Source, metabolism and function of dopamine in digestive tract / 生理学报

Dopamine (DA), as a catecholamine neurotransmitter widely distributed in the central nervous system and the peripheral tissues, has attracted a lot of attention. Especially in recent years, DA has been found to regulate the function of the immune system, and the involvement of DA in the intestinal mucosal inflammation-related diseases has become a hot research topic. The digestive tract is an important source of peripheral DA, and DA is not only produced in the enteric nervous system and gastrointestinal epithelium, but also produced by intestinal microorganisms. In addition to the synthetases of DA, the DA contents in body tissues are also affected by the two kinds of metabolic enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). This article reviewed the sources, metabolism, and functions of DA in digestive tract, especially focusing on the distribution and function of MAO and COMT, the enzymes degrading DA.

Coumarin analogue 3-methyl-7H-furo[3,2-g]chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Manejo perioperatorio de pacientes usuarios de antidepresivos / Perioperative management of patients using antidepressants

El uso de antidepresivos en el perioperatorio es muy frecuente, y la práctica clínica indica que los pacientes usuarios de antidepresivos que son sometidos a cirugía tienen un riesgo perioperatorio aumentado. No existen en la actualidad guías clínicas basadas en la evidencia que orienten el manejo de este tipo de pacientes, por lo que las recomendaciones se basan en las escasas revisiones sistemáticas y metaanálisis disponibles, reportes de casos y opinión de expertos, que en muchos casos resultan controversiales. La decisión de mantener o suspender la medicación antidepresiva implica considerar los riesgos tanto desde el punto de vista fisiológico (características generales del paciente, riesgos asociados al antidepresivo utilizado, la cirugía propiamente como tal, la interacción con fármacos frecuentemente utilizados en el perioperatorio, entre otros) como desde el punto de vista psiquiátrico (riesgo de síndrome de retirada, recaída de la enfermedad psiquiátrica, intentos suicidas), por lo que la decisión debe ser tomada idealmente de forma multidisciplinaria entre cirujanos, anestesiólogos y psiquiatras, con la idea de confeccionar un plan quirúrgico, anestésico y de manejo perioperatorio seguro para el paciente.

Antidepressant use in the perioperative is a common practice, and clinical evidence shows that surgical patients using antidepressants have an increased perioperative risk. There are not evidence-based guidelines for the perioperative management of these patients, and recommendations are based on few systematic reviews and meta-analysis, case reports and expert opinion, which in many cases are controversial. The decision to continue or discontinue the medication involves considering general patient characteristics, risks associated with the antidepressant used, type of surgery, interaction with drugs commonly used in the perioperative, risk of withdrawal symptoms, relapse of psychiatric disease and suicide risk, so decision should be made between surgeons, anesthesiologists and psychiatrists, in order to design a safe management plan for the patient who undergo surgery.

Novel Pharmacological Treatment for Depression

Development of various antidepressants such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressant has led to a tremendous progression of pharmaceutical treatment for depression, but still there are some limitations of current antidepressants, such as treatment-resistant depression and delayed onset of antidepressants. The pathogenesis of depression is unclear because depression is a heterogeneous disease state, and the mechanisms of antidepressants remain uncertain as well. Nevertheless, in an attempt to develop novel antidepressants, some trials have been conducted based on the potential biological mechanism discovered in the numerous research results. This review will provide information about the potential novel antidepressants and the current states of clinical studies using them. In particular, some potential novel antidepressants anti-inflammatory agents, antioxidants, anticholinergics, modulators of Hypothalamic Pituitary Adrenal Axis, glutamate, and opioid systems, as well as some neuropeptides such as susbstance P, neuropeptide Y, and galanin will be discussed.

Tapentadol: Can It Kill Two Birds with One Stone without Breaking Windows?

