Mitochondrial Monoamine Oxidase Activity Research Articles

Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review.

Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabis sativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics.

Effects of combined arsenic and lead exposure on the brain monoaminergic system and behavioral functions in rats: Reversal effect of MiADMSA.

In this study, we evaluated the therapeutic efficacy of monoisoamyldimercaptosuccinic acid (MiADMSA) against individual and combined effects of arsenic (As) and lead (Pb) on the monoaminergic system and behavioral functions in rats. Pregnant rats were exposed to sodium metaarsenite (50 ppm) and lead acetate (0.2%) individually and in combination (As = 25 ppm + Pb = 0.1%) via drinking water from gestation day (GD) 6 to postnatal day (PND) 21. MiADMSA (50 mg/kg body weight) was given orally through gavage for 3 consecutive days to pups from PND 18 to PND 20. The results showed increases in synaptosomal epinephrine, dopamine, and norepinephrine levels with individual metal exposures and decreases with combined exposure to As and Pb in the cortex, cerebellum, and hippocampus in PND 21, PND 28, and 3 months age-group rats. We found decreased activity of mitochondrial monoamine oxidase in the selected brain regions following individual and combined exposures to Pb and As. In addition, rats treated with Pb and As alone or in combination showed significant deficits in open-field behavior, grip strength, locomotor activity, and exploratory behavior at PND 28 and 3 months of age. However, MiADMSA administration showed reversal effects against the As- and/or Pb-induced impairments in the monoaminergic system as well as in behavioral functions of rats. Our data demonstrated that the mixture of Pb and As induced synergistic toxicity to developing brain leading to impairments in neurobehavioral functions and also suggest therapeutic efficacy of MiADMSA against Pb- and/or As-induced developmental neurotoxicity.

Monoamine Oxidase Activity in the Hepatopancreas of the Kamchatka Crab Paralithodes camtschaticus: a Substrate–Inhibitor Specificity

A study of substrate–inhibitor specificity of mitochondrial monoamine oxidase (MAO) in the hepatopancreas of the adult Kamchatka crab Paralithodes camtschaticus revealed specific catalytic properties of the enzyme. On the one hand, crab hepatopancreas MAO, like its classical hepatic counterpart, can deaminate tyramine, tryptamine, dopamine, serotonin, noradrenalin, benzylamine, β-phenylethylamine and N-methylhistamine but shows no sensitivity to 10 mM semicarbazide. On the other hand, MAO deaminates histamine but not putrescine, two classical diamine oxidase (DAO) substrates. It was established that MAO activity was several times higher toward benzylamine, β-phenylethylamine and N-methylhistamine than toward serotonin and noradrenalin. MAO was also found to be almost 500 times more sensitive to its selective inhibitor deprenyl than to chlorogilyn. A substrate–inhibitory analysis with the use of deprenyl and chloroginyl provides an indirect evidence for the existence of a sole MAO molecular form in the Kamchatka crab hepatopancreas.

Kinetics of Inhibition of Monoamine Oxidase Using Curcumin and Ellagic Acid.

Background:Curcumin and ellagic are the natural polyphenols having a wide range of pharmacological actions. They have been reported to have their use in various neurological disorders.Objective:This study was aimed to evaluate the effect of curcumin and ellagic acid on the activity of monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters which are pivotal for neuronal development and function.Materials and Methods:The in vitro effects of these selected polyphenols on MAO activities in mitochondria isolated from rat brains were examined. Brain mitochondria were assayed for MAO type-B (MAO-B) using benzylamine as substrates. Rat brain mitochondrial MAO preparation was used to study the kinetics of enzyme inhibition using double reciprocal Lineweaver–Burk plot.Results:MAO activity was inhibited by curcumin and ellagic acid; however, higher half maximal inhibitory concentrations of curcumin (500.46 nM) and ellagic acid (412.24 nM) were required compared to the known MAO-B inhibitor selegiline. It is observed that the curcumin and ellagic acid inhibit the MAO activity with both the competitive and noncompetitive type of inhibitions.Conclusions:Curcumin and ellagic acid can be considered a possible source of MAO inhibitor used in the treatment of Parkinson's and other neurological disorders.SUMMARY Monoamine oxidase (MAO) is involved in a variety of neurological disorders including Parkinson's disease (PD)Curcumin and ellagic acid inhibit the monoamine oxidase activityEllagic acid revealed more potent MAO type-B (MAO-B) inhibitory activity than curcuminKinetic studies of MAO inhibition using different concentrations of curcumin and ellagic acid were plotted as double reciprocal Lineweaver–Burk plotThe mode of inhibition of both compounds toward MAO-B is mixed (competitive and uncompetitive) type of inhibition with both the competitive and noncompetitive type of inhibitions. Abbreviations used: MAO: Monoamine oxidase, IC50: Higher half maximal inhibitory concentrations, PD: Parkinson's disease, LB: Lewy bodies, SNpc: Substantia nigra pars compacta, ROS: Reactive oxygen species, SG: Selegiline, DMC: demethoxycurcumin, BDMC: Bisdemethoxycurcumin.

