Convulsion-related activities of Scutellaria flavones are related to the 5,7-dihydroxyl structures

We screened the major bioactive flavones isolated from Scutellaria baicalensis (baicalin, baicalein and oroxylin A) for their convulsion related activities. In electrogenic response score system and the pentylenetetrazole seizure model, baicalein but not oroxylin A and baicalin exhibited anticonvulsant effects. In vitro studies also revealed that baicalein induced intracellular Cl(-) influx, whereas oroxylin A blocked muscimol- and baicalein-induced intracellular Cl(-) influx. The anticonvulsant effect of baicalein was inhibited by flumazenil, a benzodiazepine(BZD) receptor antagonist. Therefore, anticonvulsive effect of baicalein was mediated by the BZD binding site of GABA(A) receptor. The 5, 7-dihydroxyl group is present in the structure of the three flavones. It is postulated that this group played a key role in inducing convulsion-related activities.     

镇痫灵片抗癫痫作用的实验研究

目的 :探讨镇痫灵片抗癫痫作用。方法 :采用小鼠自发活动法 ;戊巴比妥钠阈下催眠法、致惊剂 (士的宁、戊四氮 )诱发惊厥法、最小休克发作法和最大电休克发作法。结果 :镇痫灵片能明显抑制小鼠自发活动 ;增加阈下剂量戊巴比妥钠的睡眠鼠数 ;并能降低阈剂量士的宁的致惊率和小鼠戊四氮 CD50 ,提高小鼠最小休克阈值。结论 :本品具有镇静、抗惊厥作用     

腺苷类似物WS090501的镇静、催眠和抗惊厥作用

腺苷是一种内源性的嘌呤核苷,具有广泛的生理性调节作用。腺苷类似物具有显著的镇静[1]、催眠和抗惊厥作用[2],可以抑制啮齿类动物的自主活动、诱导NREM睡眠(non rapid-eye-movement sleep,非快动眼睡眠)[3]。腺苷及其类似物通过腺苷受体发挥     

胡椒碱衍化物的中枢药理作用研究

胡椒碱和其衍化物是一类新型的抗癫痫药,在小于TD₅₀剂量下,对电休克、戊四唑、印防已毒素、士的宁、筒箭毒碱和谷氨酸钠引起的大鼠和小鼠惊厥均有不同程度的对抗作用,并能降低动物的死亡率,可见这是一类广谱的抗惊厥药。其作用与苯妥英钠有相似之处,均能明显对抗电惊厥(MES),但又不相同,这类药物对戊四唑惊厥(Met)有效,大剂量时不引起动物惊厥。苯妥英钠与此相反。与苯巴比妥也有近似之处,抗惊谱广,但也不相同,大剂量时不引起麻醉。此外尚有镇静作用和加强其它中枢神经系统抑制药的中枢抑制作用。     

Wogonin prevents glucocorticoid-induced thymocyte apoptosis without diminishing its anti-inflammatory action

The effect of wogonin, a flavone highly purified from the roots of Scutellaria baicalensis, on apoptotic cell death was re-evaluated in rat thymocytes. This flavone inhibited glucocorticoid-induced apoptotic changes such as DNA fragmentation, phosphatidylserine translocation, and nuclear condensation in rat thymocytes. Similar inhibition was also observed in apoptosis induced by other inducers such as etoposide. No significant changes of these apoptotic features were observed in rat thymocytes treated with wogonin alone, suggesting that this flavone protects against glucocorticoid-mediated immunosuppression caused by thymocyte apoptosis. Wogonin was reported to possess anti-inflammatory action in some previous studies, but this flavone had no effect on carrageenan-induced paw edema in this study. The simultaneous treatment of wogonin and glucocorticoid neither enhanced nor reduced the anti-inflammatory effect of glucocorticoid. These results indicate that wogonin is likely to prevent the immunosuppression of glucocorticoid without diminishing its drug efficacy as an anti-inflammatory agent.     

