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)

Selegiline (10 mg per day) selectively inhibits monoamine oxidase type B and thus thwarts the metabolism of dopamine by this enzyme. Selegiline has been used in the therapy of Parkinson's disease since 1986. It enhances the efficacy of levodopa, allows a reduction of the levodopa dose, and improves fluctuations in disability. It also interacts with mechanisms suspected of playing a role in the progression of the disease. Animal studies have shown that selegiline prevents the development of a Parkinson-like syndrome induced by the neurotoxin MPTP. It decreases oxidative stress resulting from the metabolism of dopamine via MAO-B. Clinical studies have shown that selegiline is effective in the therapy of untreated de novo patients: the progression of symptoms demanding the introduction of levodopa into the therapy was delayed, and the risk of needing levodopa treatment within one year was reduced by 57% with selegiline. The mode of action of this drug in the treatment of early Parkinson's disease is still under discussion. There is strong evidence that selegiline may slow the progression of the disease, but a direct symptomatic effect cannot be excluded.
 ...
PMID:Selegiline--an overview of its role in the treatment of Parkinson's disease. 160 Mar 60

Irreversible and unspecific inhibitors of MAO were the first modern antidepressants, but after an initial success they fell into discredit due to adverse side effects. In the past two decades interest in MAO inhibitors has been renewed because of progress in basic research, a milestone being the finding that there are two subtypes of MAO, MAO-A and MAO-B. These are distinct proteins with high amino acid homology, coded by separate genes both located on the short arm of the human chromosome X. The enzyme subforms show different substrate specificities in vitro and different distributions within the central nervous system and in peripheral organs. In the central nervous system of man MAO-A seems to be mainly involved in the metabolism of 5 HT and noradrenaline, whereas 2-phenylethylamine and probably dopamine are predominantly deaminated by MAO-B. In the intestinal tract tyramine is mainly metabolized by MAO-A. These characteristics indicate distinct physiological functions of the two MAO-subforms. Several irreversible and reversible non-hydrazine inhibitors with relative selectivities for one of the MAO-subforms have been developed. They belong to various chemical classes with different modes of enzyme inhibition. These range from covalent mechanism based interaction (e.g. by propargyl- and allylamine derivatives) to pseudosubstrate inhibition (e.g. by 2-aminoethyl-carboxamides) and non-covalent interaction (e.g. by brofaromine, toloxatone and possibly moclobemide). The most important pharmacological effects of the new types of MAO inhibitors are those observed in neuropsychiatric disorders. The inhibitors of MAO-A show a favorable action in various forms of mental depression. The drugs seem to have about the same activity as other types of antidepressants, including tricyclic and related compounds as well as classical MAO inhibitors. The onset of action of the MAO-A inhibitors is claimed to be relatively fast. Other possible indications of these drugs include disorders with cognitive impairment, e.g. dementia of the Alzheimer type. In subjects with Parkinson's disease the MAO-B inhibitor L-deprenyl exerts a L-dopa-sparing effect, prolongs L-dopa action and seems to have a favorable influence regarding on-off disabilities. The action is in general transitory (months to several years). In addition L-deprenyl has been shown to delay the necessity for L-dopa treatment in patients with early parkinsonism. Whether the drug influence the progression of the disease is still a matter of debate. L-deprenyl also appears to have some antidepressant effect (especially in higher doses) and to exert a beneficial influence in other disorders, e.g. dementia of the Alzheimer type.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:The new generation of monoamine oxidase inhibitors. 160 14

Recent developments on the clinical and therapeutic aspects of idiopathic Parkinson's disease (IPD) have focused on the role of monoamine oxidase B inhibition in IPD, strategies to manage the long-term levodopa (L-dopa) syndrome and attempts to replace nigral tissue by grafting. In addition, tools for community screening and possible identification of an 'at-risk' as well as presymptomatic population of sufferers have been suggested.
 ...
PMID:Parkinson's disease: clinical and therapeutic aspects. 162 54

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. (1) It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only MAO-B inhibitor in clinical use. (2) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not displace the transmitter from storage, ie, it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and, at present, is the only safe MAO inhibitor that can be administered without dietary precautions. (3) Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. (4) Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (5) Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significantly lengthens the life-span as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease. Newly diagnosed Parkinson's disease patients maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly the performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:(-)Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system. 163 30