Tapentadol is a novel oral analgesic with a dual mode of action as an agonist of the µ-opioid receptor (MOR), and as a norepinephrine reuptake inhibitor (NRI) all in a single molecule. Immediate release (IR) tapentadol shows its analgesic effect quickly, at around 30 minutes. Its MOR agonistic action produces acute nociceptive pain relief; its role as an NRI brings about chronic neuropathic pain relief. Absorption is rapid, with a mean maximal serum concentration at 1.25-1.5 h after oral intake. It is present primarily in the form of conjugated metabolites after glucuronidation, and excretes rapidly and completely via the kidneys. The most common adverse reactions are nausea, dizziness, vomiting, and somnolence. Constipation is more common in use of the ER formulation. Precautions against concomitant use of central nervous system depressants, including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, or use of tapentadol within 14 days of the cessation of monoamine oxidase inhibitors, are advised. The safety and efficacy have not been established for use during pregnancy, labor, and delivery, or for nursing mothers, pediatric patients less than 18 years of age, and cases of severe renal impairment and severe hepatic impairment. The major concerns for tapentadol are abuse, addiction, seeking behavior, withdrawal, and physical dependence. The presumed problem for use of tapentadol is to control the ratio of MOR agonist and NRI. In conclusion, tapentadol produces both nociceptive and neuropathic pain relief, but with worries about abuse and dependence.

Fibromialgia: princípios práticos que auxiliam na indicação e no ajuste do tratamento medicamentoso / Fibromyalgia: practical principles that help in the indication and adjustment of drug treatment

A fibromialgia (FM) é uma síndrome de dor difusa crônica acompanhada de sintomas somáticos, tais como fadiga, transtornos do humor, do sono e da cognição. Em uma abordagem prática do paciente com FM, além das medidas não farmacológicas, cada sintoma pode ser tratado com medicamento específico. O objetivo deste artigo é prover revisão atualizada da literatura sobre os principais medicamentos atualmente disponíveis no Brasil para o tratamento da FM em adultos. O sucesso terapêutico da FM depende, essencialmente, do uso racional de medicamentos voltados para os sintomas refratários às medidas não farmacológicas.

Fibromyalgia (FM) is the chronic widespread pain syndrome associated with fatigue, mood, sleep and cognitive disorders. Besides non-pharmacological approach, each symptom should be treated with a specific drug. The goal of this study is to provide up-to-date literature review on main aspects of adult FM drugs available for use in Brazil. Treatment success in FM depends essentially on using drugs based on symptoms that are not responsive to non-pharmacological approach.

Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition

This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition'. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.

Adverse Effects and Pharmacological Management of Newer Antidepressants: Focusing on Common but Under-Recognized Adverse Effect / 대한정신약물학회지

Nowadays newer antidepressants are commonly used in clinical practice, since they are as effective as tricyclic antidepressant, but show less adverse effects. However there are many unexpected adverse effects of these drugs. It is one of the most common causes of treatment failure. I reviewed these adverse effects and pharmacological management focusing on common but under-recognized adverse effects of newer antidepressant. I reviewed newer antidepressant-induced sleep related movement disorder, sweating, tremor, abnormal bleeding. In this paper, newer antidepressants include selective serotonin reuptake inhibitor (fluoxetine, fluvoxamine, citalopram, escitalopram, sertraline, paroxetine), serotonin norepinephrine reuptake inhibitor (venlafaxine, duloxetine), norepinephrine and dopamine reuptake inhibitor (bupropion), noradrenergic and specific serotonergic antidepressant (mirtazapine), and reversible inhibitor of monoamine oxidase A (moclobemide). I suggest that psychiatrists should know not only well-recognized but also under-recognized common adverse effects and their pharmacological management of newer antidepressants, so that it will be helpful to treat patients with psychiatric illness using newer antidepressants and to make better outcome.