Sensitivity of liver monoamine oxidase in the lamprey Lampetra fluviatilis to some tricyclic compounds

A comparative analysis of the effect of the five acridine, three phenothiazine and one xanten (pyronine G) derivatives on the activity of liver mitochondrial monoamine oxidase (MAO) in sexually mature male river lampreys Lampetra fluviatilis has been conducted. Tyramine, dopamine, serotonin, noradrenaline, benzylamine, β-phenylethylamine and N-methylhistamine have been used as substrates for analyzing the monoamine oxidase activity of heterocyclic compounds. The analyzed synthetic hexamerous tricyclic compounds exhibit irreversible inhibition of the enzyme but no specificity depending on the desaminated substrate. The number and identity of heteroatoms in the analyzed heterocyclic compounds have been established to influence their inhibitory efficiency. The data of substrate-inhibitory analysis obtained with the use of the specific substrates provide indirect evidence for the existence of a single MAO form in the lamprey liver.

Antidepressant-like Activity of Andrographis paniculata in Type-2 Diabetic Rats

Pharmacological observations suggesting antidepressants-like efficacy of a medicinally used Andrographis paniculata extract (AP) in type-2 diabetic are presented in this communication. Efficacies of 10 daily oral doses of 50, 100 and 200 mg/kg/day AP and 15 mg/kg/day imipramine were compared in behavioral despair and learned helplessness tests using type-2 diabetic rats, and bio- and neuro-chemical alterations in the brain tissue of treated animals subjected to learned helplessness test were quantified. Significant imipramine like antidepressant activity of AP was observed even after its lowest daily tested (50 mg/kg/day) in both behavioral tests used, and such efficacy of the extract dose dependently increased with its increasing dose. Imipramine like effects of AP in elevating lower hippocampal levels of norepinephrine, dopamine, and serotonin observed in diabetic rats towards normal values were also observed after its 50 mg/kg/day doses and such efficacy of the extract increased also with its increasing daily doses. Levels of all the three monoamines quantified in 100 mg/kg/day AP treated diabetic rats were significantly higher than those of the non-diabetic animals. Imipramine had no significant effects on body weight losses, hyperglycemia, insulin deficiency, lower catalase and superoxide dismutase activities and higher lipid peroxides in the frontal cortex, and mitochondrial monoamine oxidase activities observed in diabetic animals. All such quantified biochemical and other pathologies observed in diabetic were significantly antagonized even by 50 mg/kg daily oral doses of AP, and its efficacies always increased with its increasing daily doses. These observations strongly suggest that AP could be an herbal alternative for treatments of diabesity-associated depression resistant to imipramine like antidepressants, and that antidepressants like efficacy of the extract is most probably due to its inhibitory effects on brain mitochondrial monoamine oxidase activities. The observed beneficial of AP on brain oxidative status could be indicative of its neuro-protective potentials as well. In any case its minimal effective doses for all such efficacies should be below or around 50 mg/kg/day.

Increased Levels of Monoamine-Derived Potential Neurotoxins in Fetal Rat Brain Exposed to Ethanol

Pregnant SD rats were exposed to ethanol (25 % (v/v) ethanol at 1.0, 2.0 or 4.0 g/kg body weight from GD8 to GD20) to assess whether ethanol-derived acetaldehyde could interact with endogenous monoamine to generate tetrahydroisoquinoline or tetrahydro-beta-carboline in the fetuses. The fetal brain concentration of acetaldehyde increased remarkably after ethanol administration (2.6 times, 5.3 times and 7.8 times as compared to saline control in 1.0, 2.0 and 4.0 g/kg ethanol-treated groups, respectively) detected by HPLC with 2,4-dinitrophenylhydrazine derivatization. Compared to control, ethanol exposure induced the formation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol, Sal), N-methyl-salsolinol (NMSal) and 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (6-OH-MTHBC) in fetal rat brains. Determined by HPLC with electrochemical detector, the levels of dopamine and 5-hydroxytryptamine in whole fetal brain were not remarkably altered by ethanol treatment, while the levels of homovanillic acid and 5-hydroxyindole acetic acid in high dose (4.0 g/kg) of ethanol-treated rats were significantly decreased compared to that in the control animals. 4.0 g/kg ethanol administration inhibited the activity of mitochondrial monoamine oxidase (51.3 % as compared to control) and reduced the activity of respiratory chain complex I (61.2 % as compared to control). These results suggested that ethanol-induced alteration of monoamine metabolism and the accumulation of dopamine-derived catechol isoquinolines and 5-hydroxytryptamine-derived tetrahydro-beta-carbolines may play roles in the developmental dysfuction of monoaminergic neuronal systems.

