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In addition to the previously known induction of anti-apoptosis genes, selegiline significantly increased the mRNA level of Notch 1 receptor and its ligand Jagged 1. Immunohistochemistry demonstrated elevated Notch 1 and Jagged 1 immunoreactivities in the peri-infarct region. Double labeling with glial markers revealed that both Notch 1 and Jagged 1 were expressed in astrocytes but not in microglia. MRI examination indicated significantly reduced edema in selegiline-treated rats compared to control MCAO rats, and increased capillary network density was found in the peri-infarct region of the selegiline-treated animals.
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These results suggest that not only does 3-Me-N-proTIQ have potential as a candidate compound for disease-modifying therapy for PD, but also the N-propargyl functional group plays an important role in neuroprotection.
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The effect of (+)- and (-)-tranylcypromine (TCP), (-)-deprenyl and pargyline was tested and the interaction of these MAO inhibitors with tyramine and noradrenaline was compared on the circulation of the cat and on the isolated guinea-pig atria. 1. Anesthetised cats: An i.v. injection of 1 mg/kg of (+)- as well as (-)-TCP leads to an increase in the blood pressure and dp/dtmax. This effect is getting weaker on repeated doses. (-)-Deprenyl and pargyline decrease blood pressure and dp/dtmax. After a preadministration of (+)-TCP or pargyline the effect of tyramine on the blood pressure and contractility is prolonged. (-)-TCP prolongs slightly the cardiac effect of tyramine and is less effective than (+)-TCP. (-)-Deprenyl does not influence the effect of tyramine. The noradrenaline effect is not affected by the MAO-inhibitors. 2. Conscious cats: An i.v. injection of (+)- as well as (-)-TCP increases the blood pressure and decreases the heart rate. Desipramine (DMI) blocks this effect. Preadministration of (+)- as well as (-)-TCP and pargyline, but not (-)-deprenyl, potentiates the effect of tyramine on the blood pressure. According to this activity one can arrange these MAO-inhibitors as follows: (+)-TCP greater than (-)-TCP greater than pargyline. 3. Atrial preparations of guinea pigs: (+)- and (-)-TCP have a positive inotropic effect at concentrations from 10(-6) to 10(-5) mol/l, which is blocked by bupranolol and DMI. A pretreatment with reserpine prevents the effect of (-)- and weakens that of (+)-TCP. (+)-TCP, pargyline and (-)-deprenyl potentiate the effect of tyramine, while that of noradrenaline is potentiated by (+)- as well as (-)-TCP and (-)-deprenyl.
The glycolytic enzyme, pyruvate kinase, exhibits moderate affinity [3H]isatin binding (KD approximately 10 microM), which is inhibited by ATP (IC50 25 microM) and deprenyl (IC50 5 microM). Interaction of pyruvate kinase with isatin and its inhibition by ATP and deprenyl has also been confirmed using an independent biosensor technique and immobilized isatin analogue, aminoisatin. This effect has some specificity because the enzyme, creatine phosphokinase, does not exhibit specific isatin-binding. It is suggested that interaction of pyruvate kinase with isatin may reflect some non-glycolytic functions of this enzyme.