Flavoproteínas que actúan como amino-oxidasas: Estructura, función e importancia clínica / Flavoproteins acting as amine oxidases: Structure, function and clinical significance / Flavoproteínas atuando como amina oxidases: Estrutura, função e significado clínico

Se destaca la actividad de las flavoenzimas como amino-oxidasas, que intervienen en el metabolismo de las aminas biogénicas como biorreguladores, especialmente en el crecimiento y la diferenciación celular. La clasificación de las amino-oxidasas incluye flavoenzimas y quinoenzimas. Se analizan las amino-oxidasas que son flavoproteínas, como las monoamino-oxidasas y las poliamino-oxidasas. Se discuten las isoformas, estructuras y función de ambas, sus sustratos e inhibidores, la expresión de MAO-A y MAO-B en tejidos humanos y sus implicancias clínicas. MAO plaquetaria es un biomarcador de desórdenes mentales y neurodegenerativos. Los inhibidores selectivos de MAO-A resultaron ser eficaces antidepresivos, mientras que algunos de MAO-B se utilizan en el tratamiento de enfermedades de Parkinson y de Alzheimer. La identificación de elevadas concentraciones de poliaminas en varias enfermedades, desde cáncer y psoriasis hasta infecciones parasitarias, hace que la manipulación de su metabolismo sea un blanco terapéutico o preventivo en ciertas enfermedades. Se discute además qué poliamino-oxidasas actúan en el metabolismo de las poliaminas en humanos, frente a las presentes en plantas, bacterias y protistas. Las poliaminas y las enzimas de su metabolismo desempeñan funciones relevantes en los procesos de envejecimiento y en algunas enfermedades, como cáncer, diabetes mellitus, accidentes cerebro-vasculares, insuficiencia renal y trastornos psiquiátricos.

The activity of flavoenzymes as amine oxidases involved in the metabolism of biogenic amines as bioregulators is highlighted, particularly for cell growth and differentiation. The classification of amine oxidases includes flavoenzymes and quinoenzymes. Amine oxidases that are flavoproteins, such as monoamine oxidases and polyamine oxidases, are analyzed herein. The isoforms, structures and functions of both enzyme families, their substrates and inhibitors, the expression of MAO-A and MAO-B in human tissues, and their clinical implications are discussed. Platelet MAO is a biomarker of mental and neurodegenerative disorders. Selective MAO-A inhibitors proved to be effective antidepressants, while some MAO-B inhibitors are used for treatment of Parkinson's and Alzheimer's diseases. The identification of high concentrations of polyamines in a variety of diseases, from psoriasis to cancer and parasitic infections, makes handling their metabolism a therapeutic or preventive target for the treatment of some diseases. Also polyamine oxidase activity on polyamine metabolism in humans, compared to those present in plants, bacteria and protists,is discussed. Polyamines and the enzymes involved in their metabolism play important roles in the aging processes, as well as in certain diseases such as cancer, diabetes mellitus, stroke, kidney failure, and defined psychiatric disorders.

Foi enfatizada a atividade de flavoenzimas como as amina oxidases envolvidas no metabolismo de aminas biogênicas como biorreguladores, especialmente no crescimento e diferenciação celular. A classificação das amina oxidases inclui flavoenzimas e quinoenzimas. Amina oxidases que são flavoproteínas, tais como monoamina oxidases e poliamina oxidases, são analisadas. Isoformas, estrutura e função das duas oxidases são discutidas, os seus substratos e inibidores, a expressão de MAO-A e MAO-B em tecidos humanos e suas implicações clínicas. MAO plaquetária é um biomarcador de desordens mentais e neurodegenerativas. Os inibidores selectivos da MAO-A resultaram ser eficazes antidepressivos, embora alguns dos MAO-B sejam utilizados no tratamento da doença de Parkinson e de Alzheimer. A identificação de elevadas concentrações de poliaminas em várias doenças, desde câncer e psoríase a infecções parasitárias, faz com que a manipulação do seu metabolismo seja um alvo terapêutico ou preventivo em certas doenças. Também se discute que a poliamina oxidase atua sobre o metabolismo das poliaminas no ser humano, em comparação com aquelas presentes em plantas, bactérias e protistas. As poliaminas e enzimas do seu metabolismo desempenham papéis relevantes nos processos de envelhecimento e em algumas doenças, tais como câncer, diabetes miellitus, acidente vascular cerebral, insuficiência renal e perturbações psiquiátricas.