Perinatal lead exposure alters postnatal cholinergic and aminergic system in rat brain: reversal effect of calcium co-administration

Our earlier studies indicated the role of neurotransmitter systems in lead (Pb) induced behavioral perturbations. In this study, we examined the alterations in synaptosomal acetylcholine (ACh), epinephrine, dopamine, acetylcholinesterase (AChE), and mitochondrial monoamine oxidase (MAO) in the cerebellum and hippocampus of perinatally Pb-exposed rats. Rats (Wistar) were exposed to 0.2% Pb (Pb acetate in drinking water of mother) from gestational day 6 and the pups were exposed lactationally (through mother's milk) to Pb till weaning (postnatal day 21). Studies conducted on different postnatal days (PND 21, 28, 35 and 60) showed significant decreases in synaptosomal AChE and mitochondrial MAO activities, and increases in the levels of ACh, dopamine and epinephrine in the cerebellum and hippocampus of Pb-exposed rats. These alterations were greater at PND 35 and more pronounced in the cholinergic system (ACh and AChE) of hippocampus and the aminergic system (epinephrine, dopamine and MAO) of cerebellum. The total locomotor activity and exploratory behavior were also decreased significantly in Pb-exposed animals corresponding to the alterations observed in cholinergic and aminergic systems. Calcium administration together with Pb, however significantly reversed the Pb-induced alterations in transmitters and enzymes, as well as exploratory and motor behavior suggesting protective effect of calcium in Pb-exposed animals.

5-Hydroxytryptamine is a substrate for both species of monoamine oxidase in beef heart mitochondria.

The activity of beef heart mitochondrial monoamine oxidase towards 5-hydroxytryptamine (5-HT) is inhibited by the selective inhibitors clorgyline, PCO [5-phenyl-3-(N-cyclopropyl)-ethylamine-1,2,4-oxidiazole] and Deprenyl with a biphasic dependence on the inhibitor concentration. The activities towards tyramine, dopamine and tryptamine were also inhibited in a biphasic manner, but the apparent proportions of the two enzyme species active on dopamine and tryptamine depended on the inhibitor used. Phenethylamine oxidation was inhibited in a monophasic manner suggesting that only a single enzyme species was responsible for the oxidation of this substrate. The biphasic response of 5-HT oxidation to inhibition by clorgyline persisted when functionally competent mitochondria were used and was unaffected by the soluble amine oxidase inhibitors semicarbazine and aminoguanidine. These results indicate that the behaviour of the beef heart enzyme towards selective inhibitors is considerably different from that of any preparations previously studied and suggest that the classification of monoamine oxidase activites into A and B types may be only of limited usefulness.

Amethocaine-induced inhibition of mitochondrial monoamine oxidase activity

Amethocaine (tetracaine) (1-10 microM) produces a concentration-dependent in-vitro inhibition of mitochondrial membrane-bound MAO activity towards tyramine (18-84% in brain and 19-84% in liver) and 5-hydroxytryptamine (5-HT) (23-94% in brain and 20-100% in liver). At relatively higher concentrations (25-300 microM) of amethocaine, benzylamine oxidation is inhibited in brain (24-91%) and liver (29-100%). The extent of MAO inhibition is appreciably reduced when preincubation time of the enzyme with a low concentration (7.5 microM) of amethocaine is increased from zero to 45 min. This inhibition is reversible. The Km of MAO for tyramine is increased in brain (106-473%) and liver (121-352%) in the presence of amethocaine (2-7.5 microM) accompanied by a decrease in Vmax (21-51% in brain and 18-57% in liver). Similarly the Km of MAO for 5-HT is increased to the extent of 79-336% in brain and 51-225% in liver and the corresponding Vmax is decreased by 35-55% and 39-74%, respectively, in the presence of 2-5 microM amethocaine. At relatively higher concentrations (25-100 microM), amethocaine increases the Km of MAO for benzylamine in brain (25-101%) and liver (26-85%) and decreases the Vmax by 28-64% and 32-63% in the respective tissues. Thus these results suggest that amethocaine preferentially inhibits MAO-A and the nature of inhibition is reversible and of mixed type.

Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 2) modulation of glucose uptake and monoamine oxidase activity

Beta3-adrenergic agonists are well-recognited to promote lipid mobilisation and adipose tissue remodeling in rodents, leading to multilocular fat cells enriched in mitochondria. However, effects of beta3-adrenergic agonists on glucose transport are still controversial. In this work, we studied in white adipose tissue (WAT) the influence of sustained beta3-adrenergic stimulation on the glucose transport and on the mitochondrial monoamine oxidase (MAO) activity. As one-week administration of CL 316243 (CL, 1 mg/kg/d) induces beta-adrenergic desensitization in rat but not in guinea pig adipocytes, attention was paid to compare these models. When expressing glucose uptake as nmoles of 2-deoxyglucose/100 mg cell lipids, maximally stimulated uptake was increased in adipocytes of WAT from treated rats but not from treated guinea pigs. However, basal hexose uptake was also increased in CL-treated rats and, as a consequence, the dose-dependent curves for insulin stimulation were similar in control and CL-treated rats when expressed as fold increase over basal. Insulin-induced lipogenesis was unchanged in rat or guinea pig adipocytes after CL-treatment. The glucose carriers GLUT4 and corresponding mRNA were increased in subcutaneous WAT or in brown adipose tissue (BAT) but not in visceral WAT or muscles of CL-treated rats. There was an increase of MAO activity in WAT and BAT, but not in liver, of CL-treated rats while no change was detected in guinea pigs. These findings show that only rat adipocytes, which are beta3-adrenergic-responsive, respond to chronic beta3-AR agonist by an increase of GLUT4 content and MAO activity, despite a desensitization of all beta-adrenoceptor subtypes.

Increased monoamine oxidase and semicarbazide-sensitive amine oxidase activities in white adipose tissue of obese dogs fed a high-fat diet

Adipocytes express two types of amine oxidases: the cell surface semicarbazide-sensitive amine oxidase (SSAO) and the mitochondrial monoamine oxidase (MAO). In human abdominal subcutaneous adipose tissue, it has been reported that SSAO substrates stimulate glucose transport and inhibit lipolysis while MAO activity is decreased in obese patients when compared to age-matched controls. However, no information has been reported on visceral WAT. To further investigate the obesity-induced regulations of MAO and SSAO in white adipose tissue (WAT) from different anatomical locations, enzyme activities and mRNA abundance have been determined on tissue biopsies from control and high-fat fed dogs, an obesity model already described to be associated with arterial hypertension and hyperinsulinemia. MAO activity was increased in the enlarged omental WAT of diet-induced obese dogs, but not in their mesenteric WAT, another intra-abdominal fat depot. Subcutaneous WAT did not exhibit any change in MAO activity, as did the richest MAO-containing tissue: liver. Similarly, SSAO was increased in omental WAT of diet-induced obese dogs, but was not modified in other WAT and in aorta. The increase in SSAO activity observed in omental WAT likely results from an increased expression of the AOC3 gene since mRNA abundance and maximal benzylamine oxidation velocity were increased. Finally, plasma SSAO was decreased in obese dogs. Although the observed regulations differ from those found in subcutaneous WAT of obese patients, this canine model shows a tissue- and site-specific regulation of peripheral MAO and SSAO in obesity.

Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N‐methyl(R)salsolinol, leading to apoptosis in SH‐SY5Y cells