Zonisamide is an FDA-approved antiepileptic drug that blocks voltage-dependent Na(+) channels and T-type Ca(2+) channels and improves clinical outcome in Parkinson's disease (PD) patients when used as an adjunct to other PD therapies. Zonisamide also modifies dopamine (DA) activity, provides protection in ischemia models and influences antioxidant systems. Thus, we tested it for its ability to protect DA neurons in a mouse model of PD and investigated mechanisms underlying its protection. Concurrent treatment of mice with zonisamide and 1-methyl-4-phenyl-1,2,3,6-tetraydropyridine (MPTP) attenuated the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH). We also discovered that zonisamide inhibited monoamine oxidase B (MAO-B) activity in vitro with an IC(50) of 25 muM, a concentration that is well within the therapeutic range used for treating epilepsy in humans. Moreover, the irreversible binding of systemically administered selegiline to MAO-B in mouse brain was attenuated by zonisamide as measured by ex vivo assays. Zonisamide treatment alone did not produce any lasting effects on ex vivo MAO-B activity, indicating that it is a reversible inhibitor of the enzyme. Consistent with the effects of zonisamide on MAO-B, the striatal content of 1-methyl-4-phenylpyridinium (MPP(+)), which is derived from the administered MPTP via MAO-B actions, was substantially reduced in mice treated with MPTP and zonisamide. The potency and reversibility with which zonisamide blocks MAO-B may contribute to the ability of the drug to improve clinical symptoms in PD patients. The results also suggest that caution in its use may be necessary, especially when administered with other drugs, in the treatment of epilepsy or PD.
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CIB1 is a 22-kDa regulatory protein previously implicated in cell survival and proliferation. However, the mechanism by which CIB1 regulates these processes is poorly defined. Here, we report that CIB1 depletion in SK-N-SH neuroblastoma and MDA-MB-468 breast cancer cells promotes non-apoptotic, caspase-independent cell death that is not initiated by increased outer mitochondrial membrane permeability or translocation of apoptosis-inducing factor to the nucleus. Instead, cell death requires nuclear GAPDH accumulation. Furthermore, CIB1 depletion disrupts two commonly dysregulated, oncogenic pathways-PI3K/AKT and Ras/MEK/ERK, resulting in a synergistic mechanism of cell death, which was mimicked by simultaneous pharmacological inhibition of both pathways, but not either pathway alone. In defining each pathway's contributions, we found that AKT inhibition alone maximally induced GAPDH nuclear accumulation, whereas MEK/ERK inhibition alone had no effect on GAPDH localization. Concurrent GAPDH nuclear accumulation and ERK inhibition were required, however, to induce a significant DNA damage response, which was critical to subsequent cell death. Collectively, our results indicate that CIB1 is uniquely positioned to regulate PI3K/AKT and MEK/ERK signaling and that simultaneous disruption of these pathways synergistically induces a nuclear GAPDH-dependent cell death. The mechanistic insights into cell death induced by CIB1 interference suggest novel molecular targets for cancer therapy.
Effects of chronic L-deprenyl administration on hyperactive behaviour and brain monoamine levels were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. SHR were hyperactive, impulsive and had impaired sustained attention when tested with a multiple 2-min fixed interval (FI) 5-min extinction (EXT) schedule of reinforcement. Even low, 0.25 mg/kg, doses of chronically-administered L-deprenyl reduced the impulsiveness (bursts of responses with short interresponse times) of SHR, without altering the general hyperactivity or the impaired sustained attention. The drug had no effect on WKY behaviour. The levels of noradrenaline (NA), dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and their metabolites, measured in neostriatum, nucleus accumbens and frontal cortex, showed that L-deprenyl effectively inhibited monoamine oxidase (MAO) activity. These results suggest that impulsiveness is a behavioural component that may be operating independent of the other components, like hyperactivity and deficient sustained attention, and that can be reduced by chronic MAO-B inhibition with L-deprenyl in this strain of rats. The positive effect of L-deprenyl on impulsiveness is discussed as due either to normalization of an asymmetric dopaminergic activity in the nucleus accumbens, or to a restoration of normal DA function in the prefrontal cortex.