Wogonin suppresses arrhythmias, inflammatory responses, and apoptosis induced by myocardial ischemia/reperfusion in rats

Wogonin is a flavonoid isolated from Scutellaria baicalensis Georgi, a traditional Chinese medicine, and it possesses antioxidant and anti-inflammatory effects. The aim of this study is to investigate the in vivo effect of wogonin on myocardial ischemia/reperfusion injury in an open-chest anesthetized rat model, which was induced by 45-minute left coronary artery occlusion and 2-hour reperfusion. Rats were treated with wogonin (5, 10, and 20 mg/kg, intraperitoneal) 40 minutes before ischemia or treatment with 10 mg/kg of wogonin 15 minutes after occlusion. Pretreatment with 10 mg/kg of wogonin significantly delayed the occurrence of ventricular premature contractions and tachycardia, and it suppressed the incidence of ventricular tachycardia and ventricular fibrillation, and mortality elicited by ischemia when compared with that in the control group, accompanied by reducing the arrhythmia scores. After 2-hour reperfusion, pretreatment and posttreatment with wogonin significantly reduced the infarct size and plasma levels of creatine kinase muscle-brain fraction and lactate dehydrogenase. Wogonin also significantly reduced the elevation of plasma tissue necrosis factor-α and superoxide anion production in the myocardium with ischemia/reperfusion. The expression of monocyte chemoattractant protein-1, phosphorylated p38 mitogen-activated protein kinase, p65 and IκBα, and active caspase-3 in ischemic myocardium pronouncedly increased in the control group; these were significantly attenuated by treatment with wogonin. In conclusion, wogonin demonstrated in vivo cardioprotective effects by the attenuation of the severity of ischemia-induced arrhythmias and irreversible ischemia/reperfusion injury, which is associated with its antioxidant capacity and anti-inflammatory effects. The suppression of nuclear factor-κB and p38 mitogen-activated protein kinase activation and the inhibition of monocyte chemoattractant protein-1 expression contribute to the beneficial effects of wogonin.     

琥珀酸的中枢抑制作用

琥珀为古代松科松属植物的树脂,埋藏地下年久凝结而成的化石样物质,据本草纲目记载,琥珀有“安五脏、定魂魄……止心痛癲邪”等功效。历代以琥珀为主的许多方剂及近代的一些验方,均利用这一作用治疗心神不宁、惊悸多梦、失眠及惊风癫痫等。由于药源稀缺,故属名贵中药之列。     

Wogonin induces apoptosis and down-regulates survivin in human breast cancer MCF-7 cells by modulating PI3K-AKT pathway

Wogonin, one of flavonoid compounds isolated from Chinese herbal plants Scutellaria baicalensis Georgi, has been recognized as a potent anti-cancer agent acting through control of growth, differentiation and apoptosis. However, the underlying molecular mechanism of its anti-cancer activity remains to be further elucidated. In this study, we investigated the potential role of wogonin in the induced-apoptosis of human breast cancer cells MCF-7. Wogonin was found to inhibit the proliferation of MCF-7 in a concentration and time-dependent manner, notably wogonin could induce G1 phase arrest of MCF-7 cells. Wogonin-induced apoptosis was accompanied by a significant decrease of the Bcl-2 and survivin and increase of Bax and p53. Wogonin also increased active apoptosis forms of caspases-3, -8, -9 significantly. Z-DEVD-fmk, a specific caspase-3 inhibitor, significantly inhibited wogonin-induced cell apoptosis. Wogonin also suppressed the phosphorylation of PI3K/Akt and induced phosphorylation of ERK. PD98059, a specific ERK inhibitor, significantly blocked wogonin-induced apoptosis. On the other hand, LY294002, a specific PI3K inhibitor, significantly increased wogonin-induced cell apoptosis. Further study indicated that LY294002 not only down-regulated the expression of survivin alone, but also enhanced the inhibition of survivin expression combined with wogonin. In conclusion, the pro-apoptotic effect of wogonin is mediated through the activation of ERK and the activation of caspases, and is correlated with the block of the PI3K/Akt/survivin signal pathways in MCF-7 cells.     

Relaxant effect induced by wogonin from Scutellaria baicalensis on rat isolated uterine smooth muscle

Context: Wogonin is a flavone derivative isolated from Scutellaria baicalensis Georgi (Labiatae) root, which is a traditional Chinese drug used as an anti-inflammatory and for management of dysmenorrhea.