Mitochondrial monoamine oxidase (MAO) has been considered to be involved in neuronal degeneration either by increased oxidative stress or protection with the inhibitors of type B MAO (MAO-B). In this paper, the role of type A MAO (MAO-A) in apoptosis was studied using human neuroblastoma SH-SY5Y cells, where only MAO-A is expressed. An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, an MAO-A inhibitor, reduced membrane potential, DeltaPsim, in isolated mitochondria, and induced apoptosis in the cells, which 5-hydroxytryptamine, an MAO-A substrate, prevented. In contrast, beta-phenylethylamine, an MAO-B substrate, did not suppress the DeltaPsim decline by N-methyl(R)salsolinol. The binding of N-methyl(R)salsolinol to mitochondria was inhibited by clorgyline, a MOA-A inhibitor, but not by (-)deprenyl, an MAO-B inhibitor. RNA interference targeting MAO-A significantly reduced the binding of N-methyl(R)salsolinol with simultaneous reduction in the MAO activity. To examine the intervention of MAO-B in the apoptotic process, human MAO-B was transfected to SH-SY5Y cells, but the sensitivity to N-methyl(R)salsolinol was not affected, even although the activity and protein of MAO increased markedly. These results demonstrate a novel function of MAO-A in the binding of neurotoxins and the induction of apoptosis, which may account for neuronal cell death in neurodegenerative disorders, including Parkinson's disease.

Design of Optical Switches as Metabolic Indicators: New Fluorogenic Probes for Monoamine Oxidases (MAO A and B)

This study describes the design of sensitive, selective, and fluorogenic reporter substrates for monoamine oxidase (MAO) enzymes. This was achieved by an iterative effort, guided by PET and TICT photophysical concepts, which led to the development of irreversible redox switches based on a facile oxidation-cyclization reporting mechanism. Specifically, enzymatic oxidation of the ethylamino group in probe 9 proceeded via a putative aldehyde intermediate, which subsequently underwent spontaneous and intramolecular condensation with the aniline amino group furnishing an indole product in an irreversible fashion. This overall change resulted in a significant change in the emission intensity. When expressed in terms of brightness, the origins of this emission switch may be rationalized by the changes in quantum yield and absorbance strength. The fluorescence readout directly correlated with the kinetics of the oxidative step (i.e., reporting mechanism was fast, the intermediate aldehyde was not detected). Probe 9 is a good substrate for MAO B (Km = 510 +/- 40 muM, kcat = 21 min-1) with the kinetic parameters comparable to physiological substrates. This probe not only allows for direct and continuous measurement of MAO activity in mitochondria and tissue homogenates, but more importantly sets the stage for future studies in intact cells and organs.

Developmental lead exposure alters mitochondrial monoamine oxidase and synaptosomal catecholamine levels in rat brain

Rats were lactationally exposed to low- (0.2%) and high-level (1%) lead (Pb) from postnatal day 1 (PND1) through PND21 through the drinking water of the mother. The levels of catecholamines, epinephrine, norepinephrine and dopamine and the activity of the enzyme monoamine oxidase (MAO) were determined in the cerebellum, hippocampus and cerebral cortex in young (1-month-old) and adult (3-month-old) rats. Pb-exposure decreased the activity of mitochondrial MAO in all the brain regions in a dose-dependent manner. The synaptosomal catecholamines (epinephrine, norepinephrine and dopamine), however, increased with low level (0.2%) Pb-exposure and significantly decreased with high level (1%) Pb-exposure in both the age groups. In general, the young rats seem to be more vulnerable to Pb-neurotoxicity. These data suggest that Pb-exposure perturbs the aminergic system in the cerebral cortex, cerebellum and hippocampus and may contribute to the cognitive and behavioural impairments observed in Pb-exposed rats.

Nitric oxide inhibits mitochondrial monoamine oxidase activity and decreases outer mitochondria membrane fluidity

The recent finding that mitochondria contain a nitric oxide (NO) synthase suggests that this compound is involved in the regulation of various mitochondrial functions. Monoamine oxidase (MAO) is embedded in the outer mitochondrial membrane. NO modulates membrane fluidity. Thus, the aim of the present work was to study the effect of NO on mitochondrial MAO activity and membrane fluidity. An outer mitochondrial membrane fraction (OMMF) was obtained from rat liver. OMMF was incubated with various concentrations of S-nitroso- N-acetylpenicillamine (SNAP), a NO donor. MAO activity and fluidity were measured by a spectrophotometric assay and by the polarization of fluorescence technique, respectively. It was found that small concentrations of SNAP (0.4–40 μM) were capable of inhibiting MAO activity but unable to decrease fluidity significantly. In contrast, larger amounts of SNAP (40–300 μM) effectively decreased membrane fluidity, but were not able to further decrease MAO activity. This information suggests that mitochondrial MAO and membrane fluidity possess different sensitivity to the effect of NO. Unfortunately, the mechanism by which NO inhibits MAO remains unknown at present. However, it seems likely that the effect of NO on MAO activity is by a direct interaction of the compound or a metabolite to the protein.