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Selegiline (L-deprenyl), a selective inhibitor of monoamine oxidase type B, is an established adjuvant to levodopa therapy in Parkinson's disease (PD). To evaluate whether selegiline also effects the severity and progression of autonomic nervous system dysfunction in PD, we studied autonomic functions by measuring cardiovascular responses to normal breathing, deep breathing, the Valsalva maneuver, the tilting test, and the isometric contraction test prospectively in 52 PD patients receiving either selegiline (n = 27) or placebo (n = 25) in randomized order in a double-blind parallel trial. The study also continued double-blind after the introduction of levodopa. Recordings of cardiovascular responses were carried out annually, with the median follow-up period being 6 years. Cardiovascular autonomic reflexes were diminished in the patient groups compared with those of healthy control subjects (n = 45). There was no progression (except age-related) in dysautonomia in patients on placebo, but there was a decrease in cardiovascular responses in the selegiline group. The heart rate variability in normal breathing, in the Valsalva maneuver, and in the tilting test was clearly diminished during the selegiline treatment. In addition, in the tilting test, the fall in diastolic blood pressure immediately after tilting and in systolic blood pressure 2 minutes after standing up was more pronounced in the selegiline group than in the placebo group. Levodopa treatment had no effect on the measured autonomic responses. In the isometric contraction test, the two treatment groups showed no difference. We conclude that selegiline treatment diminishes autonomic responses, especially those of the sympathetic division. This sympatholytic effect may signal an increased risk of orthostatic hypotension.
PF9601N is an acetylenic tryptamine derivative devoid of amphetamine-like properties, that behaves as suicide MAO-B inhibitor more potent than l-deprenyl. It is highly selective towards MAO-B and it neuroprotects from the neurotoxicity induced in C57Bl/6 adult mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PF9601N also shows in vitro antioxidant properties by inhibiting the dopamine autoxidation. A potential therapeutic use in Parkinson's disease treatment is proposed for this compound.
Individuals with current or past depression are often smokers who are more nicotine dependent, more likely to suffer from negative mood changes after nicotine withdrawal, and more likely to relapse to smoking after quitting than the general population, which contributes to their higher morbidity and mortality from smoking-related illnesses. It remains unclear what interventions can help them to quit smoking.
(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), structurally closely related to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective irreversible inhibitor of B-type monoamine oxidase (MAO) and interferes with the uptake of catecholamines and indirectly acting symphathomimetics. In striking contrast to PEA and its relatives, which displace the transmitter from the storage places, (-)deprenyl inhibits the releasing effect of tyramine and is up to the present the only safe MAO inhibitor which can be administered without dietary restrictions. Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activities in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity and this effect too, is unrelated to either the MAO or the uptake inhibitory effects of the drug. Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. As a consequence of its complex spectrum of activity male rats maintained on (-)deprenyl live longer, lose their capacity to ejaculate later, show improved performance in learning tests and maintain this activity for a longer period than their untreated peers. Patients with Parkinson's disease maintained on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Freshly diagnosed patients treated with (-)deprenyl need levodopa later than their placebo-treated peers. Continuous administration of (-)deprenyl improves the performance of patients with Alzheimer's disease.
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Aged rats were treated (for 36 days) with rivastigmine (0.3 mg/kg rat/day ip), selegiline (0.25 mg/kg rat/day im), rivastigmine plus selegiline in the same doses and way of administration as separately. Aged and adult control groups received NaCl 0.9% 0.5 ml ip.
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It has been suggested that levodopa (L-dopa), a dopamine precursor used to treat Parkinson's disease, may be toxic to grafted fetal neuroblasts; if so, the use of the monoamine oxidase B inhibitor selegiline might prevent such toxicity. We randomly assigned 30 unilaterally 6-hydroxydopamine-lesioned male Sprague-Dawley rats, whose lesions were verified with low-dose apomorphine-induced rotations, to one of five treatment groups: (i) L-dopa methyl ester (125 mg/kg/day) with benserazide (a peripheral decarboxylase inhibitor; 25 mg/kg/day), (ii) L-dopa methyl ester with benserazide and selegiline (L-deprenyl; 0.5 mg/kg/day), (iii) selegiline only, (iv) and (v) vehicle (ascorbate in normal saline) only. After 2 weeks of twice-daily ip injections, the rats received fetal ventral mesencephalic grafts into the lesioned striatum; one vehicle group received sham grafts. Drug therapy was continued for 2 1/2 months post grafting. At 1 month after grafting, and every 2 weeks thereafter, the rats were tested using low-dose apomorphine-induced rotation. A 70% decrease in rotations among all grafted groups, relative to the shams, was found. No statistical differences among groups receiving various drug therapies were seen in behavior or in counts or dimensions of tyrosine hydroxylase-positive cells. We therefore conclude that, in the unilaterally lesioned rat model of Parkinson's disease, there is no adverse effect of L-dopa nor any significant effect of selegiline, either alone or coadministered with L-dopa, on behavioral recovery induced by fetal ventral mesencephalic grafts.
