ABSTRACT
Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone (GD) effect in vitro to inhibit the A and B isoforms of human monoamine oxidase (hMAO) enzyme and their citotoxicity in human hepatoma cell line (HepG2). Also, binding studies to A1, A2A A2B and A3 adenosine receptors were performed. A docking study of gamma-decanolactone has been carried out with the molecular targets of MAO-A and MAO-B isoforms. The physicochemical properties and ability to cross physiological barriers, as the blood brain barrier (BBB), was elucidated by computational studies. The in vivo assays, the rota-rod test, body temperature assessment and open field test were performed in reserpinized mice (1.5 mg/kg, i.p.; 18:00 before) to evaluate the effect of gamma-decanolactone (300 mg/kg), alone or associated with Levodopa plus Benserazide (LD + BZ, 100:25 mg/kg, i.p.). Gamma-decanolactone inhibited preferentially the MAO-B in a reversible manner, with an inhibitory concentration of 50% (IC50) 55.95 ± 9.06 µM. It was shown to be a safe drug since only at the highest concentration decreased the viability of HepG2 cells. It also does not bind to adenosine receptors investigated in this study. The molecular docking study show that the gamma-decanolactone ligand adopts a relatively compact conformation in the active site of hMAO-B, while we note an extended conformation of gamma-decanolactone ligand in the hMAO-A isoform. The physicochemical properties obtained, and the theoretical models utilized for the evaluation of ability to cross the BBB, predict a good gamma-decanolactone bioavailability and access to the central nervous system (CNS). In the in vivo studies, gamma-decanolactone partially reversed the ataxia of the reserpinized mice at 01:00 h and 01:30 h post-administration. Concomitant treatment of gamma-decanolactone with LD + BZ, at 01:30 h showed a potentiation of the reversibility of ataxia and facilitated the reversal of hypothermia caused by reserpine for all measured times (P <0.01 vs vehicle), except at 24:00 h, but not reversed the hypokinesia in the open field test. In summary, the results herein obtained and in conjunction with previous studies, suggest that gamma-decanolactone could be a drug with potential utility as antiparkinsonian drug.
Subject(s)
Antiparkinson Agents/pharmacology , Lactones/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Parkinson Disease, Secondary/drug therapy , Parkinson Disease/drug therapy , Animals , Antiparkinson Agents/chemistry , Antiparkinson Agents/therapeutic use , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Enzyme Assays , Hep G2 Cells , Humans , Lactones/therapeutic use , Male , Mice , Molecular Docking Simulation , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/therapeutic use , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/pathology , Permeability , Receptors, Purinergic P1/metabolism , Recombinant Proteins/metabolism , Reserpine/administration & dosage , Reserpine/metabolism , Reserpine/toxicity , Structure-Activity RelationshipABSTRACT
ABSTRACT Sida acuta Burm. f., Malvaceae, is regarded as astringent, tonic and useful in treating urinary diseases and blood disorders, bile, liver and as treatment for nervous diseases. Different methods were developed: sodium pentobarbital-induced sleeping time, anxiolytic activity, test for muscle-effects, pentylenetetrazole (PTZ)-induced seizures, effect on normal body temperature. All experiments were performed in an isolated room with 12/12 h light/dark cycles at 22 ± 1 ºC. The effects described in this work for Sida acuta are according to what is known in traditional medicine, where is used as sedative agent. At the higher doses used in this work (500 and 1000 mg/kg), the Sida acuta extract reduced the latency time (T1) and increased the sleeping time (T2) induced by pentobarbital, indicating a sedative and hypnotic effect of the plant's extract. The extract of Sida acuta shows an increase in open arm exploration (anxiolytic activity). Results obtained in the rota-rod test showed that only the elevated dose (750 mg/kg) of Sida acuta extract, acutely administered, promotes significant changes, at 60 and 120 min post-administration, in the time of permanence in the rod. The ethanolic extract from the leaves and stems of Sida acuta, causes effects on the central nervous system in experimental animals.
ABSTRACT
Anxiety is one of the behavior disorders that has been studied more together with depression in the world, and that has enormous interference in the mental health of the affected patients. The states of panic and phobia are a part of the psychological characteristics that some drugs have tried to control though with varied side effects that are proven to be difficult to control. The use of perimidinone derivatives against the effects of anxiety has generated that A5 is the most active and selective anxiolytic compound, differing with regard to diazepam (DZP) used as control reference in elevated plus-maze (EPM) test. This test allows to conclude that it is feasible to differentiate the use selective as anxiolytic or antidepressant of certain perimidinones, because A4 had been characterized by our research group as an important antidepressant respect to A5 studied in previous reports.
Subject(s)
Alkaloids/pharmacology , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Alkaloids/chemistry , Animals , Behavior, Animal/drug effects , Maze Learning/drug effects , Mice , Molecular StructureABSTRACT
In this study we evaluate the in vivo antidepressant effect of a natural phenolic compound, trans-resveratrol, and a synthetic derivative from Menispermum dauricum DC (Menispermaceae) 5-methoxy-7H-dibenzo[de,h]quinolin-7- one known as 5-methoxyoxoisoaporphine (OXO 4). The antidepressant-like effect of trans-resveratrol and OXO 4 were evaluated through a Forced Swimming Test (FST), and they were compared with reference antidepressants: imipramine, desipramine, nomifensine, bupropion, nisoxetine, citalopram and moclobemide. Trans-resveratrol (10 mg/kg, intraperitoneally i.p. significantly decreased the immobility time in mouse model of despair test (69.03 ± 8.74 sec) p<0.05, as well as OXO 4 (1mg/kg, i.p. (60.92 ± 11.37 sec); p<0.05. We also evaluate the OXO 4 at 15, 30 and 45 min. affording the mayor reduction at 30 minutes after the administration. Thus, our results suggest that OXO 4 has a great antidepressant effect non-reported for this type of isoquinoline alkaloids. The pharmaceutical use of OXO 4 in the treatment of depressive disorders is a therapeutic alternative to be studied.
Subject(s)
Antidepressive Agents/pharmacology , Aporphines/pharmacology , Stilbenes/pharmacology , Animals , Aporphines/administration & dosage , Aporphines/chemistry , Dose-Response Relationship, Drug , Mice , Mice, Inbred Strains , Resveratrol , SwimmingABSTRACT
A series of (coumarin-3-yl)carbamates was synthesized and evaluated in vitro as monoamine oxidase (MAO-A and MAO-B) inhibitors. Most of the new compounds selectively inhibited MAO-B isoenzyme with IC50 values in the micro or nanoMolar ranges. Since these compounds must achieve the brain cells, theoretical evaluation of ADME properties were also carried out. Compound 8 (benzyl(coumarin-3-yl)carbamate), which presented the most interesting in vitro MAO-B inhibitory profile (IC50 against MAO-B = 45 nM), was subjected to further studies. This in vitro MAO-B inhibitory activity is comparable with that of the selegiline, the reference compound (IC50 against MAO-B = 20 nM). Taking into account the in vitro results of compound 8, in vivo assays and docking calculations were also carried out for this derivative.
