Antidepressant drugs and their progress in research methods

 

Depression (depression) is caused by a variety of mood disorders as the main feature in the syndrome. With the intensification of various stress factors, and its incidence is rising fast, high and difficult to cure. But its pathogenesis is very complex and has not yet been clarified, from the earliest monoamine hypothesis, the hypothalamic-pituitary-adrenal (HPA) axis negative feedback disorders, to cellular and molecular mechanisms and so may be associated with the pathogenesis of depression. With the proposed pathogenesis, in elucidating the etiology of depression and further enrich the experimental research methods, but also for the development of safe and effective drugs specified direction. In recent years, especially in the natural antidepressant drug research achieved a certain development, clinical obtain high efficacy and low side effects of the drug provides a broad prospect. Summary of focus for nearly five years, domestic natural antidepressant drug research progress and on the progress of the corresponding research methods are summarized.

    An antidepressant progress

    Its development and the development of new breakthroughs in the treatment of depression, particularly in natural medicine research will become the new hot spots and trends.

    1.1 Chemical antidepressants

    In recent years, the development of antidepressant drugs, including: both dopamine (DA) D2 receptor partial agonist and 5 - by serotonin 1 A (5-HT1A) receptor agonist drugs in animal models have a good anti- depressive effect bifeprunox, lE conducting Phase ? clinical study. Corticotropin releasing hormone (CRH) receptor antagonist antalarmin can reverse the chronic stress caused by changes in the HPA axis, efficacy and quite atmosphere Paxil. Melatonin agonist agomelatine is the first one to melatonin hormone receptor as a target of antidepressants, melatonin receptor 1 and receptor 2 agonist, while also 5-HT2. Receptor antagonists, drug effectiveness and the selectivity of the currently used 5 - serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs) are similar, but rare adverse reactions typical of both, Patients with better tolerated. Currently the company has been in the EU Servier submitted an application for registration of the drug for the treatment of adult depression. According to reports, the U.S. pharmaceutical company found that one kind of Synaptic new, potent with I kind of G-protein coupled receptors as targets of antidepressant drugs, the antidepressant effect with Eli Lilly's antidepressant fluoxetine is similar, and few adverse reactions.

    1.2 Antidepressant Natural Medicine

    1.2.1 antidepressant active ingredient

    1.2.1.1 made rutin flavonoids Noldner (rutin) is Hypericum antidepressant active ingredient. Li Yunfeng et al reported that cottonseed total flavonoids (CTN-1) shorten the big mouse forced swimming (FST) and tail suspension (TST) immobility time, enhance 5 - hydroxy tryptophan (5-HTP)-induced head twitch behavior. Zhang Liming, etc. explore one kind of new antidepressants quercetin -3-0 - Celery glucoside (CTN-986) on neural precursor cell proliferation discovery, CTN-986 can promote neuronal precursor cell proliferation and play the role of the activation of the 5-HT1A receptor close. Wendy et al reported that one kind from bassiana (beauveria ap) metabolites extracted new biologically active substances (mainly glycosides, ketones, etc.), TST and FST in mice significantly reduced the immobility time; small model of chronic stress Rat brain mitochondrial monoamine oxidase weight (MAO-A, B) significantly inhibited activity, and showed a dose-effect relationship.

    1.2.1.2 lignans Takahiro N and other studies show that: human oral Magnolia Magonodia officinalis leaf aqueous extract in human urine samples obtained Magnolol (magnolol) and its metabolites dihydroxy-dihydro Magnolol (dihydroxydromagnol- ol), with desipramine as a control, and Magnolol dihydroxy-dihydro metabolites in mice Magnolol FST, showed Magnolol and dihydroxy dihydro Magnolol all have antidepressant effects, mechanism of action may be Y-aminobutyric acid (GABAergic) function.

    1.2.1.3 organic acids Xu Y and other research turmeric Curcuma longa Turmeric acid can reduce the rat FST immobility time; confrontation with bilateral olfactory bulb damage model (0B) abnormal behavior in rats. Takeda et al reported that antidepressants Perilla Perilla frtecehs traditional leaf water extract can significantly shorten the FST immobility time in mice, isolated rosmarinic acid (rosmarinic acid) is the main active ingredient antidepressant.

    1.2.1.4 oligosaccharides Yunfeng other research Morinda inulin-type oligosaccharides monomer composition on the mechanism of antidepressant effect in mice, that it may be associated with increased expression of nerve cell growth factor, and thus induced corticosterone neuronal injury produce protective effects.

    1.2.1.5 benzene piperazine propane Lee SA, etc. from Piperaceae Piper longum Piper lon-gum fruit ethanol extract obtained benzene piperazine propane with monoamine oxidase inhibition, MAO-A and MAO-B with IC50 20.9,7.0 mmol · L-1, inhibition constant Ki was 19.0 + / -0.9,3.19 = / -0.5 mmol · L-1, and the inhibition is reversible.