Objective: The effect of wogonin on the uterus has not yet been examined. We investigated the relaxant effects of wogonin on contractile activity of isolated uterine strips of rats.

Materials and methods: The effect of wogonin on spontaneous uterine contraction, and uterine contraction induced by agonists, K⁺-depolarization and oxytocin in Ca²⁺-free solution was observed. To clarify the type of potassium channel, we tested the effects of 4-aminopyridine, tetraethylammonium and glibenclamide.

Results: Wogonin reduced the contractile amplitude of uterine strip smooth muscle of rats in a dose-dependent manner. The concentration of wogonin for reducing the contraction amplitude by 50% (IC₅₀) on spontaneous contractions was 60.5 μM. Wogonin also inhibited the contraction induced by three agonists (oxytocin, prostaglandin F_2α and acetylcholine). For the uterine strips pretreated with oxytocin in Ca²⁺-free solution or K⁺-depolarization, wogonin showed relaxant effect on the induced uterine contractions. In addition, whereas the inhibitive effect of wogonin on the contraction of uterine smooth muscle in rats could be partly blocked by 4-aminopyridine and tetraethylammonium, it was not influenced by glibenclamide.

Discussion and conclusion: Wogonin significantly inhibited the contraction of rat uterine smooth muscle probably through the inhibition of the inflow of extracellular calcium into cells via cell membrane, and intracellular release of calcium ions. In addition, the relaxant effect induced by wogonin might be due in part to the opening of voltage-dependent and large conductance Ca²⁺-activated K⁺ channels.     

川芎嗪抗小鼠实验性癫痫的研究

目的:系统评价川芎嗪(Tetramethylpyrazine,TMP)是否具有抗小鼠实验性癫痫作用。方法:采用最大电惊厥(MES)及戊四氮、士的宁、匹罗卡品等癫痫模型。观察川芎嗪(TMP)低、中、高(200、400、800mg.kg-1)剂量对动物惊厥发作数、阵挛潜伏期及动物存活时间等指标的影响,从而分析川芎嗪抗惊厥作用及其时量关系。结果:中、高剂量(400、800mg.kg-1)川芎嗪可明显减少MES发作次数,延长戊四氮、士的宁所致小鼠阵挛潜伏期,同时延长死亡时间。高剂量川芎嗪可延长小鼠匹罗卡品癫痫模型的阵挛时间,与模型组相比,差异有统计学意义。结论:川芎嗪对癫痫有一定防治作用,并存在一定的量效关系。     

Wogonin attenuates inflammation by activating PPAR-γ in alcoholic liver disease

Alcoholic liver disease (ALD) is one of the predominant causes of liver-related morbidity and mortality worldwide. However, effective therapy for ALD is still lacking. Wogonin, a major flavonoid compound, is found in Scutellaria baicalensis Georgi. Accumulating studies have revealed that wogonin possesses anti-inflammatory and anti-tumour activities in various models. However, the hepatoprotective activity of wogonin in ALD is still obscure. In this study, we found that wogonin significantly attenuated inflammatory response in EtOH-fed mice, and reduced the expression of inflammatory cytokines such as TNF-α and IL-6 in EtOH-induced RAW264.7 cells. Furthermore, our findings showed that wogonin remarkably induced the expression of PPAR-γ in vivo and in vitro. Compared with the wogonin-treated group, blockade of PPAR-γ with inhibitor (T0070907) or PPAR-γ small interfering (si)-RNA were applied in RAW264.7 cells to evaluate the involvement of wogonin in alleviating EtOH-induced inflammation. Moreover, forced expression of PPAR-γ further suppressed the expression of TNF-α and IL-6 when treated with wogonin on EtOH-induced RAW264.7 cells. In addition, it was demonstrated that wogonin remarkably suppressed PPAR-γ-meditated phosphorylation and activation of NF-κB-P65. In conclusion, our results indicated that wogonin may serve as an effective modulator of PPAR-γ by down-regulating NF-κB pathway, thereby attenuated inflammatory response in ALD.     