Calcium channel agonist, (±)-Bay K8644, causes a transient increase in striatal monoamine oxidase activity in Balb/c mice

We investigated in vivo effects of the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl] pyridine-3-carboxylic acid ((±)-Bay K8644) on mitochondrial monoamine oxidase (MAO) activity and striatal dopamine (DA) content employing fluorimetric and HPLC-electrochemical procedures, respectively. (±)-Bay K8644 administration resulted in visible behavioral dysfunctions in mice. A reversible dose-independent inhibition of striatal DA levels and a significant increase in the brain mitochondrial MAO-A and -B activities were observed in animals treated with the calcium agonist. A positive relationship between the rise in the enzyme activity and decrease in DA content in (±)-Bay K8644 treated animals indicates a direct, but transient effect of this channel activator on DA metabolism, which may be related to acute behavioral syndromes exhibited following administration of the drug. Moreover, a direct involvement of L-type dihydropyridine sensitive calcium channels is indicated in this action, since nicardipine could effectively attenuate (±)-Bay K8644-induced behavioral aberrations, or block the striatal DA depletion and the increase in MAO activity. The present results have far-reaching implications in neuropharmacological research, where co-treatment of calcium channel drugs and MAO inhibitors are warranted.

Rosmarinic acid and caffeic acid produce antidepressive-like effect in the forced swimming test in mice

We previously showed that rosmarinic acid from the leaves of Perilla frutescens Britton var. acuta Kudo (Perillae Herba) has antidepressive-like activity. The aim of the present study was to examine (i) whether caffeic acid, a major metabolite of rosmarinic acid, also has antidepressive-like activity, and (ii) whether these substances inhibit either the uptake of monoamines to synaptosomes or mitochondrial monoamine oxidase activity. Rosmarinic acid (2 mg/kg, i.p.) and caffeic acid (4 mg/kg, i.p.) each significantly reduced the duration of immobility in the forced swimming test in mice. In contrast, neither substance, at doses that produced a significant reduction in the immobile response in the forced swimming test, affected spontaneous motor activity. These results indicate that, like rosmarinic acid, caffeic acid also possesses antidepressive-like activity. In neuropharmacological studies, neither rosmarinic acid (10 −9–10 −3 M) nor caffeic acid (10 −9–10 −3 M) affected either the uptake of monoamines to synaptosomes or mitochondrial monoamine oxidase activity in the mouse brain. These results suggest that both caffeic acid and rosmarinic acid may produce antidepressive-like activity via some mechanism(s) other than the inhibition of monoamine transporters and monoamine oxidase.

Effect of MPTP on Dopamine metabolism in Ames dwarf mice.

Hypopituitary dwarf mice exhibit a heightened antioxidative capacity and live extensively longer than age-matched controls. Importantly, dwarf mice resist peripheral oxidative stress induced by paraquat, and behaviorally, they maintain cognitive function and locomotor activity at levels above those observed in old wild-type animals. We assessed monoaminergic neurotransmitters in nigrostriatal tract and cerebellum after the administration of the dopaminergic neurotoxin, MPTP. There was no significant change in mitochondrial monoamine oxidase (MAO)-B and total MAO activity in the substantia nigra and nucleus caudatus putamen of wild-type and dwarf mice. Coenzymes Q-9 and Q-10 were present in similar quantities, as were dopamine, norepinephrine, and serotonin levels in the cerebellum and nigrostriatal tract. MPTP set off tremor, hind limb abduction, and straub tail behavior and induced significant dopamine depletion in the striatum of both dwarf and normal mice. This study shows that the MAO activity and the coenzyme content of dwarf mice are similar to those of their wild-type controls and hence susceptible to MPTP-induced toxicity.

Monoamine oxidase in amphistomes and its role in worm motility

The quantitative assay of mitochondrial monoamine oxidase (MAO) activity revealed a higher enzyme level in Explanatum explanatum than Gastrothylax crumenifer. The specific MAO inhibitors, chlorgyline, pargyline, deprenyl and nialamide produced different degrees of interspecific inhibition. The differential effects on enzyme activity of chlorgyline and deprenyl suggests the possible existence of polymorphic forms of the enzyme, MAO-A and MAO-B, in amphistomes. These specific inhibitors also had a differential influence on the in vitro motility of amphistomes, further indicating the involvement of different forms of MAO in the oxidative deamination of biogenic monoamines which might be partly responsible for neuromuscular coordination in amphistomes. The experimental procedures used in this study could be conveniently used for quick screening and evaluation of some of the qualitative effects of anthelmintic drugs under in vitro conditions.