Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Individual neurons were recorded extracellularly in the precentral forelimb area of two monkeys trained to perform rapid, large amplitude flexion and extension movements of the contralateral forearm in response to auditory signals. Electromyographic (EMG) activity in the biceps/triceps muscles was recorded separately under the same conditions. The dopaminergic (DA) neurons of the substantia nigra (SN) were destroyed selectively by repeated series of intravenous injections of MPTP. The lesion was verified on serial slices using both tyrosine hydroxylase immunocytochemistry and classical staining methods. 2. In normal monkeys, the frequency of firing of precentral neurons shows rapid changes shortly before the onset of displacement. In our sample (n = 102), most of the neurons (49%) tested during movement in both directions (flexion, extension) showed a reciprocal pattern of activity for the two directions of movement, a small percentage (19%) exhibited a change for only one direction (unidirectional neurons), and the remaining 32% displayed a similar change for both directions of movement (bidirectional neurons). 3. In MPTP-treated monkeys, movement-related modification of neuronal activity was more gradual, beginning earlier and lasting longer relative to the onset of movement. The cellular reaction time (the time between the auditory cue and a significant change in neuronal activity) was not significantly altered. Spontaneous firing of precentral neurons (n = 124) did not increase significantly, and the dynamic discharge rate was unchanged after the nigral lesion. However, only 18% of cortical neurons still presented a reciprocal pattern of discharge for the two directions of movement, while the percentage of unidirectional neurons increased (50%), and the percentage of bidirectional neurons remained the same (32%). 4. After MPTP treatment, alterations in movement parameters and EMG activity were observed. Mean reaction time and movement duration increased by 20-25% and 25-30% respectively. The movements were slower and were associated with a generalized depression in the shape and the amplitude of EMG activity in the agonist muscle. 5. The neuronal basis for the observed central and peripheral disturbance in the MPTP-treated monkeys is discussed. We conclude that SN lesion leads to two main disturbances of cortical activity: i) the loss of the reciprocal pattern of response of movement-related cortical cells, and ii) an inability of the motor cortex to modify its activity in response to peripheral input.
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PMID:Modifications of precentral cortex discharge and EMG activity in monkeys with MPTP-induced lesions of DA nigral neurons. 197 80

Possibility of ortho-, para-, meta-methylphenyl and methoxyphenyl-derivates of MPTP to produce parkinsonism was investigated. Only ortho-methylphenyl- and ortho-methoxyphenyl-derivates of MPTP cause a persistent loss in dopamine content in the brain and produced the clinical symptoms of parkinsonism. All substances produced Parkinsonian-like syndrome gives the symptoms of activation of nervous system during 0.5-1 h after injection and symptoms of depression in following 3 h of observations.
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PMID:[Clinical and biochemical parameters of parkinsonism induced by 1-methyl-4-phenyl-1,2,2,6-tetrahydropyridine and its methyl-phenyl and methoxy-phenyl derivatives in C57Bl/6 mice]. 227 92

Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B). It also inhibits the reuptake of catecholamines into the presynaptic nerve and enhances the synthesis of dopamine by blocking the presynaptic dopamine autoreceptors. Thanks to these properties it potentiates and prolongs the duration of action of levodopa. Several clinical trials have shown its efficacy as an adjuvant to levodopa therapy. Improvement in parkinsonian disability and reduction of fluctuations in disability can be achieved by adding selegiline to the prevailing levodopa therapy. End-of-dose type fluctuations, in particular, react favourably to selegiline. Side-effects of the therapy can be managed by reducing the dose of levodopa. According to preliminary studies selegiline may also have some benefit as monotherapy in de novo parkinsonian patients. High doses of selegiline have been found to have some antidepressant efficacy, especially in patients with nonendogenous depression. It may also have an effect on bradyphrenia and some symptoms of cognitive dysfunction and dementia. In animal models selegiline has been shown to prevent parkinsonism caused by MPTP and also to increase the life span of rats. Whether selegiline slows down the progression of Parkinson's disease needs further examination.
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PMID:Selegiline in the treatment of Parkinson's disease. 251 15

