Effects Of Monoamine Oxidase Inhibitors Research Articles

Cudratricusxanthone A protect pancreatic beta cells from cytokines-mediated toxicity through the inhibition of NF-κB and STAT pathways.

Cudratricusxanthone A (CTXA) has an isoprenylated xanthone skeleton that is known to exert a variety of biological activities, including anti-inflammatory, neuroprotective, hepatoprotective, anti-proliferative, and mono-amine oxidase inhibitory effects. In this study, we investigated the effect of CTXA on IL-1β (5 ng/ml) and IFN-γ (100 U/ml)-induced β-cell damage. Pre-treatment with CTXA increased the viability and reactive oxygen species (ROS) inhibition of cytokine-treated RINm5F cells at concentrations of 1-10 μM. CTXA prevented nitric oxide (NO) production, and this effect was correlated with reduced levels of protein and mRNA expression of inducible nitric oxide synthase (iNOS). The molecular mechanism by which CTXA inhibits iNOS gene expression appeared to involve the inhibition of NF-κB activation. Moreover, pancreatic β-cells treated with cytokines upregulated the phosphorylation of STAT-1, STAT-3 and STAT-5; however, pretreatment with CTXA attenuated these effects. Additionally, in a second set of experiments in which rat islets were used, the protective effects of CTXA in rat islets were essentially the same as those observed when RINm5F cells were used. CTXA prevented cytokines-induced NO production, iNOS expression, JAK/STAT activation, and NF-κB activation and inhibition of glucose-stimulated insulin secretion (GSIS). Collectively, these results suggest that CTXA can be used for the prevention of functional β-cell damage.

The interactions of caffeine with monoamine oxidase

AimsCaffeine has been used as a scaffold for the design of inhibitors of monoamine oxidase (MAO) A and B. Substitution at the C8 position with a variety of moieties yields structures with high MAO inhibition potencies. Although the MAO inhibitory properties of numerous caffeine derivatives have been characterized, the possibility that caffeine inhibits the MAOs has not been investigated in detail. Based on the therapeutic applications and potential adverse effects of MAO inhibition, this study examines the interactions of caffeine with the MAOs. Main methodsEmploying the recombinant human enzymes, the potencies by which caffeine inhibits the in vitro catalytic activities of the MAOs were recorded and expressed as the IC50 and Ki values. The reversibility of inhibition was determined by measuring the recovery of enzyme activity after dialysis of enzyme–caffeine mixtures. Key findingsCaffeine acts as a MAO inhibitor with Ki values of 0.70mM and 3.83mM for the inhibition of MAO-A and MAO-B, respectively. The results show that caffeine binds reversibly and competitively to both MAO enzymes. SignificanceAlthough structural modifications of caffeine lead to highly potent MAO inhibitors, caffeine is a weak inhibitor of MAO-A and MAO-B. At plasma concentrations (approximately 1–10μM) achieved by normal human consumption, the MAO inhibitory potencies of caffeine are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of caffeine should however be taken into consideration when using this drug in vitro and in tissue culture experiments where higher doses and concentrations of caffeine are often used.

The Inhibition of Monoamine Oxidase by Esomeprazole

Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 µM and 48 µM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 µM and 31.7 µM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered.

Synthesis of New 7-Oxycoumarin Derivatives As Potent and Selective Monoamine Oxidase A Inhibitors

New series of 4-methyl and 3,4-dimethyl-7-oxycoumarin derivatives (oxadiazoles, thiadiazoles, triazoles, and thiazolidinones) were designed, synthesized, and evaluated for their monoamine oxidase (MAO) A and B inhibiting effect. All the synthesized compounds showed in vitro high affinity and selectivity toward MAO-A isoenzyme, compared to clorgyline and moclobemide, with Ki values on the picomolar range. Moreover, most of the tested compounds displayed MAO inhibitory effect when tested in vivo. The docking experiments carried out on MAO-A and MAO-B structures proved new information about the enzyme-inhibitor interaction and the potential therapeutic application of 7-oxycoumarin scaffold.

Ladostigil: A Novel Multimodal Neuroprotective Drug with Cholinesterase and Brain-Selective Monoamine Oxidase Inhibitory Activities for Alzheimers Disease Treatment

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer's and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug.