Metals such as lead, zinc, copper, aluminum and manganese have been implicated in neuropsychiatric disorders. However, until fairly recently the role of iron in brain function was rather obscure, because little attention was paid to its metabolism in the brain. It is now apparent that maintenance of brain iron homoeostasis is important for the normal functioning of his organ. Most of the studies have been directed towards the cognitive and attentional deficit resulting from nutritional iron deficiency. Evidence so far suggests subsensitivity of striatal dopamine neurotransmission. By contrast the selective increase in free iron in the substantia nigra pars compacta of parkinsonian brains is thought to initiate oxidative stress, from iron-induced liberation of cytotoxic oxygen free radicals. Such radicals are known to promote membrane fluidity, alteration in cellular calcium homoeostasis, lipid peroxidation and finally cell death in systemic organs. Evidence supporting similar processes being responsible for nigrostriatal dopamine neuron degeneration in Parkinson's disease is now becoming available. Such possibilities afford the development of neuroprotective drugs as a means to retard the progression of this disorder. These include other selective monoamine oxidase B inhibitors, iron chelators with the ability to cross the blood-brain barrier, selective calcium channel antagonists and mitochondrial electron transport system protectors.
 ...
PMID:Iron in brain function and dysfunction with emphasis on Parkinson's disease. 164 57

1-Methyl-3-phenyl-1,2,3,6-tetrahydropyridine (M-3-PTP) is an analogue to the Parkinson-producing dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), M-3-PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M-3-PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M-3-PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10-fold increase in the level of 3-methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M-3-PTP produced no acute or long-term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M-3-PTP does not inhibit monoamine oxidase B. Thus, the present data show that M-3-PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M-3-PTP for monoamino oxidase B.
 ...
PMID:Investigation of the possible dopaminergic toxicity of 1-methyl-3-phenyl-1,2,3,6-tetrahydropyridine, an isomer to the neurotoxin MPTP. 168 9

Deprenyl slows the progression of disabling symptoms in Parkinson's disease (PD) by an unknown mechanism. It can block the action of MPTP on substantia nigra compacta (SNc) neurons by inhibiting monoamine oxidase B necessary to mediate the conversion of MPTP to MPP+, its active metabolite, in astroglia. Mice were pretreated with saline or the PD-producing toxin, MPTP (30 mg/kg) daily for 5 days and then after a further 3 days (to allow for the metabolism and excretion of the MPTP) were treated with deprenyl (0.25 or 10 mg/kg) or saline 3 times weekly for 20 days. In three series of mice treated with MPTP alone or MPTP-saline, serial sections through the SNc showed that averages of 37-42% of tyrosine hydroxylase (TH) immunoreactive neurons were lost gradually over 20 days. Joint counts of the numbers of TH-immunoreactive and Nissl-stained SNc somata from immediately adjacent sections established that the reductions in the numbers of TH-immunoreactive somata at 20 days after MPTP treatment represented neuronal death. Deprenyl treatment reduced the loss of TH-immunoreactive SNc neurons to averages of 14-16% for the 10-mg/kg and 0.25-mg/kg doses, respectively, and joint Nissl/TH counts for adjacent sections showed that reduction in the loss of TH-immunoreactive soma represented the rescue of SNc neurons that would have died by 20 days. The gradual loss of SNc neurons over the 20 days following MPTP exposure may reflect the toxin's axotomy-like effects on SNc neurons or the prolonged action of sequestered MPP+.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. 168 84

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.
 ...
PMID:A review of the pharmacology of selegiline. 168 54

Enzymes involved with the metabolic transformation of xenobiotics have recently been studied in patients with the neurodegenerative diseases, Alzheimer's disease, Parkinson's disease and motor neurone disease. Defects were detected in sulphur pathways and also, in the case of Parkinson's disease, in monoamine oxidase B. The possibility exists that the ability to cope safely with endogenous and exogenous substances which have neurotoxic properties is important in the pathogenesis of these diseases. Potentially such individuals could be identified preclinically and these diseases postponed by reduction in the load of toxin or modification of the relevant enzymic activity.
 ...
PMID:Hereditary variation of liver enzymes involved with detoxification and neurodegenerative disease. 174 11

Eighteen patients with Parkinson's disease were treated with placebo for 4 weeks and with the MAO-B inhibitor selegiline for 8 weeks without levodopa in a randomized double-blind clinical study. The maximum dose of selegiline was 30 mg/day and the patients' cognitive functions were evaluated before treatment and at week 12 when they were either on 30 mg selegiline or placebo. A series of neuropsychological tests were used to study general cognitive reasoning, memory, visuospatial abilities, attention, cognitive flexibility, motor functions and depression. Specific cognitive effects were not observed. Slight improvement occurred mainly in learning (easy word associations) which may reflect a limited, nonspecific arousal effect.
 ...
PMID:Selegiline and cognitive function in Parkinson's disease. 177 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>