    1.2.1.6 curcumin Xu Ying and other studies have found that curcumin can reverse reserpine-induced hypothermia in mice, increased 5-HTP-induced mice shakes times antagonize high doses of apomorphine induced hypothermia in mice decline significantly increased in mice brain 5 - hydroxytryptamine (5-HT) levels. Wan Choi Ha and other studies have shown that curcumin derivatives FMO2 has good water solubility, dose 5,10 mg · kg-1 mice fed with good antidepressant effect.

    1.2.1.7 glycosides Pan Y et al reported that icariin can shorten the FST and TST immobility time in the fight against forced swimming induced brain monoamine oxidase activity and plasma corticotropin-releasing factor (CRF) concentration increased, reversing the brain reduce the concentration of monoamine neurotransmitters. Gu et al reported that daidzein Chaoyang Juan salt antidepressant effects and drug dose, time of administration and sex of mice is closely related to the interaction between the male and female differences may be related daidzein Juan salt estrogen-like effects about. Chen Yao et al reported Centella celecoxib mechanism of antidepressant activity and improvement of HPA axis function and increased monoamine relevant. Masuda et al study Kami-shoyo-san can significantly alleviate the despair behavior in mice, determination of active ingredient is oxygen glycoside structure. Zhao Zhiyu glycosides such as studies have shown that glycyrrhizin can improve depression symptoms of anhedonia model, antidepressant effect may be by increasing the body superoxide dismutase activity, eliminate free radicals, prevent lipid peroxidation, reducing the formation of malondialdehyde achieved.

    1.2.2 single herb

    1.2.2.1 Hypericum Sanchez-Mateo CC, etc. [211 reported two Hypericum field Pericum canariense and H.glandulosum methanol extract of the aerial parts of its two parts butanol and chloroform can significantly shorten the small FST immobility time in mice, H.glandulosum chloroform site may antagonize SBR quinolizine induced eye drooping; H.glandulosum chloroform extract on immobility time of FST and imipramine considerably. Wan De-guang et al reported Hypericum H.perforatum, sampsonii H.sampsonii and Yangtze small forsythia H.faberi, 3 ? group Hypericum Hypericum medicinal plants with the same mouse FST and TST can shorten the immobility time, but ethanol extract of Hypericum perforatum antidepressant effect was stronger than the Yangzi small forsythia.

    1.2.2.2 ginkgo Sakakibara H et al reported that ethanol extract of Ginkgo biloba 10,50 mg · kg-1 administered 14 d or a single intraperitoneal given 50,100 mg · kg-1 can significantly shorten the FST in rats and mice do not move the TST time.

    1.2.2.3 licorice licorice Dhingra D et al reported that water extract 150 mg · kg-1 reduced male albino mice in FST and TST immobility time of the experiment, its mechanism may monoamine oxidase inhibition.

    1.2.2.4 sage Mora S and other studies of sage Salvia elegans Vahl leaves 60% ethanol extract in rat FST, the immobility time reduced role and 10 mg · kg-1 fluoxetine or 12. 5 mg · kg-1 intraperitoneal injection of imipramine efficacy considerably.

    1.2.2.5 lantana Mora S et al verbena Coma lantana Aloy-sia that plus tachya (Griseb.) Moldenke leaf ethanol extract reduced rat FST immobility time role.

    1.2.2.6 Catuama Campos MM, etc. will Catuama acute and chronic administration, can shorten the mouse and retaining FST FST immobility time; vitro experiments showed that: Catuama dose-dependent inhibition of rat brain synaptic monoamine neurotransmitter re- intake, and can increase the release of monoamine neurotransmitters, has a significant antidepressant effect.

    1.2.2.7 Kudzu Pueraria Yan B et al reported an ethanol extract can significantly shorten the brain ischemia-reperfusion (CIR) model of mouse FST and TST immobility time; while reversing CIR mouse hippocampus and striatum to go norepinephrine (NE), and 4 - dihydroxyphenyl acetic acid (DOPAC) decreased effect.

    1.2.2.8 one kind of Paecilomyces metabolite extract Kan Hongwei observe one kind of Paecilomyces metabolite extract (bioactive compounds from paecilomy-ces tenuipes, BCPT), can improve chronic unpredictable mild stress (CUMS) Large mouse serum glutathione peroxidase (GSH-PX), catalase (CAT), total superoxide dismutase (T-SOD) activity, decreased serum MDA, NO content, improve CUMS rat serum mouse spleen lymphocytes in vitro. Fang Zheng et al BCPT antidepressant effect may reduce chronic stress rat hypothalamus, pituitary arginine vasopressin (AVP) levels, reduced hypothalamic AVPmRNA expression.

    1.2.2.9 Epimedium Zhong Haibo and other studies have shown that Epimedium can significantly shorten the FST and TST immobility time in mice significantly inhibited TST mouse brain and liver MAO-A and MAO-B activity, reversing liver MDA elevated levels.

    In addition, Xu C et al reported front Planwgo asiatica and Maodongqing I-lex pubescens petroleum ether extract, Scrophulariaceae Scrophularia ningpoensis ethyl acetate extract and petroleum ether extract Maodongqing aqueous extract - acidic products are a significant reduction in the learned helplessness experiments failed to evade the number of rats with antidepressant effect.