Effect of Monoamine Oxidase Inhibition on Rewarding Effects of Nicotine in Rodents

Nicotine, the primary psychoactive compound in tobacco, is responsible for the addictive effects of smoking; however, there is a paucity of information indicating whether the presence of other biological chemicals in tobacco alters nicotine's rewarding effects. It has been suggested that the addictive effects of smoking may be due, in part, to the inhibition of the pair of monoamine oxidase enzymes responsible for a significant fraction of monoamine metabolism, Monoamine Oxidase A and B (MAO-A and MAO-B). This paper reviews the current, limited literature examining the role of MAO inhibition on the rewarding effects of nicotine (e.g., self-administration) in rodents. Overall, studies with rats and mice do suggest that MAO plays a role in nicotine reward. However, results are mixed regarding the MAO subtype responsible for the rewarding effects of nicotine, most likely due to methodological variation across the limited number of studies. Important individual difference factors such as age, sex and genetics are discussed, along with relevant brain and neurotransmitter systems. Future research is needed that builds on the available literature to map out the relationship between MAO inhibition and nicotine reward. These data will enhance our understanding of the neuropharmacological effects of smoking and the value of implementing MAO inhibitors as pharmacotherapies for smoking cessation.

Effect of monoamine oxidase inhibitors on codeine disposition and pentobarbitone sleep-times in the rat.

Effect of monoamine oxidase inhibitors on codeine disposition and pentobarbitone sleep-times in the rat.

The effect of monoamine oxidase inhibition on guanethidine-induced noradrenaline release and sympathetic blockade.

The effect of monoamine oxidase inhibition on guanethidine-induced noradrenaline release and sympathetic blockade.

Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy- N, N-dimethyltryptamine metabolism and pharmacokinetics

5-Methoxy- N, N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6- and 40-fold lower catalytic efficiency ( V max/ K m), respectively, in producing bufotenine from 5-MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1′-hydroxylase activities ( R 2 = 0.98; P < 0.0001) and CYP2D6 contents ( R 2 = 0.77; P = 0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg- CYP2D6) mouse models showed that Tg- CYP2D6 mice receiving the same dose of 5-MeO-DMT (20 mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pretreatment of harmaline (5 mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2 mg/kg, i.p.), and 9.9- and 6.1-fold higher systemic exposure to bufotenine in Tg- CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as bufotenine formation that is mediated by CYP2D6.

Interaction of psychotropic drugs with monoamine oxidase in rat brain.

Literature observations indicate that some psychotropic drugs may have inhibitory activity towards monoamine oxidase (MAO). This study was undertaken to assess the potency, isozyme selectivity and mechanism of inhibition of representative first- and second-generation antidepressant drugs towards rat brain MAO-A and MAO-B. Five tricyclic antidepressants (imipramine, trimipramine, clomipramine, amitriptyline and doxepine) and three selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine and citalopram) were examined. They showed inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B (Ki in the micromolar range). Their mechanism of inhibition was competitive towards MAO-B and of a mixed competitive type towards MAO-A. The results suggest that some of the drugs examined might also contribute an MAO inhibitory effect in chronically treated patients.

Long-term administration of monoamine oxidase inhibitors alters the firing rate and pattern of dopamine neurons in the ventral tegmental area

Monoamine oxidase inhibitors (MAOIs) exert their antidepressant action by increasing the function of the serotonin (5-HT), norepinephrine and dopamine (DA) systems. There is, however, limited electrophysiological data on the effects of MAOIs on DA neurons. The effects of 2-d and 21-d administration of three MAOIs were investigated (clorgyline, selective MAOI-A; deprenyl, selective MAOI-B; phenelzine, non-selective MAOI) on the firing activity of DA neurons in the ventral tegmental area using in-vivo electrophysiology in rats. Short-term clorgyline (1 mg/kg) and phenelzine (2.5 mg/kg) was devoid of effect on DA neurons, whereas prolonged administration significantly decreased their firing rate (by 30% and 20%, respectively), number of bursts (by 80% and 45%, respectively), and percentage of spikes occurring in bursts only in clorgyline-treated rats (70%). Deprenyl (0.25 mg/kg) was without effects. DA firing was restored in clorgyline-treated rats by inhibiting 5-HT synthesis using para-chlorophenylalanine (p-CPA; 300 mg/kg. d for three consecutive days). The 5-HT3 antagonist ondansetron (0.5 mg/kg) was devoid of effect in control rats, but completely reversed the alterations of DA neuronal activity in clorgyline-treated rats. An attenuation of DA neuronal activity was thus produced by prolonged blockade of MAOA activity. The absence of effect of MAOA inhibition after subacute administration suggested an indirect mechanism. This was confirmed by the observation that p-CPA antagonized the effects of clorgyline. Since ondansetron completely reversed the effects of clorgyline on DA neuronal activity, the effects of MAOA inhibition appeared to be mediated by 5-HT3 receptors.