Inhibition of monoamine oxidase A through pretreatment of rats with clorgyline (10 mg/kg ip) or the pro-drug MDL 72,394 (0.5 mg/kg ip) did not block the amine-depleting action of xylamine (25 mg/kg ip). Xylamine treatment resulted in a loss of approximately 60% of the control level of norepinephrine in the cerebral cortex. A 1-hr pretreatment, but not a 24-hr pretreatment, with the monoamine oxidase B inhibitor, L-deprenyl (10 mg/kg ip), prevented the depletion of norepinephrine by xylamine. In addition, pretreatment with MDL 72,974 (1.25 mg/kg ip), a monoamine oxidase B inhibitor without amine-releasing or uptake - inhibiting effects, did not protect cortical norepinephrine levels. Inhibition of monoamine oxidase by either MDL 72,974 or MDL 72,394 did not prevent the inhibition of [3H]norepinephrine uptake into rat cortical synaptosomes by xylamine. These data indicate that monoamine oxidase does not mediate the amine-releasing or uptake inhibiting properties of xylamine. The protection afforded by L-deprenyl following a 1-hr pretreatment most probably was due to accumulation of its metabolite, L-amphetamine, which would inhibit the uptake carrier. A functional carrier is required for depletion since desipramine (20 mg/kg ip) administered 1 hr prior to xylamine, was also able to prevent depletion of norepinephrine.
This study investigated whether rasagiline and selegiline (MAO-B inhibitors) induce serotonin syndrome in fluoxetine-treated rats. Rats received rasagiline (0.1, 0.5, 2.0 mg/kg), or selegiline (0.8, 4.0, 16.0 mg/kg) (doses reflecting the clinical ratio of 1:8 base) in drinking water for 28 days. During the last 21 days, they received injections of fluoxetine 10 mg/kg (controls received water only, then saline injections; a fluoxetine only group received water only then fluoxetine). Serotonin syndrome was assessed using neurological severity score (NSS), food intake and weight gain. Mean NSS significantly increased, and weight and food consumption significantly decreased in rats receiving fluoxetine alone compared with controls. Selegiline 16 mg/kg but not rasagiline (regardless of dose) exacerbated these effects. We concluded that selegiline's amphetamine-like metabolites may increase synaptic cathecholamines and possibly serotonin, aggravating fluoxetine's effect. Rasagiline is devoid of this effect and may therefore be safer for use with serotonergic drugs in parkinsonian patients.
The catecholaldehyde hypothesis predicts that monoamine oxidase (MAO) inhibition should slow the progression of Parkinson's disease, by decreasing production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). Inhibiting MAO, however, diverts the fate of cytoplasmic dopamine toward potentially harmful spontaneous oxidation products, indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels. 3,4-Dihydroxyphenylethanol (hydroxytyrosol) is an abundant anti-oxidant phenol in constituents of the Mediterranean diet. Whether hydroxytyrosol alters enzymatic or spontaneous oxidation of dopamine has been unknown. Rat pheochromocytoma PC12 cells were incubated with hydroxytyrosol (10 µM, 180 min) alone or with the MAO-A inhibitor clorgyline (1 nM) or the MAO-B inhibitors rasagiline or selegiline (0.5 µM). Hydroxytyrosol decreased levels of DOPAL by 30 % and Cys-DA by 49 % (p < 0.0001 each). Co-incubation with hydroxytyrosol prevented the increases in Cys-DA seen with all 3 MAO inhibitors. Hydroxytyrosol therefore inhibits both enzymatic and spontaneous oxidation of endogenous dopamine and mitigates the increase in spontaneous oxidation during MAO inhibition.