Xanthoangelol and 4-Hydroxyderricin Are the Major Active Principles of the Inhibitory Activities against Monoamine Oxidases on Angelica keiskei K

Monoamine oxidase inhibitors (MAOI) have been widely used as antidepressants. Recently, there has been renewed interest in MAO inhibitors. The activity-guided fractionation of extracts from Angelica keiskei Koidzumi (A. keiskei K.) led to the isolation of two prenylated chalcones, xanthoangelol and 4-hydroxyderricin and a flavonoid, cynaroside. These three isolated compounds are the major active ingredients of A. keiskei K. to inhibit the MAOs and DBH activities. Xanthoangelol is a nonselective MAO inhibitor, and a potent dopamine beta-hydroxylase (DBH) inhibitor. IC50 values of xanthoangelol to MAO-A and MAO-B were calculated to be 43.4 microM, and 43.9 microM. These values were very similar to iproniazid, which is a nonselective MAO inhibitor used as a drug against depression. The IC50 values of iproniazid were 37 microM, and 42.5 microM in our parallel examination. Moreover, IC50 value of xanthoangelol to DBH was calculated 0.52 microM. 4-Hydroxyderricin is a potent selective MAO-B inhibitor and also mildly inhibits DBH activity. The IC50 value of 4-hydroxyderricin to MAO-B was calculated to be 3.43 microM and this value was higher than that of deprenyl (0.046 microM) used as a positive control for selective MAO-B inhibitor in our test. Cynaroside is a most potent DBH inhibitor. The IC50 value of cynaroside to DBH was calculated at 0.0410 microM. Results of this study suggest that the two prenylated chalcones, xanthoangelol and 4-hydroxyderricin isolated from A. keiskei K., are expected for potent candidates for development of combined antidepressant drug. A. keiskei K. will be an excellent new bio-functional food material that has the combined antidepressant effect.

Evidence-Based Korean Pharmacological Treatment Guideline for Depression, Revised Edition (II) : Antidepressant Efficacy Compared with Placebo, Difference in Efficacy of Antidepressants, and Appropriate Time of Efficacy Judgment in Antidepressant Therapy / 신경정신의학

OBJECTIVES: The purpose of this study was to suggest recommendations of antidepressant efficacy compared with placebo, difference in efficacy of antidepressants, and appropriate time of efficacy judgment in antidepressant therapy. METHODS: Using recommendations from 12 international and domestic clinical practice guidelines for depression, drawing of recommendation drafts, and peer review, the executive committee developed the guideline. RESULTS: Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific serotonergic antidepressants (NaSSAs), norepinephrine and dopamine reuptake inhibitors (NDRIs), and serotonin antagonist and reuptake inhibitors (SARIs) were strongly recommended as having antidepressant efficacy compared with placebo. Difference in efficacy of antidepressants was as follows. TCAs, MAOI, SSRI, SNRIs, and NaSSAs were strongly recommended, however, NDRIs, SARIs were weakly recommended. If there was no or minimal improvement with treatment, appropriate time of efficacy judgment in antidepressant therapy was estimated to be after two to four weeks. CONCLUSION: We hope that the results of this study will be helpful in encouraging the optimal treatment by understanding antidepressant efficacy compared with placebo, difference in efficacy of antidepressants, and appropriate time of efficacy judgment in antidepressant therapy.

