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Modern Pharmacological Study of Matrine Alkaloids

2018-02-09 19:21:56

Matrine alkaloids are a general term for a class of quinolinic acid alkaloids widely found in Sophora? Avescens Ait, Sophora alopecuroides and Sophora subprostrata. Modern research found that Sophora flavescens mainly contain alkaloids and flavonoids, alkaloids to matrine alkaloids mainly belong to Quinonesidine alkaloids, including matrine, oxymatrine, Sophora flavescens alcohol , Different matrine, do not matrine, 14b-hydroxy matrine, sophocarpine, sophoridine, sophoramine and so on. Modern pharmacological studies have found matrine alkaloids with analgesic, cardiac, anti-arrhythmia, anti-virus, anti-inflammatory, anti-tumor, swelling diuretic, immunosuppressive, antibacterial insecticide and other effects. This article is based on the research status of its pharmacological effects.

First, the analgesic effect

Matrine has a significant effect on analgesia. Junzo Kamei et al. Found that matrine functions mainly through the activation of k-opioid receptors and some μ-opioid receptors. But also has a high selectivity for the receptor with no morphine-like side effects of current analgesic drugs. Junzo Kamei and other experiments induced by acetic acid abdomen showed that matrine dose-dependently inhibited the analgesic effect of mice in the dose range of 1-10 mg / kg. Do not matrine ((+) - allomatrine) is matrine C-6 stereoisomers, which mainly through the activation of k-opioid receptor and exert analgesic effect of analgesic effect of matrine third one. Kimio higashiyama other studies found that matrine and other matrine by stimulating the decay of enkephalin-like neurons, thereby activating the spinal cord k-opioid receptor to achieve analgesic effect. Huperzine alcohol with hydrophilic groups, 14 b-hydroxy matrine, N-oxide of matrine ie oxymatrine, and sophocarpine with double bonds, whereas sophoramine has no significant analgesic activity .

Second, anti-inflammatory effect

Matrine has the characteristics of non-steroidal anti-inflammatory drugs. The rat hind limbs by the angle * gums induced inflammation and intraperitoneal injection of glacial acetic acid-induced exudative inflammation were significantly inhibited, but the rat buried cotton ball induced granulation tissue hyperplasia of chronic inflammation is not obvious. At the same time, the author also believes that the anti-inflammatory effects of matrine and the pituitary-adrenal system has nothing to do and speculated that the anti-inflammatory effect of matrine may be through direct action. Bao Shujuan, Li Shufang's study also reached a similar conclusion, but inhibition of granulation tissue mastitis inhibition rate was 53.5%, slightly less than 60.0% of hydrocortisone. Matrine on the ocular inflammatory response induced by the lens protein, has a significant inhibitory effect. Matrine inhibited the activity of phospholipase (PLA2), the proliferation of splenocytes and the release of TNF, IL-1 and IL-6, all of which were correlated with the anti-inflammatory effects of matrine. Hong Cheng and other experiments with mouse colitis induced by 2,4,6-trinitrobenzene sulfonic acid found that matrine significantly improved its role, and its mechanism of action may be to inhibit the colon of TNF-a Up-regulated Studies by Ji Yong Liu et al. Have shown that matrine inhibits the expression of substance P receptors and regulates the production of inflammatory cytokines and thus has the potential to inhibit the inflammatory response associated with substance P.

13a-hydroxy matrine (I think it should be 14b-hydroxy matrine), oxymatrine also has anti-inflammatory effects. Liao Jie et al found that oxymatrine and hydrocortisone similar effect, can significantly combat croton oil, angle * (rat) and glacial acetic acid (mouse) induced exudative inflammation, but for rats by The chronic inflammation induced by cotton balls is ineffective and further confirms that its anti-acute inflammation is not associated with the pituitary-adrenal system. Oxymatrine can also inhibit the activation of NH-kB, reduce the formation of TNF-a, IL-6 and ICAM-1, thereby reducing colitis damage and diarrhea, blood stool symptoms. Jiao Xia et al found that oxymatrine has obvious anti-airway allergic inflammation and inhibition of IL-4 mRNA and ICAM-1 mRNA expression in asthmatic mice.

Third, the anti-arrhythmia A large number of experiments show that a variety of alkaloids matrine with significant anti-arrhythmic effect against aconitine, chloroform-adrenaline-induced rat arrhythmia, and chloroform-induced mice Ventricular fibrillation. Matrine, oxymatrine clinical trial found that premature ventricular contractions and paroxysmal tachycardia better. Zhang Baoheng and other rats intravenous oxymatrine 15,30 mg / kg significantly against aconitine, BaCl2 and coronary artery ligation induced arrhythmia. And matrine can make the colon segment in high K + depolarization, with the cumulative dose of Ca2 + tension increased. Zhang Mingfa, Shen Yaqin that matrine-type alkaloids on the heart has a negative frequency, negative self-discipline and prolong the effective refractory period of the role, which can produce anti-arrhythmic effect, which sophoridine and sophocarine anti-heart rhythm Abnormal activity is relatively high, while the sophocarpine is relatively low. Chen Ruifeng through clinical observation of oxymatrine treatment of arrhythmia found that oxymatrine significant effect on ischemic cardiomyopathy, heart valve disease is poor, we can see that oxymatrine has the protection of ischemic myocardium, relieve coronary artery Spasm and increase the role of coronary flow. At the same time, it has been demonstrated that the anti-arrhythmic mechanism of oxymatrine is to increase the DET of cardiac diastolic phase and extend the effective refractory period (ERP).