Statistically significant inhibition of oxidative deamination of several biogenic amines was found in mitochondrial fraction of heart muscle from rabbits and rats with experimental atherosclerosis and hypercholesterolemia, caused by various methods. Sensitivity of oxidative deamination of tryptamine to inhibitory effect of clorgyline (selective inhibitor of mitochondrial monoamine oxidases) was unaltered in rats with experimental hypercholesterolemia. The rate of oxidative deamination of beta-phenyl ethylamine, tryptamine, benzylamine as well as histamine and putrescine was inhibited after treatment of the mitochondrial fragments from healthy rabbit and rat heart muscles with preparations of oxidized linoleic and linolenic acids, concentration of which was increased in tissues under conditions of atherosclerosis.
The aim of the study was to assess the effect of pimozide voltage-dependent calcium channel blocker on the progression of ALS patients as compared to the potentially neuroprotective drugs, selegiline and vitamin E. There were 44 patients (17 females and 27 males, aged from 30 to 80 years, mean age: 56.2 years) diagnosed as either definite or possible ALS. The study design was open randomised. Patients were treated 3-12 months; the daily dose of pimozide was 1 mg. The disease progression index was calculated as a difference between scores of Norris scale before and after treatment. Statistical analysis showed a significant decrease of the index of progression of the disease in pimozide treated patients as compared to the others. This effect was neither related to the progression of the disease nor advance of the disease at the beginning of treatment.
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Rasagiline (Azilect) is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO) type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug which inhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl, Jumex, Eldepryl). Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatal microdialysate, possibly by the build-up of β-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT). Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-like cell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time.
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1. The efficacies of various agents that affect monoamine synthesis, oxidation and methylation were evaluated in the scallop, Placopecten magellanicus, through the use of high performance liquid chromatography with electrochemical detection. 2. Central ganglia, labial palps and feet from animals bathed in 10(-5) M or 10(-4) M alpha-methyl-p-tyrosine for 1 day followed by 3-6 day recovery in artificial sea water had significantly reduced concentrations of 3,4-dihydroxyphenylalanine, norepinephrine, epinephrine, dopamine and 3,4-dihydroxyphenylacetic acid. 3. Central ganglia, labial palps and feet from scallops incubated in 10(-5) M or 10(-4) M para-chlorophenylalanine for 1 day followed by a 3-6 day wash in artificial sea water had significantly reduced concentrations of 5-hydroxytryptophan, 5-hydroxytryptamine and 5-hydroxy-3-indoleacetic acid. 4. Monamine oxidase inhibitors (administered at 10(-4) M for 1 day followed by a 2-day recovery) significantly decreased the concentrations of 3,4-dihydroxyphenylalanine and 5-hydroxy-3-indolacetic acid and increased the concentrations of their corresponding precursors in tissues. Deprenyl, a monoamine oxidase type B inhibitor, generally had more potent effects than pargyline, which inhibits monoamine oxidase type B and type A. Clorgyline, a monoamine oxidase type A specific inhibitor, showed few significant effects on the levels of the monoamines or their precursors or metabolites. 5. Bath application of 10(-4) M 3,5-dinitrocatechol, a blocker of catechol-O-methyl transferase, resulted in significant decreases in the concentrations of normetanephrine and metanephrine in nervous and other tissues and increased the levels of their corresponding precursors, dopamine, norepinephrine and epinephrine. 6. Generally, treatments that appeared to directly cause changes in levels of catecholaminergic compounds indirectly resulted in inverse changes in levels of indolaminergic compounds, and vice versa. This suggests an interaction between these transmitter systems. 7. The detection of monoaminergic compounds and dramatic changes in their concentrations following various drug effects strongly suggests the presence of mammalian-type metabolic pathways leading to synthesis and subsequent inactivation of monoamines.