    1.3 Chinese herbal compound

    Zhu WL, etc. from Chaihujialonggumuli soup saponins extracted parts (SCLM) may be dose-dependent decrease in the FST in mice and rats TST immobility time; PC12 cells induced by corticosterone injury protective effect; reduced intracellular Ca2 + overload; improve nerve cell growth factor mRNA expression, with significant antidepressant activity. Kim SH et al reported CHSGS (CSS) and one of the main components of Bupleurum drugs can shorten the rat FST immobility time reversal of chronic stress (CMS) in rats decreased the amount of sugar consumed. Guo Y, etc. Studies have shown that Banxiahoupu soup extract polysaccharides can significantly shorten the mouse TST and the FST immobility time; low doses given 4 weeks significantly increased the mouse brain monoamine neurotransmitters 5 - HT and DA concentrations. Wang Yemin Banxiahoupu Tang et al reported antidepressant active ingredients mainly in petroleum ether and water-soluble portion, which may be in part through on monoamine neurotransmitter systems integration to achieve the purpose of anti-depressants. Kuribara H et al Sho-ju-sen, by the Japanese pattern bamboo Sasa kurwien-sis Makino et Sibata, Japanese red pine Pinus densiflora and ginseng Panax ginseng3 kinds of Japanese herbal extract composition of the drug, in the learned helplessness experiments showed anti- depressive effect, the active ingredient, mainly from Japan Akamatsu leaf extract. Another BST, Sini, Su Yu capsules, Xinpikaiyu Formula, the more Ju alcohol extract pills and other anti-depressants have been reported.

    2 Advances in Research Methods

    2.1 Establishment of animal model of depression

    From the study drug situation can be clearly seen, depression results of basic research is based on a large part of the basis of animal models. The initial drug-induced animal model of depression, because poor selectivity, credibility is limited, is now only used for screening. Establishment of animal model of depression present method is mainly divided into three categories: behavioral despair, learned helplessness and chronic unpredictable mild stress. However, these models are still used to study separately insurmountable false positive and false negative reactions. Therefore, the combination of which present several models simultaneously, in order to improve the credibility of the results.

    2.1.1 behavioral despair model

    Rat or mouse forced swimming is the evaluation of effects of antidepressants most commonly accepted animal model of depression. This model has a good antidepressant predictive validity, however, this explanation still controversial, animal floating either depressed performance, but also can be an adaptive mechanism, animals in order to save energy in order to maintain a longer float time.

    2.1.2 learned helplessness model

    The animals were exposed to inescapable stress (for example: electric shock) conditions, animal after several attempts could not escape stress situations, became passive acceptance, in the subsequent cognitive task appears more behavioral defects. The main drawback of this model is in humans and other animals lack of reliability, and no evidence of learned helplessness is the individual characteristics of depressive behavior.

    2.1.3 Chronic mild stress

    Currently the most commonly used sub-chronic mild stress and raise a combination of two classic models. And clinical combined together, in a certain extent, can simulate human mood disorders some of the core requirements, consistent with a certain clinical, have become a class of valuable animal model: ? simulation of behavior (models and clinical disease consistency between the symptoms), such as model animals to reduce sugar intake to better simulate the behavior of the human anhedonia, decreased interest in this core symptoms; ? reasonable theoretical foundation, namely modeling tools with clinical depression correlation between the etiology; ? animal models of human pathophysiology of depression are similar, as is currently mainly determined after modeling animal monoamine neurotransmitter associated with some of the HPA axis hormones, cell signaling systematic engagement mode.

    On the current animal models of view, there inadequacies are: ? ignoring gender differences, now mostly in male, and in the incidence of mood disorders, there are significant differences between men and women, including psychological and social factors, endocrine, pathophysiology. ? psychosocial stress in animal models with physical stress component. Usually resulting in the emergence and development of human emotional disorders principal stress is social in nature. Currently, the inevitable physical stress component contains the same human psychosocial stress compared to the lack of face validity.

    2.2 of double and multiple drug effects

    With the mechanism of drug action and clinical effects of extensive research and evaluation, more attention to the development of antidepressants enhance the efficacy, shorten the onset time and reduce adverse reactions, etc., and clinical studies have shown that affect both the system of antidepressants role in these areas better than a single anti-depressant drugs, so double and multiple effects of antidepressants have become the focus of research applications.

    3 Summary and Outlook

    Research data from an existing view, the etiology of depression is indeed complex and antidepressants may target a variety of purposes, such as receptors, the concentration of monoamine neurotransmitters, G protein-AC coupling, etc., various antidepressants may act through a different target. Its research should not just be limited to a theoretical basis, an animal model. For the final clinical, the more attention clinical effects of antidepressants. From a focus on drug safety and the rehabilitation of patients with social functions look only at the onset, the efficacy and safety of drugs is superior to the existing circumstances, the development of new drugs have value; evaluate the efficacy of antidepressant drugs also need to be more specific means. Treatment now only effective to some extent, does not fundamentally solve the problem of depression. In short, the development of novel and effective, safe and fast with antidepressants will pathogenesis of depression deepening, and a variety of experimental methods of continuous innovation, continuous improvement model of depression in the near future.