Cudratricusxanthone A Protects Mouse Hippocampal Cells against Glutamate-Induced Neurotoxicity via the Induction of Heme Oxygenase-1

Cudratricusxantone A (CTXA), isolated from the roots of Cudrania tricuspidata Bureau (Moraceae), has potent hepatoprotective, antiproliferative, and monoamine oxidase inhibitory effects. In this study, we examined whether CTXA could protect HT22-immortalized hippocampal cells against glutamate-induced oxidative stress through the induction of heme oxygenase (HO)-1 expression. CTXA induced the expression of HO-1 and increased HO activity dose- and time-dependently. CTXA also suppressed glutamate-induced ROS generation in HT22 cells. Interestingly, treatment of neuronal cells with CTXA enhanced cellular resistance to glutamate oxidative stress. The protective effect of CTXA was abrogated by tin protoporphyrin IX, an HO inhibitor. In addition, treatment with the HO-1 inducer, cobalt protoporphyrin IX, and bilirubin, one of the enzymatic products of HO-1, produced comparable protection. These results demonstrate that CTXA protects neuronal cells from glutamate-induced oxidative stress via the induction of HO-1.

The monoamine oxidase inhibitor phenelzine enhances the discriminative stimulus effect of nicotine in rats

In addition to delivering nicotine, tobacco smoke also inhibits monoamine oxidase (MAO). Although MAO inhibitors (MAOIs) can increase nicotine self-administration in rodents, the effects of MAOIs on the discriminative stimulus effect of nicotine are not known. This study examined the effects of three MAOIs (phenelzine, clorgyline and pargyline) with varying selectivity for MAOA and MAOB in the nicotine drug discrimination procedure in rats. Adult male Sprague-Dawley rats were trained to discriminate nicotine (0.3 mg/kg, subcutaneously) from saline in a standard, two-lever food-reinforced operant task. Once the discrimination was acquired, the ability of each MAOI to substitute for or alter the discriminative stimulus effect of nicotine was determined. In substitution tests, nicotine (0.03-0.3 mg/kg) produced full, dose-dependent substitution. Although the selective MAOA inhibitor clorgyline (3-56 mg/kg) and the selective MAOB inhibitor pargyline (3-56 mg/kg) did not elicit any nicotine-appropriate responding, partial substitution was obtained with the nonselective MAO inhibitor phenelzine (1-17 mg/kg). Phenelzine (10 mg/kg) also enhanced the discriminative stimulus effect of a low dose of nicotine (0.056 mg/kg) and prolonged the time course effect of the nicotine-training dose. These findings indicate that concomitant inhibition of MAOA and MAOB can enhance the discriminative stimulus effect of nicotine in rats.

How antidepressants work: cautionary conclusions based on clinical and laboratory studies of the longer-term consequences of antidepressant drug treatment.

Time-dependent alterations in the functional activity of adrenergic and serotonergic neurotransmitter systems and, in particular, a frequently observed down-regulation of brain beta-adrenoceptors have been implicated in antidepressant drug effects. Current studies of catecholamine and serotonin neurotransmitter systems suggest that the net physiological output changes in neuroendocrine responses, blood pressure, sleep and motor activity which follow various antidepressant treatments in psychiatric patients, normal controls and different experimental animals are not indicative of a common response pattern to all therapeutically effective agents. Rather, antidepressant treatment effects differ according to many variables, including the pre-existing state of the organism (e.g. depressed, stressed or normal), the species, the duration of treatment and the particular brain or peripheral circuits investigated. Examples are cited from our studies of the effects of monoamine oxidase inhibitors and other antidepressants on noradrenergic-serotonergic interactions that affect melatonin release and other neuroendocrine responses, on some additional functional end-points, and on depressive mood and other symptoms in patients with depression or other tricyclic-responsive disorders. These examples illustrate the complexity found in attempts to identify a unitary mechanism of antidepressant drug action.