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The serotonin toxicity syndrome (STS) is a potential risk with concurrent use of the monoamine oxidase type-B inhibitor rasagiline and antidepressants.
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The use of the combination of fluoxetine, an anti-depressant serotonin uptake inhibitor, and selegiline, a monoamine oxidase -B inhibitor, was reviewed in a large population of patients with Parkinson's disease. All records were reviewed from a Parkinson's disease clinic to determine how many patients were treated simultaneously with selegiline and fluoxetine. Patient characteristics, duration and dose of treatment, side effects and reasons for discontinuation were noted. Twenty-three patients received both medications at the same time. No additional side effects were noted with the combination therapy that had not already been reported with each medication alone. No serious side effects were found. In this clinic population, fluoxetine and selegiline were used in combination without major side effects, but further observation is warranted.
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The characteristics and regulation of monoamine oxidase (MAO) were studied in rat thyroid tissue. A measured Michaelis constant (Km) value of 102 mumol/l was similar to the Km values found in other tissues. Maximal velocity (Vmax) was 1.028 nmol/mg protein per min. It is known that MAO is present as two isoenzymes, A and B, which are sensitive to clorgyline and deprenyl respectively. The in-vitro effect of graded concentrations of these selective MAO inhibitors was used to estimate the relative proportion of A and B isoenzymes. Clorgyline strongly decreased thyroid MAO activity at concentrations as low as 1 pmol/l while the effect of deprenyl was observed only at concentrations higher than 10 mumol/l. These results indicated that MAO-A is the main form of the enzyme in the rat thyroid. In-vivo administration of L-thyroxine (5.6-224 nmol/kg) significantly reduced thyroid MAO activity at doses equal to or greater than those which have been reported to inhibit iodine output from the thyroid. Increased TSH levels, induced either by exogenous TSH or methimazole administration, resulted in a significant increase in thyroid MAO activity. Theophylline, a phosphodiesterase inhibitor and dibutyryl cyclic AMP were also able to stimulate MAO activity when administered in vivo. Iodide organification (protein-bound 131I) in vivo as well as the relative proportion of the different thyroid iodo-compounds were not affected in animals with reduced or increased thyroid MAO activity induced by clorgyline or theophylline respectively. It was concluded that rat thyroid MAO activity is under the influence of TSH.(ABSTRACT TRUNCATED AT 250 WORDS)
The antiapoptotic effect of (-) deprenyl on human phaeochromocytoma cells after serum deprivation has been reported by earlier. Two melanoma (M-1 and HT-2058) cell lines were used in our experiments. Serum deprivation for five days resulted in excessive number of apoptosis in the cell cultures. Very low doses of (-)-deprenyl (10(-7)-10(-13) mol) caused an approximately 2 days delay in the onset of apoptosis. At the same time, +deprenyl was ineffective. In further experiments (-)-deprenyl and (-)desmethyl-deprenyl was administered in higher doses (10(-2), 10(-3) and 10(-4) mol) to A-2058 melanoma and HT-1080 fibrosarcoma cells in culture. In these experiments no serum deprivation was applied and the treatment was started 24 hours after plating. Total eradication of the A-2058 cells was caused by 10(-2) mol (-)-deprenyl and (-)-desmethyl-deprenyl. The type of cell death appeared to be apoptosis. Sixty percent apoptotic ratio was seen 24 hours and 72 hours after 10(-3) mol (-)-desmethyl-deprenyl treteatment. The same dose of (-)-deprenyl caused 50% apoptosis an 72 h. Only (-)-desmethyl-deprenyl induced apoptosis (20%) at 24 hours, in the dose of 10(-4) mol. Interestingly (-)-deprenyl treatment resulted in 60% apoptosis.