Evidence-Based Korean Pharmacological Treatment Guideline for Depression, Revised Edition (III) : Dose Increment, Switching, Combination, and Augmentation Strategy in Antidepressant Therapy / 신경정신의학

OBJECTIVES: The aim of this study was to demonstrate the recommendations for antidepressant treatment strategy of dose increment, switching, combination, and augmentation therapy derived from Evidence-Based Korean Pharmacological Treatment Guideline for Depression, Revised Edition. METHODS: The guideline was developed through adaptation of 12 domestic and foreign clinical guidelines for depression, with key questions concerning pharmacotherapy of depression, and drawing of recommendations. RESULTS: The guideline strongly recommended dose increment, switching, and combination and augmentation therapy of antidepressant when patients with depression showed inadequate treatment outcomes from initial antidepressant treatment. The dose increment was strongly recommended when the patients had insufficient response from treatment with tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), and serotonin and norepinephrine reuptake inhibitors (SNRIs). Switching from SSRI to non-SSRI was also strongly recommended. The combination of initial medication and other classes of antidepressants could benefit from treatment with TCAs, SSRIs, SNRIs, and noradrenergic and specific serotonergic antidepressants. Combination with norepinephrine and dopamine reuptake inhibitors or serotonin-2 antagonist/reuptake inhibitors was weakly recommended. The guideline strongly recommended use of the augmentation strategy of adding lithium or benzodiazepine to initial antidepressants. Augmentation of lamotrigine, T3, methylphenidate, and modafinil was weakly recommended. CONCLUSION: If the initial outcomes of antidepressant therapy are unsatisfactory to the patients the next-step strategies of dose increment, switching, combination and augmentation of antidepressants should be considered after rechecking the patients' drug compliance, dose, and diagnosis.

Multi Target Neuroprotective and Neurorestorative Anti-Parkinson and Anti-Alzheimer Drugs Ladostigil and M30 Derived from Rasagiline

Present anti-PD and -AD drugs have limited symptomatic activity and devoid of neuroprotective and neurorestorative property that is needed for disease modifying action. The complex pathology of PD and AD led us to develop several multi-target neuroprotective and neurorestorative drugs with several CNS targets with the ability for possible disease modifying activity. Employing the pharmacophore of our anti-parkinson drug rasagiline (Azilect, N-propagrgyl-1-R-aminoindan), we have developed a series of novel multi-functional neuroprotective drugs (A) [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase and brain selective monoamine-oxidase (MAO) A/B inhibitory activities and (B) the iron chelator-radical scavenging-brain selective monoamine oxidase (MAO) A/B inhibitor and M30 possessing the neuroprotective and neurorescuing propargyl moiety of rasagiline, as potential treatment of AD, DLB and PD with dementia. Another series of multi-target drugs (M30, HLA-20 series) which are brain permeable iron chelators and potent selective brain MAO inhibitors were also developed. These series of drugs have the ability of regulating and processing amyloid precursor protein (APP) since APP and alpha-synuclein are metaloproteins (iron-regulated proteins), with an iron responsive element 5"UTR mRNA similar to transferring and ferritin. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats after oral doses. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain. Ladostigil acts like an anti-depressant in the forced swim test in rats, indicating a potential for anti-depressant activity. Ladostigil prevents the destruction of nigrostriatal neurons induced by infusion of neurotoxin MPTP in mice. The propargylamine moiety of ladostigil confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells. The multi-target iron chelator M30 has all the properties of ladostigil and similar neuroprotective activity to ladostigil, but is not a ChE inhibitor. M30 has a neurorestorative activity in post-lesion of nigrostriatal dopamine neurons in MPTP, lacatcystin and 6-hydroxydopamine animal models of PD. The neurorestorative activity is related to the ability of the drug to activate hypoxia inducing factor (HIF) which induces the production of such neurotrophins as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and erythropoietin as well as glia-derived neurotrophic factor (GDNF). The unique multiple actions of ladostigil and M30 make the potentially useful drugs for the treatment of dementia with Parkinsonian-like symptoms and depression.