Idiopathic Parkinson's disease has been postulated to result from exposure to environmental toxins similar to the parkinsonism-causing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This study examines the interactions of MPTP with the cytochrome P-450 system--an enzyme system which is known to be involved in the detoxication of MPTP. In vitro studies, using control hepatic microsomes, studied changes in cytochrome P-450 content and enzyme activity with varying concentrations of MPTP and substrates. In vivo liver and brain studies were conducted using groups of 4 animals treated intraperitoneally with varying doses of MPTP and sacrificed at varying time intervals after treatment. Changes in cytochrome P-450 enzyme contents and activities were determined using standard analytical procedures. MPTP was found from in vitro studies to cause a mixed non-competitive inhibition of cytochrome P-450 dependent ethoxyresorufin O-dealkylase activity with an inhibition constant (Ki) of 0.06 mM. Two binding sites of MPTP to hepatic cytochrome P-450 were found by spectral perturbation studies--the higher affinity site binding about a hundred times more avidly to MPTP than the other. In vivo studies showed a depression of cytochrome P-450 content and activity in a dose-dependent manner. Cytochrome P-450 levels were lowest 3 to 6 hours after treatment with MPTP. MPTP was also found to cause a dose-dependent decrease in the cytochrome P-450 enzyme activities bufuralol hydroxylase (buf) and aryl hydrocarbon hydroxylase (AHH) in the brain. Bufuralol hydroxylase activity was found to be about 2000 times more sensitive than aryl hydrocarbon hydroxylase to the effects of MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies on the interactions of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with the cytochrome P-450 enzyme system--clues to a possible aetiological factor in Parkinson's disease. 278 64

The effects of the neurotoxic compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the hepatic cytochrome P-450 monooxygenase system were assessed using C57 BL/6J mice. Treatment with MPTP caused a marked depression of hepatic cytochrome P-450 content, ethoxyresorufin O-dealkylase and NADPH cytochrome C reductase activities. This effect was maximal 3 to 6 hours after treatment and was dependent on the dose of MPTP administered. Depression of spectrophotometrically measured cytochrome P-450 content was associated with increase in cytochrome P-420 content and lipid peroxidation. In vitro studies showed the formation of a metabolic-intermediate complex with cytochrome P-450 which may partially explain the depression of cytochrome P-450 content and activity by MPTP.
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PMID:Depression of the hepatic cytochrome P-450 monooxygenase system by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 278 11

The results reported here indicate that treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused significant changes in the dopamine-synthesizing enzyme, tyrosine hydroxylase. The authors examined the effects of two doses of MPTP on the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) in the striatum, and also the time-course of these effects. Rats received an intraperitoneal loading dose, followed by a 24-hr infusion of MPTP (total doses of 21 or 42 mg) from subcutaneously-implanted osmotic pumps. Seven days after treatment, the activity of tyrosine hydroxylase was decreased by MPTP (42 mg); however, the activity of tryptophan hydroxylase was not affected. In time-course experiments, the activity of tyrosine hydroxylase was maximally reduced at 3 and 7 days after treatment with MPTP (42 mg). The activity of tryptophan hydroxylase did not significantly change at any time-point. Concurrent administration of haloperidol (HALO; 2 mg/kg, 4 doses) with MPTP significantly enhanced the depression of the activity of tyrosine hydroxylase in the striatum caused by MPTP, while treatment with haloperidol alone had no such effect. Concentrations of dopamine in the striatum were maximally decreased to approx. 50% of control in animals treated with haloperidol and MPTP (42 mg), whereas treatment with MPTP alone decreased concentrations of dopamine to approx. 70% of control.
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PMID:Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal tyrosine hydroxylase and tryptophan hydroxylase in rat. 287 13

In Charles River CFW mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused lethality with an LD50 of 53.8 mg/kg s.c. In mice pretreated with deprenyl, no lethality occurred with MPTP doses up to 110 mg/kg s.c. MPTP alone at doses of 30 to 90 mg/kg s.c. caused marked salivation, licking and grooming, hyperlocomotion, hyperreactivity and convulsions during the 1st hr, followed by depression, continued salivation and respiratory distress at 2 to 3 hr and at longer times, with death occurring at the higher doses. In deprenyl-pretreated mice, MPTP produced only mild and transient effects. 1-Methyl-4-phenylpyridinium (MPP+) was more potent in causing lethality than was MPTP, and deprenyl did not affect its lethality. MPTP lethality was not antagonized by EXP 561 [4-phenyl-bicyclo-(2,2,2)octan-1-amine hydrochloride monohydrate], an uptake inhibitor that prevented the neurotoxic effects of a lower dose of MPTP on striatal dopamine and cortical norepinephrine neurons. In addition to deprenyl, other monoamine oxidase (MAO) inhibitors effective in inhibiting MAO-B (MD 240928 (R-3-[4-((3-chlorophenyl)methoxy)phenyl]-5-[(methylamino)methyl]-2- oxazolidinone methanesulfonate) and pargyline) protected against MPTP-induced lethality, but LY 51641 (N-[2-(o-chlorophenoxy)ethyl]cyclopropylamine hydrochloride) (a selective inhibitor of MAO-A) did not. The protective effect of deprenyl against MPTP-induced lethality was dose-dependent over a dose range of 0.01 to 10 mg/kg; in this range deprenyl inhibited MAO type B (MAO-B) in brain and liver. A 10-mg/kg i.p. dose of deprenyl antagonized MPTP-induced lethality as long as 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Deprenyl antagonizes acute lethality of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. 314 9