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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Role of R-(-)-deprenyl in adhesion of neuronal and non-neuronal cells. The beneficial effect of the anti-parkinsonian monoamine oxidase-B inhibitor, R-(-)-deprenyl has been shown in a number of different diseases, such as Parkinson's and Alzheimer's disease, atherosclerosis or tumor formation. The role of the cytoskeleton, the main component of cell adhesion, has been suggested in the development of these diseases. Nevertheless, the effect of the drug on cell adhesion has never been examined. In the present study, the authors studied the effect of R-(-)-deprenyl on cell-cell adhesion of neuronal (PC12, rat phaeochromocytoma) and non-neuronal (NIH3T3, NIH3T3/EGFR, NIH3T3/EGFR-e3B1 mouse embryo fibroblasts, and 5180 mouse sarcoma) cells using cell association assay. R-(-)-deprenyl treatment resulted in a cell type- and concentration-dependent increase in cell-cell adhesion of PC12 cells, which contain no monoamine oxidase-B, and we observed the same effect in NIH3T3 cells at concentrations lower than those needed for monoamine oxidase-B inhibition. Interestingly, R-(-)-deprenyl increased cell-cell adhesion of tumor cell lines as well. The effect of R-(-)-deprenyl was not reversible during a 24-hour recovery period. At the same time, the monoamine oxidase-B inactive isomer of the drug, S-(+)-deprenyl had no effect on cell-cell adhesion in PC12 and NIH3T3 cells. In this study, the authors described a new, monoamine oxidase-B independent effect of R-(-)-deprenyl on cell-cell adhesion both in neuronal and non neuronal cells. The authors' results with S-(+)-deprenyl suggest that the sterical structure of the drug is an important factor of the observed effect, which is probably a consequence of an irreversible change in the cells.
Five patients were examined with [(11)C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [(11)C]-d-deprenyl-PET/CT. Nine large AAAs (54-66 mm) scheduled for repair and six small AAA (35-44 mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on.
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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)
It was found that in the rat striatum DA was oxidized extrasynaptosomally to 11% by MAO-A and to 3% by MAO-B. The corresponding intrasynaptosomal oxidations were 84% and 2%, respectively. Those figures were virtually unchanged even if the rat brain MAO-B was selectively inhibited to 87% by deprenyl. In the human brain extrasynaptosomal oxidation was 16% and 66%, respectively, by MAO-A and -B. Intrasynaptosomally the corresponding figures were 12% and 6%, respectively. Selective inhibition of human caudate MAO-B was calculated to give a total reduction of DA oxidation of 63%. The differences between man and rat are due to the proportionately greater oxidation of DA by MAO-B in man, which is a consequence of a higher ratio of concentration of MAO-A/-B in the rat.
1. Oxidative mechanisms in dopaminergic neurons may contribute to cell death and the progression of Parkinson's Disease. 2. The free radical auto-toxicity concept has scientific evidence to support it. 3. Clinical trials are underway to assess the protective effect of augmenting the free radical scavenging system with vitamin E and inhibiting catecholamine oxidation with deprenyl.
The LD50 of pethidine was determined in mice pretreated (4 h) either with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine or with clorgyline, a selective inhibitor of MAO A or deprenyl, a selective inhibitor of MAO B. Phenelzine or combined clorgyline plus deprenyl pretreatments decreased pethidine LD50. Clorgyline or deprenyl alone did not affect pethidine toxicity. Whole brain 5-hydroxytryptamine (5-HT) concentrations were measured in the pretreated mice. 5-HT levels were approximately doubled (P less than 0.001) after phenelzine or clorgyline plus deprenyl treatment, but not after clorgyline or deprenyl given alone. These results indicate that both MAO A and MAO B need to be inhibited to increase pethidine toxicity and brain 5-HT levels. They support the involvement of 5-HT in the toxic interaction between pethidine and MAO inhibitors.