Effects of monoamine oxidase inhibitors on cocaine discrimination in rats

This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, intraperitoneal) from saline using a two-lever choice methodology. The nonselective monoamine oxidase inhibitors tranylcypromine (0.01-5 mg/kg) and phenelzine (1-25 mg/kg), the monoamine oxidase-A selective compound clorgyline (1-25 mg/kg), and the monoamine oxidase-B selective compounds pargyline (0.005-50 mg/kg) and selegiline (1-25 mg/kg) were tested for substitution 15 min or 24 h following administration, and in combination with 10 mg/kg of cocaine 24 and 48 h after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 h, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 h than at 15 min. When cocaine was administered 24 h after clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 h, the effects of all compounds except phenelzine were markedly reduced. Selectivity for monoamine oxidase-A or monoamine oxidase-B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that monoamine oxidase inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 h, and may be useful for treatment of cocaine abuse.

Effect of monoamine oxidase inhibition on amphetamine-evoked changes in dopamine receptor availability in the living pig: A dual tracer PET study with [11C]harmine and [11C]raclopride

The activity of both isozymes of monoamine oxidase (MAO) is reduced by 50% in the brain of human smokers. We hypothesized that this is not an epiphenomenon, but should bring about potentiation of the action of psychostimulant drugs. To test this hypothesis, we carried out serial positron emission tomography (PET) studies in Göttingen miniature pigs to measure the binding of the MAO-A ligand [11C]harmine and to measure the changes in [11C]raclopride binding evoked by a low dose of amphetamine (0.7 mg/kg as free base, i.v.), first in a baseline condition, and, one month later, after acute treatment with pargyline (2 x 3 mg/kg as free base, i.m.). In the baseline, the distribution volume of [11C]harmine relative to the arterial input (V(d), ml g(-1)) ranged from 74 ml g(-1) in cerebellum to 139 ml g(-1) in the medial hypothalamus. Pargyline treatment reduced the magnitude of V(d) globally to 34-54 ml g(-1). Nearly complete displacement of [11C]harmine binding was detected in neocortex and striatum, but there was evidence for pargyline-resistant binding in the pituitary gland and diencephalon. In the baseline condition, the low dose of amphetamine evoked a 14% decline in the binding potential (BP) (pB) of [11C]raclopride in striatum (P = 0.026). After pargyline treatment, the amphetamine effect was of similar magnitude (-11%), although not statistically significant (P = 0.054). However, the second amphetamine challenge evoked a 24% reduction in [11C]raclopride pB relative to the original baseline condition (P = 0.018). Present results do not strongly support our hypothesis that MAO inhibition should potentiate the amphetamine-evoked dopamine release as measured in the [11C]raclopride competition paradigm.

Nicotine and nonnicotine factors in cigarette addiction

A great deal of research supports the role of nicotine in cigarette addiction. However, the effectiveness of nicotine replacement therapy (NRT) as a smoking cessation treatment has fallen short of initial hopes. A key reason may be that NRT does not address nonnicotine components of smoking reinforcement. These include constituents that provide reinforcing sensory stimulation, components that minimize excessive irritation from inhaled nicotine and other pharmacologically active compounds in cigarette smoke. Studies using various paradigms to dissociate nicotine from other components of smoking are summarized. Nonnicotine components provide many rewarding effects, often surpassing the direct effects of nicotine. Substitutes for the sensory effects of smoking may be effective in relieving craving for cigarettes and in facilitating smoking cessation. Moreover, techniques for devaluing smoking-related cues may decrease craving and enhance subsequent abstinence. Promising approaches for devaluing smoke cues include extinction-based treatments employing denicotinized cigarettes and the use of nicotinic agonist and/or antagonist treatment during the weeks leading up to a quit attempt. Recent studies suggest that incorporating these approaches into a treatment program may significantly increase smoking abstinence rates. Preliminary findings also suggest that replacement of the effects of monoamine oxidase inhibitors contained in cigarette smoke may enhance quit rates. While current NRT methods have been the mainstay of smoking cessation treatment and will likely continue to serve a useful role, the next stage of progress will likely entail the development of tools designed with recognition of the importance of nonnicotine components of cigarette smoking.