In the use of oxymatrine treatment of coronary heart disease patients found that oxymatrine can significantly improve heart rate variability in patients with coronary heart disease, atrial and ventricular arrhythmias have a significant effect, so three times a day, each time taking 0.2 ~ 0.4g oxymatrine safe and effective treatment of tachyarrhythmia, the exact effect, fewer adverse reactions. Ai Jing, Huang Caiyun and other studies have shown that oxymatrine can inhibit sodium, calcium channels, negative frequency and negative conductivity, increase the threshold of diastolic myocardial excitability, prolong myocardial effective refractory period and play a significant anti- Experimental arrhythmia. Compared with amiodarone and RP58866, matrine has a weaker inhibitory effect on anti-arrhythmic targets IKr, IKs, Ito and IK1, which is a molecular role of matrine in clinical anti-arrhythmic effects and mild side effects Mechanism, so this also suggests that we can improve the inhibitory effect of matrine on the target by structural transformation or compatibility, so as to improve its weakness of anti-arrhythmia. Chen Xia and other studies have confirmed that intravenous administration of 30mg / kg of oxymatrine can reduce the amplitude of cardiomyocytes action potential (AP), shortening APD50 and APD90, reducing Vmax, which may be its anti-arrhythmic mechanism In part because of the reduced open probability of sodium channels because oxymatrine decreases the open time and open probability of monosodium channels in cardiomyocytes without affecting the current amplitude of monosodium channels. The mechanism of oxymatrine against ischemia-reperfusion-induced arrhythmia may be related to the shortening of action potential duration. Oxymatrine can reduce the expression of intercellular adhesion molecule 1 (ICAM-1) in rats, which may also be one of its anti-arrhythmic mechanisms.

Fourth, anti-tumor

The antitumor effect of matrine has long been a concern. As early as the 1960s, the National Cancer Chemotherapy Research Center (CCNSN) reported that 50% of the extract of Sophora alopecuroides had obvious activity on Lewis lung cancer in mice. In recent years, studies have found matrine and oxymatrine and other matrine alkaloids on liver cancer cells, gastric cancer cells, lung cancer cells, breast cancer, cervical cancer, leukemia and so has obvious inhibition and therapeutic effect. Matrine has a direct toxic effect on P185 tumor cells, which can reduce 3H-TdR infiltration of P185 cells. This suggests that matrine may be a direct inhibitor of cell metabolism. Matrine can effectively inhibit the proliferation of human hepatocellular carcinoma cell line HepG2, human erythroleukemia cell line K562 and human fibrosarcoma cell line HT1080, and its inhibition rate is dose-dependent. Wang Bing et al found that oxymatrine has an inhibitory effect on the proliferation of vascular endothelial cells induced by lung cancer and gastric cancer cells. Zhang Junping and Hu Zhenlin et al. By studying the effects of matrine on the release of tumor necrosis factor (TNF) and its protein kinase C (PKC) activity by macrophages, it was found that matrine inhibits the secretion of TNF by inhibiting the activity of PKC in macrophages. Ma Lingdi study found that matrine in vitro can significantly inhibit the growth and proliferation of mouse H22 tumor cells, 0.5,1.0,1.5 and 2.0mg / ml of H22 cell growth inhibition rate of 15%, 54%, 86% and 92% , In a dose-dependent manner, while the immune function of mice also have some inhibitory effect.

The anti-tumor mechanism of matrine mainly through the inhibition of cell cycle progression, regulation of cell signaling, inhibition of telomerase activity and induction of apoptosis and differentiation. Matrine could significantly inhibit the proliferation of human osteosarcoma MG-63 cells, arrest the cell cycle in G0 / G1 phase, and induce S phase arrest in U937 cells in a dose-dependent manner. Telomerase activity was significantly inhibited after treated with matrine k562 cells and retinoic acid for a certain period of time, that is, matrine reduced hTERT-mRNA expression in K562 cells and hepg2 cells, accompanied by decreased telomerase activity . Zhu Ningxi and other experimental results show that matrine can significantly inhibit the proliferation of HL60 cells and induce their differentiation into mature granulocytes, and the induction of differentiation and its down-regulation of c-myc gene expression, blocking cells in the G1 phase. At the same time also found that matrine liposomes anti-tumor effect than matrine increased, but also inhibit the tumor but also enhance the body's immunity. Dai Bi Tao, Jiang Jikai's research also found that matrine combined with vincristine, cytarabine, harringtonine and other antineoplastic agents can enhance its inhibition of K562 cell proliferation. When matrine combined with vinblastine and doxorubicin respectively, the expression level of P-pg in KBV200 drug-resistant cell line was decreased and the drug resistance was reversed.