The changes occurring during the first few hours after subcutaneous administration of the catecholaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were investigated. Injections of MPTP (30-60 mg/kg s.c.) reduced the impulse rate by 12-45% in all dopaminergic neurones tested in the pars compacta of the substantia nigra. Depressions were maximal at 11 min and remained present for more than 2 hr after injection. This effect was completely abolished by prior administration of the catecholamine uptake inhibitor, nomifensine (13-69 mg/kg s.c.), which prevents the toxic metabolite of MPTP 1-methyl-4-phenylpyridine (MPP+) from entering dopaminergic neurones. These results suggest an intraneuronal mechanism underlying the observed depressions in impulse rate. Levels of dopamine (DA) were decreased at 3 hr after administration of MPTP (50 mg/kg s.c.) by 60% and 54% in the striatum and substantia nigra, respectively. Pretreatment with nomifensine (25 mg/kg, intraperitoneally) prevented the decrease in DA only in the striatum. This suggests an acute DA-releasing effect of MPTP in the striatum, mediated by intracellular accumulation of MPP+, while not explaining the depression of activity of DA neurones occurring with a different time course.
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PMID:Acute electrophysiological and neurochemical effects of administration of MPTP in mice. 326 84

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces symptoms similar to idiopathic Parkinson's disease in primates. A metabolite of MPTP, MPP+ (1-methyl-4-phenylpyridinium), is actively accumulated by dopaminergic (DA) terminals and selectively destroys nigrostriatal DA neurons. The mechanism of this effect remains unknown but reports that MPP+ inhibits electron transport in isolated mitochondria and increases oxidation of cytochrome b in striatal slices suggest that depression of ATP production is involved. To relate metabolic effects of MPP+ with tissue electrophysiology, extracellular potassium ion activity [K+]o was measured by microelectrodes simultaneous to optical monitoring of reduction/oxidation (redox) activity of cytochrome b during superfusion of MPP+ onto rat striatal and hippocampal slices. MPP+ increased oxidation of cytochrome b and increased [K+]o in slices of striatum. These increases were greater than expected from a selective effect of MPP+ on DA terminals which likely comprise no more than 3% of the total striatal mass. These effects of MPP+ were slowed by a dopamine uptake inhibitor (mazindol) and did not occur in hippocampal slices. These findings indicate that MPP+ influences ion transport as well as metabolic activity and that these actions require the presence of functioning DA terminals. However, the large amplitudes of the MPP+-induced changes suggest that consequences of MPP+-neurotoxicity are not ultimately confined to DA terminals. Two hypothesis are proposed: that energy failure in DA terminals results in leakage of neurotoxic substances or metabolites altering membrane conductance properties of adjacent cells and thereby placing additional demand upon ion transport pumps and mitochondrial oxidative phosphorylation; or that there is secondary uptake of MPP+ leading to mitochondrial inhibition in cells neighboring DA terminals.
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PMID:MPP+-induced increases in extracellular potassium ion activity in rat striatal slices suggest that consequences of MPP+ neurotoxicity are spread beyond dopaminergic terminals. 326 70

Unilateral injection of MPTP into the pars compacta of the substantia nigra in rats induced contraversive turning immediately after the injection. Contraversive turning decreased, and reversed its direction after about 30 min. Ipsiversive turning was still present 24 h after the injection of MPTP. These results suggest that MPTP has an initial stimulatory effect on dopaminergic neurons followed by a depression of the activity of these cells.
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PMID:Unilateral intranigral injection of MPTP in the rat induces contraversive turning. 349 64


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