Effects of Monoamine Oxidase Inhibitors on Methamphetamine-Induced Stereotypy in Mice and Rats

In male ICR mice, a single intraperitoneal administration of methamphetamine (METH) (10 mg/kg) induced stereotyped behavior such as continuous sniffing, circling, and nail biting, reaching a plateau level 20 min after the injection. Subcutaneous pretreatment with clorgyline, a monoamine oxidase (MAO)-A inhibitor, at a dose of 0.1 mg/kg 2 h prior to the drug challenge significantly decreased the initial (first 20 min) intensity of stereotypies and increased the latency to onset. The effect was not observed with either higher doses of clorgyline (1 and 10 mg/kg) or l-deprenyl, a MAO-B inhibitor, at doses of 0.1-10 mg/kg. In male Wistar rats, the inhibitory effect of clorgyline on METH-induced stereotypy was not observed. Pretreatment of the mice with clorgyline (0.1 mg/kg) had no effect on apparent serotonin and dopamine turnover in the striatum, although the higher doses of clorgyline (1 and 10 mg/kg) significantly decreased the turnover. These results suggest that a low dose of clorgyline tends to increase the latency and decrease the intensity of stereotypies induced by METH in a dopamine metabolism-independent manner in mice.

Effect of l-Deprenyl and Gliclazide on Oxidant Stress/Antioxidant Status and DNA Damage in a Diabeticrat Model

Background: This study investigates the possible effect of monoamine oxidase inhibitor (MAOI), selegyline (l-deprenyl), in combination with oral antidiabetic-gliclazide (OAD), in preventing oxidative stress in streptozotocin-induced diabetes model in male Swiss Albino rats by measuring oxidant stress/DNA damage and antioxidant levels.Methods: Diabetic rats were divided into four groups (n = 10) as [] diabetic untreated (DM), [] deprenyl treated (DM + D), [] gliclazide treated (DM + O), and [] gliclazide and deprenyl treated (DM + O + D). Controls were divided into two groups (n = 8) [] untreated (C), and [] deprenyl treated (C + D). Gliclazide 5 mg/kg and/or MAOI 0.25 mg/kg daily were given orally by gavage for 4 weeks. At the end of the 12th week, catalase and superoxide dismutase (SOD) levels in erythrocyte lysates (EL); total antioxidant status (TAS), 8-hydroxy-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and vitamin A and E levels in plasma, MDA, and MAO in liver homogenates were determined.Results: Diabetic rats showed a decrease in EL-SOD, plasma TAS, and vitamin E, and an increase in plasma 8-OHdG, plasma, and liver MDA levels (p < 0.05). Gliclazide and/or deprenyl decreased 8OHdG levels and increased antioxidant levels and survival when compared with untreated diabetic rats (p < 0.05). The lowest 8-OHdG levels were determined in the DM + O + D group.Conclusions: The combined treatment of deprenyl and gliclazide may contribute to the control of the physiopathological mechanisms underlying both the process of aging and type 2 diabetes by reducing oxidant stress and DNA damage, improving antioxidant status, and increasing survival, and may have implications for further clinical studies.

Effects of monoamine oxidase inhibitors on the diethyldithiocarbamate-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in C57BL/6 mice.

Diethyldithiocarbamate (DDC) is known to potentiate the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The aims of the present study were to provide biochemical, pathological and behavioral evidence for the degeneration of dopamine (DA) neurons in C57BL/6 strain mice treated simultaneously with DDC and MPTP, and to evaluate the effects of monoamine oxidase (MAO) inhibitors on DDC-enhanced MPTP toxicity. DDC (400 mg/kg)+ MPTP (30 mg/kg) treatment decreased significantly the levels of striatal DA and its metabolites and induced bradykinesia. In mice treated with DDC+MPTP, degenerative areas were found in striatum, substantia nigra and tuberculum olfactorium by assessment of the binding of [125I]RTI-121, a DA transporter ligand. Pretreatment with a MAO-B inhibitor selegiline prior to the administration of DDC and MPTP completely inhibited the decrease in the levels of DA and its metabolites, bradykinesia and degeneration of dopaminergic nerve terminals. In contrast, the protective action of clorgyline was not clearly observed in this model system.