Fifth, anti-virus

The anti-viral effect of matrine is mainly against Hepatitis B virus (HBV), Hepatitis C virus (HBC) and Coxsackie B virus type 3 (CVB3). Liu Jingxing, Lu Deyuan matrine and other anti-Coxsackie B virus preliminary study found that Sophora flavescens both in vitro and in vivo have a significant antiviral effect. A large number of studies have shown that Sophora alkaloids in vitro significantly inhibited the Coxsackie virus B virus type 3 proliferation, inhibition of cytopathic effect, and in a dose-dependent manner, its mechanism for the inhibition of viral protein synthesis. Li Jiqiang and other studies have shown that oxymatrine can inhibit HCV proliferation, anti-liver fibrosis and the role of regulating the host immune response. There are also studies have shown that matrine combined with Shuganjianpi treatment can improve immune disorders in patients with chronic hepatitis C, inhibition of HCV-RNA replication. Wu found that matrine and duck hepatitis B virus has better inhibitory effect. Lu Haiying, Wang Qinhuan and so on through the study of different dosage forms of matrine in vitro anti-HBV effect found that intramuscular injection of matrine has obvious anti-HBV effect and speculated that HBV suppression point may be in HBV-DNA levels. Currently in the treatment of hepatitis B oxymatrine, matrine has been combined with other drugs used in clinical and achieved good results.

Six, immunosuppression and biological regulation

In 1987, Li Ruisong and Huang Tianyou studied the effects of oxymatrine on the immune function. The study found that oxymatrine (intraperitoneal injection of 375mg / kg) can reduce the weight of mouse thymus mesenteric lymph nodes, so that thymus ANAE + lymphocytes increased, so HA Titer, PFC value and percentage of phagocytosis of Mf cells decreased, indicating that oxymatrine can inhibit certain immune responses and immune organs. Matrine, sophoramine, oxymatrine, sophoridine, sophocarpine on T cell-mediated immune response with different intensity of immunosuppressive effects, including matrine stronger, weaker sophocarpine, Anti-SRBO serum antibody assay found oxymatrine, sophoramine, matrine had a significant inhibitory effect, while the sophocarpine and sophoridine inhibitory effect was not obvious. Phagocytosis of macrophages, matrine, sophoridine inhibitory effect, the remaining three alkaloids did not inhibit the effect.

Cui Wei, Wang Runtian study found that oxymatrine can significantly down-regulate Colon26 tumor cells TGF-b1 and L-10 secretion, by down-regulating the secretion of immunosuppressive molecules Colon26 tumor cells affect the immunosuppression and speculated that this may be oxidized Anti-tumor effect of matrine one of the mechanisms. Liu Xin Yan and other studies also showed that oxymatrine can significantly down-regulate the secretion of L929 immunosuppressive molecules and down-regulate the immunosuppressive effect of L929 tumor cells, and also think that the down-regulation of tumor cell immunosuppression may be one of its anti-tumor mechanisms. Qinze Lin through the study of oxymatrine on immune function in normal and transplanted mice found that oxymatrine can significantly inhibit the normal mouse antibody secreting cells - hemolytic plaques (PFC) generation, oxymatrine Normal mice showed no significant effect on carbon particle clearance, but it appears to restore normalized carbon clearance in transplanted mice. In addition, studies have confirmed that oxymatrine also has a significant reversal of liver fibrosis. Matrine can significantly improve liver function, reverse liver damage, immune suppression in immunocompromised mice significantly inhibited and enhance their non-specific immunity, while matrine can inhibit mouse lymphocyte proliferation and release in vitro L-2 and peritoneal macrophages release L-1.

Seven, cardiac effect

Jin Zhaojun et al through the study of matrine on myocardial contractility of guinea pig found that matrine in the range of 1 × 10-6 ~ 1 × 10-3mol / L significant positive inotropic effect, and a dose-dependent. Li Qing, Wang Jin and a variety of experimental animals with oxymatrine cardiac effect, the results show that oxymatrine (0.5,5.0,50.0 mmol / L) can significantly increase the normal in vitro cardiac contractile force, heart Cardiac output, cardiac output, 50mmol / L can make myocardial contractility, cardiac output completely restored to Heart failure before the level of no significant effect on heart rate, and in the same dose, whether it is positive inotropic effect or cardiac output, oxymatrine on the role of failure of the heart than normal heart; but also to varying degrees of enhancement Body guinea pigs, rats, rabbits papillary muscle contractility, and showed a good dose-effect relationship, more sensitive to guinea pig papillary muscle; oxymatrine can increase contractile force of rat isolated right atrial myocardium while reducing the spontaneous contraction frequency , This can change the role of variable time is obviously the role of oxymatrine cardiac function.

Li Qing and other hearts in the rat heart study showed that oxymatrine can increase in vivo rat heart contractility, while reducing the tendency of heart rhythm, that is, oxymatrine increase in contractility without increasing heart rate . Wang Jin and other studies of oxymatrine blood flow

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