滋肾宁神丸抗小鼠和大鼠惊厥的作用

中成药滋肾宁神丸4g/(kg·d)灌胃能显著降低最大电休克致小鼠惊厥率和筒箭毒碱侧脑室注射致大鼠惊厥率;2g/(kg·d)和4g/(kg·d)灌胃能明显减少ip 士的宁致小鼠惊厥率,4g/(kg·d)和8g/(kg·d)灌胃能明显延长ip 戊四唑至小鼠惊厥的诱导期,但对电刺激小鼠足部引起的小鼠激怒行为无影响。表明滋肾宁神丸具有明显的安神、抗惊厥作用。     

吡唑烷酮类化合物的抗惊厥作用

对3类14种吡唑烷酮类化合物的抗惊厥作用进行了比较研究,它们对最大电休克惊厥均有对抗作用,作用出现快,但维持时间较短,其中II-f作用最强,对听源性发作和家兔海马注射硫酸锌形成的慢性癫痫模型也有效。此外,III-类尚能对抗戊四唑引起的阵挛性惊厥。     

Wogonin inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion

The present study evaluated the effect of wogonin, a flavonoid originated from the root of Scutellaria baicalensis GEORGI, on focal ischemic brain injury in rats. Focal brain ischemia was induced by the permanent occlusion of middle cerebral artery (pMCAO) for 24 h with a silicone rubber cylinder inserted through the right internal carotid artery. We found that wogonin, intraperitoneally administered at a dosage of 20 mg/kg at 30 min before and 4 h after the surgery, reduced the pMCAO-induced infarct areas in the cerebral cortex as well as in the striatum. The total volume of infarction was significantly reduced by the treatment with wogonin. In addition, wogonin was found to significantly improve the pMCAO-induced behavioral deficits at 24 h after the surgery. Taken together, these results demonstrate that wogonin inhibits ischemic brain injury and improves behavioral dysfunction caused by pMCAO. These findings, along with previous reports demonstrating the neuroprotective effects of wogonin, provide strong pharmacological basis for the use of wogonin or Scutellaria baicalensis in the treatment of stroke.     

吲哚醌对大鼠杏仁核点燃的抑制作用

目的：研究吲哚醌对大鼠杏仁核点燃发作的影响及其抗惊厥作用。方法：建立大鼠杏仁核点燃模型,观察发作的电生理指标和行为学变化;在小鼠最大电休克惊厥、戊四唑惊厥和氨基脲惊厥模型计数惊厥发生率。结果： ip吲哚醌50～200 mg.kg-1均可升高杏仁核点燃大鼠的局灶性后放电阈值,降低发作强度和全身性发作 (stage 5) 百分率;可剂量依赖性地对抗小鼠最大电休克发作,并能取消戊四唑惊厥和氨基脲惊厥的强直相,降低戊四唑惊厥的死亡率。结论：吲哚醌对癫痫发作有抑制作用,其机制与抑制MAO-B活性、升高发作阈值有关。     

Effects of brotizolam, a new thieno-triazolo-diazepine derivative, on the central nervous system

The effects of brotizolam, a new thieno-triazolo-diazepine derivative, on the central nervous system were analyzed in mice, rats and rabbits. Diazepam, estazolam and triazolam were used as control drugs. Brotizolam inhibited spontaneous motor activities; performances in the rotarod test, staircase test, and maximal electroshock seizure test; and pentetrazol- or bemegride-induced convulsion. Moreover, catalepsy inducing action and potentiating effect on sleep elicited by pentobarbital or ethanol were observed. Following intraperitoneal or oral administration of brotizolam to rabbits with chronically implanted electrodes, the electroencephalographic profile in spontaneous EEG was characterized by slow waves with high amplitudes in the neocortex. The arousal responses by stimulation of the midbrain reticular formation and posterior hypothalamus were slightly inhibited, but the recruiting responses induced by stimulation of the diffuse thalamic projecting system were not inhibited, and seizure discharges induced by stimulation of the dorsal hippocampus were inhibited markedly. When motor activities and pentetrazol-induced convulsions were observed as indices of tolerance for brotizolam, tolerance was not developed by repeated administration of brotizolam up to 14 days. These results suggested that brotizolam, a new thieno-triazolo-diazepine derivative, is judged to be a safer and stronger sleep inducer than diazepam and estazolam.     

Effects of subacutely administered saiboku-to, an oriental herbal medicine, on pharmacodynamics and pharmacokinetics of diazepam in rodents.

