from activation of Ca2+-permeable cation channels. The present study has been performed to test for an effect of amantadine on eryptosis. Erythrocytes from healthy volunteers were exposed to amantadine and annexin V binding (disclosing phosphatidylserine exposure), forward scatter (reflecting cell volume), and Fluo3-dependent fluorescence (reflecting [Ca2+]i) were determined by flow cytometry. Exposure of erythrocytes to amantadine (> or =0.2 microg/ml) increased [Ca2+]i and triggered annexin V binding, and increased forward scatter. The effect on annexin V binding was virtually abolished in the absence of extracellular Ca2+. The present observations disclose mechanisms presumably contributing to amantadine induced anemia.
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PMID:Stimulation of suicidal erythrocyte death by amantadine. 1820 39

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIMs. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the anti-dyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIMs or contraversive rotation. In addition, in L-DOPA-primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIMs, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIMs. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism.
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PMID:MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism. 2007 62

Amantadine (AMA) is an uncompetitive antagonist of the N-methyl-d-aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF-1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg(-1) ) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step-down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg(-1) AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3-day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity.
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PMID:DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine. 2057 81

To investigate the possible efficacy of amantadine in the control of pathological gambling (PG) associated with Parkinson disease (PD), 17 PD patients with PG were randomly selected for a double-blind crossover study with amantadine 200mg/day versus placebo and an open follow-up. Assessments included PG-specific scales (Yale-Brown Obsessive-Compulsive Scale for PG, Gambling-Symptom Assessment Scale, South Oaks Gambling Screen) and assessment of expenditures and time spent gambling. Amantadine abolished or reduced PG in all treated patients, as confirmed by scale score and daily expenditure reduction. Amantadine might be useful to treat PG. The effect of amantadine, acting as an antiglutamatergic agent, also opens new insights into the pathogenesis of PG.
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PMID:Pathological gambling in Parkinson disease is reduced by amantadine. 2128 95

Amantadine is becoming more commonly used for Parkinson's disease (PD), particularly for its efficacy in treating the drug-induced dyskinesias. Corneal edema is a known but unusual side effect of amantadine therapy, rarely reported in the neurological literature. We report amantadine-induced reversible corneal edema in a patient with advanced PD.
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PMID:Amantadine induced reversible corneal edema. 2116 53

The antiviral agent amantadine has been used to manage Parkinson's disease or levodopa-induced dyskinesias for nearly 5 decades. Amantadine is often associated with hallucinations as an adverse effect, but a long-term study reported no serious motor complications. We describe an unusual patient who had Parkinson's disease with dropped head syndrome (DHS) caused by amantadine. When the patient, who had DHS while receiving only 2 kinds of antiparkinsonian drugs, was rechallenged with amantadine, DHS developed, accompanied by increased muscle tone in the neck muscles on surface electromyogram. The DHS resolved after the withdrawal of amantadine. Moreover, an intravenous infusion of levodopa did not alter the DHS. These findings collectively suggest that the DHS in our patient was most likely caused directly by amantadine. Our findings suggest that amantadine may carry the risk of augmenting dystonic syndrome in humans.
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PMID:Dropped head associated with amantadine in Parkinson disease. 2124 45

Dementia with Lewy-bodies (DLB) and Parkinson's disease dementia (PDD) are no rare causes of dementia. Both have neuropathologically, clinically, and neurochemically much in common. In the course of both conditions frequently psychotic symptoms occur, often induced by antiparkinsonian medication. Treatment of psychotic features with conventional antipsychotics is not tolerated in many cases. Therefore low-dose clozapine treatment is acknowledged usual practise for psychosis in Parkinson's disease and a case report indicates efficacy for psychosis in DLB, too. All other atypical antipsychotics except risperidone are not licensed for dementia in Germany, but risperidone is contraindicated in DLB due to manufacturer's notice and usually not well tolerated in DLB and Parkinson's disease. Open trials indicate safety for treatment of psychosis in DLB and PDD with quetiapine. Randomized controlled trials indicate, that quetiapine is less effective than clozapine against psychotic symptoms in both conditions, although comparatively safe. Cholinesterase inhibitors, especially rivastigmine, are a therapeutic alternative for treating both psychotic and cognitive symptoms in both conditions. Parkinsonism in DLB-patients responds worse to levodopa compared to patient with Parkinson's disease. Anticholinergic drugs often induce delirium in demented patients and therefore should be avoided. The same problem is associated with dopamine agonists in PDD and DLB. Amantadine, a NMDA-receptor antagonist like memantine, potentially bears the same risk of worsening psychotic symptoms. The following preliminary recommendation for drug treatment of PDD and DLB can be given: Stop all anticholinergic medication and reduce levodopa and other antiparkinsonian medication to the tolerated minimum. Levodopa alone is preferred. Treat with cholinesterase inhibitors to the maximum tolerated dose. If there is no adequate response regarding psychotic symptoms, add quetiapine. If this approach fails, replace quetiapine by low-dose clozapine. If behavioural disturbances are due to depression, anxiety, or irritability, treatment with an antidepressant, preferably citalopram, is an option.
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PMID:[Drug treatment of dementia with Lewy bodies and Parkinson's disease dementia--common features and differences]. 2142 15

Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson's disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotective capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP(+) or lipopolysaccharide (LPS), two toxins commonly used as PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP(+)-induced toxicity of dopamine neurons through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factors such as GDNF from astroglia. Lastly, differently from the general view on amantadine's action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia.
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PMID:Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia [corrected]. 2158 98

Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents.
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PMID:Therapies for dopaminergic-induced dyskinesias in Parkinson disease. 2202 28

Amantadine is currently used as an antiviral and an antiparkinsonian drug. Although the drug is known to bind a viral proton channel protein, the mechanism of action in Parkinson's disease (PD) remains to be determined. This study investigated whether the drug has an inhibitory effect on microglial activation and neuroinflammation, which have been implicated in the progression of neurodegenerative processes. Using cultured microglial cells, it was demonstrated that the drug inhibited inflammatory activation of microglia and a signaling pathway that governs the microglial activation. The drug reduced the expression and production of proinflammatory mediators in bacterial lipopolysaccharide-stimulated microglia cells. The microglia-inhibiting activity of amantadine was also demonstrated in a microglia/neuron coculture and animal models of neuroinflammation and Parkinson's disease. Collectively, our results suggest that amantadine may act on microglia in the central nervous system to inhibit their inflammatory activation, thereby attenuating neuroinflammation. These results provide a molecular basis of the glia-targeted mechanism of action for amantadine.
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PMID:Microglia-inhibiting activity of Parkinson's disease drug amantadine. 2203 88


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