Effect of monoamine oxidase inhibitor on the differentiation of malignant glioma cell / 生物医学工程学杂志

To investigate the effect of monoamine oxidase inhibitor tranylcypromine (TCP) on the differentiation of human U251 glioma cells, we treated U251 cells with TCP and/or 100 nmol/L histone deacetylase inhibitor trychostatin A (TSA). The differentiation of U251 cells was observed with inverted microscopy. The cell proliferation and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Apoptosis was observed by Hoechst 33258 staining. The levels of differentiation-related genes were assessed by real-time PCR and Western blotting. TCP-induced differentiation was characterized by typical morphological changes, inhibition of cellular proliferation, accumulation of cells in the G1 phase of the cell cycle, decreased expression of the pluripotency transcription factors Oct4 and Sox2, and increased expression of glial fibrillary acid protein (GFAP). The combination of TCP and TSA treatment also triggered an over-expression of GFAP. These findings suggest that TCP may induce differentiation of U251 glioma cells, and the differentiation process may be promoted by histone deacetylase inhibitor TSA.

Design of acetylcholinesterase inhibitor for Alzheimer's disease therapy: from multi-binding site inhibitors to multi-target directed ligands / 药学学报

Alzheimer's disease (AD) is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide. Drug discovery for Alzheimer's disease therapy has been a hot research area and a big challenge, in which development of acetylcholinesterase (AChE) inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already. However, practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects. Thus, it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects. Based on the accurate crystallographic studies about AChE, strategies for multi-binding site AChE inhibitors have been formed, followed by design of the multi-target directed ligands. In this review, the structures and binding modes of commercial AChE inhibitors were briefly discussed, together with the development of AChE inhibitor design for AD therapy: from multi-binding site inhibitors to multi-target directed ligands.

MAO-inhibitors in Parkinson's Disease

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD.

Treatment of Parkinson's disease in Thailand: review of the literature and practical recommendations.

The mainstay of treatment for Parkinson's Disease (PD) remains symptomatic despite the rapid expansion in knowledge of its neurodegenerative process. Therapeutic options, both medical and surgical, have been markedly improved over the past decades, resulting in better motor function, activities of daily living, and quality of life for PD patients. The principle of PD management should be individualized and the selection of treatments should aim to control symptoms as well as to prevent or delay motor complications. In Thailand, various pharmacologic and surgical options are available, including different formulations of levodopa, dopamine agonists, monoamine oxidase B inhibitor, cathechol-O-methyltransferase inhibitor pallidotomy, and lastly deep brain stimulation. The use of dopamine agonists in early PD has a levodopa-sparing effect and reduces the incidence of motor complications. Continuous dopaminergic stimulation (CDS), which mimics physiological activation of dopaminergic receptors, has been proposed as a strategy to prevent motor complications. Based on current evidence, practical guidelines in the medical management of different types of motor complications are outlined in the present article according to what are available in Thailand. Surgical interventions should be reserved for patients with intractable motor complications after careful patient selection.

Inhibition of MAO and GABA: probable mechanisms for antidepressant-like activity of Nardostachys jatamansi DC. in mice.

Ethanolic extract (100, 200 and 400 mg/kg, po) of N. jatamansi administered for 14 successive days to Swiss young albino mice (either sex) produced significant antidepressant-like effect in both tail suspension and forced swim tests. The efficacy of the extract was found to be comparable to imipramine (15 mg/kg, po) and sertraline (20 mg/kg, po). Ethanolic extract (200 mg/kg, po) did not show any significant change on locomotor activity of mice as compared to control; hence it did not produce any motor effects. Further, the extract decreased the whole brain MAO-A and MAO-B activities as compared tocontrol, thus increased the levels of monoamines. The antidepressant effect of the extract was also significantly reversed by pretreatment of animals with baclofen (GABAB agonist); when tested in tail suspension test. The results suggested that the antidepressant-like effect of the extract may also be due to interaction with GABAB receptors, resulting in decrease in the levels of GABA in mouse brain. Thus, the extract may have potential therapeutic value for the management of mental depression.