Subacute treatment with saiboku-to (2000 mg/kg, p.o., once a day) for 7 days induced an anxiolytic-like effect in rats. It did not, however, produce any other effects, such as sedative and hypnotic effects, anticonvulsive and muscle relaxant effects except for anxiolytic effect observed in diazepam-injected rats or mice. Diazepam (1.0 mg/kg, s.c.) induced anxiolytic-like effect was enhanced in saiboku-to treated rats as an additional effect of that induced by saiboku-to. To elucidate whether the enhancement of the anxiolytic-like effect following combined administration of diazepam and saiboku-to is due to the inhibition of hepatic drug-metabolizing enzymes, the pharmacokinetics of diazepam were further investigated in saiboku-to treated rats. The pharmacokinetic studies clearly demonstrated that subacute treatment with saiboku-to did not affect plasma concentration and protein binding rate of diazepam, and the activities of hepatic drug-metabolizing enzymes related to diazepam metabolism. These results, taken together, suggest that the enhancement of diazepam-induced anxiolytic-like effect observed in saiboku-to-treated rats is not due to an inhibition of diazepam metabolism.     

Protective effects of baicalein and wogonin against benzo[a]pyrene- and aflatoxin B(1)-induced genotoxicities.

To evaluate the protective effects of baicalein and wogonin against benzo[a]pyrene- and aflatoxin (AF) B(1)-induced toxicities, the effects of these flavonoids on the genotoxicities and oxidation of benzo[a]pyrene and AFB(1) were studied in C57BL/6J mice. Baicalein and wogonin reduced benzo[a]pyrene and AFB(1) genotoxicities as monitored by the umuC gene expression response in Salmonella typhimurium TA1535/pSK1002. Baicalein added in vitro decreased liver microsomal benzo[a]pyrene hydroxylation (AHH) activity with an ic(50) of 33.9 +/- 1.4 microM at 100 microM benzo[a]pyrene. Baicalein also inhibited AFQ(1) and AFB(1)-epoxide formation from AFB(1) (50 microM) oxidation (AFO) with ic(50) values of 22.8 +/- 1.4 and 5.3 +/- 0.8 microM, respectively. However, the in vitro inhibitory effects of wogonin on AHH and AFO activities in liver microsomes were less than those of baicalein as inhibition by 500 microM wogonin was only about 51-65%. Treatment of mice with liquid diets containing 5 mM baicalein and wogonin resulted in 22 and 49% decreases in hepatic AHH activities, respectively. Baicalein treatment resulted in 39 and 32% decreases in AFQ(1) and AFB(1)-epoxide formation from liver microsomal AFO, respectively. Wogonin treatment resulted in 39 and 47% decreases in AFQ(1) and AFB(1)-epoxide formation, respectively. A 1-week pretreatment with wogonin significantly decreased hepatic DNA adduct formation in mice treated with 200 mg/kg of benzo[a]pyrene via gastrogavage. These in vitro and in vivo effects suggested that baicalein and wogonin might have beneficial effects against benzo[a]pyrene- and AFB(1)-induced hepatic toxicities and that wogonin had a stronger protective effect in vivo.     

Neuroprotective effect of wogonin: Potential roles of inflammatory cytokines

Wogonin (5,7-dihydroxy-8-methoxyflavone), an active component originated from the root of Scutellaria baicalensis Georgi, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the neuroprotective effect of wogonin in a focal cerebral ischemia rat model. Wogonin markedly reduced the infarct volume after 2 h middle cerebral artery occlusion followed by 22 h reperfusion. Wogonin decreased the production of nitric oxide and inflammatory cytokines such as TNF-α and IL-6 in lipopolisaccharide-stimulated microglial cells. While wogonin reduced the activity ofNF-kB, it did not change the activity of mitogen-activated protein kinases family members, p38, ERK and JNK. The lipopolisaccharide-stimulated production of NO and cytokines was significantly blocked by various kinds ofNF-kB inhibitors such asN-acetyl cysteine, pyrrolidinedithiocarbamate and MG-132. The data may indicate that wogonin has neuroprotective effect by preventing the over-activation of microglial cells, possibly by inactivatingNF-kB signaling pathway