Antiepileptic geissoschizine methyl ether is an inhibitor of multiple neuronal channels.

Geissoschizine methyl ether (GM) is an indole alkaloid isolated from Uncaria rhynchophyll (UR) that has been used for the treatment of epilepsy in traditional Chinese medicine. An early study in a glutamate-induced mouse seizure model demonstrated that GM was one of the active ingredients of UR. In this study, electrophysiological technique was used to explore the mechanism underlying the antiepileptic activity of GM. We first showed that GM (1-30 µmol/L) dose-dependently suppressed the spontaneous firing and prolonged the action potential duration in cultured mouse and rat hippocampal neurons. Given the pivotal roles of ion channels in regulating neuronal excitability, we then examined the effects of GM on both voltage-gated and ligand-gated channels in rat hippocampal neurons. We found that GM is an inhibitor of multiple neuronal channels: GM potently inhibited the voltage-gated sodium (NaV), calcium (CaV), and delayed rectifier potassium (IK) currents, and the ligand-gated nicotinic acetylcholine (nACh) currents with IC50 values in the range of 1.3-13.3 µmol/L. In contrast, GM had little effect on the voltage-gated transient outward potassium currents (IA) and four types of ligand-gated channels (γ-amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainite (AMPA/KA receptors)). The in vivo antiepileptic activity of GM was validated in two electricity-induced seizure models. In the maximal electroshock (MES)-induced mouse seizure model, oral administration of GM (50-100 mg/kg) dose-dependently suppressed generalized tonic-clonic seizures. In 6-Hz-induced mouse seizure model, oral administration of GM (100 mg/kg) reduced treatment-resistant seizures. Thus, we conclude that GM is a promising antiepileptic candidate that inhibits multiple neuronal channels.

Dendrobium candidum aqueous extract attenuates isoproterenol-induced cardiac hypertrophy through the ERK signalling pathway.

CONTEXT: The pharmacological functions of Dendrobium candidum Wall. ex Lindl. (Orchidaceae) in cardiac hypertrophy remains unclear. OBJECTIVE: To evaluate whether D. candidum aqueous extract (DCAE) can attenuate experimental cardiac hypertrophy. MATERIALS AND METHODS: Cardiac hypertrophy in SD rats was induced by subcutaneously injection of isoproterenol (2 mg/kg), once a day for ten days. Rats were gavaged with DCAE (0.13 and 0.78 g/kg) daily for one month. At the end of treatment, measurement of left ventricular systolic pressure (LVSP), heart-to-body weight ratio (HW/BW), left ventricular/tibia length (LV/TL), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) levels, haematoxylin-eosin staining, and Masson's trichrome staining were conducted. In cultured H9c2 cells, DCAE (2 mg/mL) and U0126 (10 µM) were added 2 h before the isoproterenol (10 µM) stimulus. Phalloidin staining was used to evaluate cellular hypertrophy. The mRNA expression of ANP and BNP was measured by qRT-PCR. The expression of p-ERK was determined by immunoblotting. RESULTS: DCAE treatment significantly reduced the following indicators in vivo: (1) the LVSP (16%); (2) HW/BW (13%); (3) LV/TL (6%); (4) ANP (39%); (5) BNP (32%). In cultured H9c2 cells, phalloidin staining showed that DCAE relieved cellular hypertrophy (53% reduction). Furthermore, immunoblotting showed that DCAE can significantly inhibit p-ERK protein expression in vivo and in vitro (39% and 27% reduction, respectively). DISCUSSION AND CONCLUSIONS: DCAE prevents cardiac hypertrophy via ERK signalling pathway and has the potential for treatment of cardiac hypertrophy.

[Analysis of Regularity of Acupoint Selection in Acupuncture Treatment of Urticaria Based on Data Mining Technology].

OBJECTIVE: To analyze the regularity of acupoint selection, main acupoints and theoretical basis in acupuncture treatment of urticaria. METHODS: Papers collected from the time of establishment of each database to September of 2017 were retrieved from databases CNKI, CBM, VIP and WF by using keywords of "acupuncture" "moxibustion" "blood-letting therapy" "autohemotherapy" "cupping" "acupoint catgut embedding" "auricular points" "acupoint injection" "fire-needle" (or red-hot needle), "dermal needle" "needle-embedding" "urticaria" in both Chinese and English. The collected papers were brought into analysis according to the inclusion and exclusion criteria, from which the prescriptions for acupuncture treatment of urticaria were subjected into descriptive statistical analysis, association rule analysis, and cluster analysis by using Access 2010, Clementine 18.0 and Stata software. RESULTS: Outcomes of analysis indicated that the treatment methods of urticaria with acupuncture and moxibustion, with different emphases, may be classified into eight categories. For treating the exterior syndrome of urticaria, acupoints of the Bladder Meridian, Governor Vessel and Conception Vessel were often employed to harmonize Ying and Wei and to dispel the pathogenic wind, while for treating the interior syndrome, acupoints of the Large Intestine Meridian, Spleen Meridian, and Stomach Meridian were usually used to invigorate the spleen to dispel dampness and to regulate blood circulation. The top five frequently used acupoints were Quchi (LI 11), Xuehai (SP 10), Zusanli (ST 36), Sanyinjiao (SP 6) and Geshu (BL 17). It was crucial to make use of the specific acupoints with adequate meridian-qi, such as He-Sea points, Back-Shu points, and Yuan-Primary points. There were some fixed forms in the combination of acupoints, including LI 11, SP 10, Dazhui (GV 14) and auricular Lung, Shenmen, Fengxi, Adrenal gland, which had the highest confidence coefficient for the meridian points and ear acu-points, respectively. The outcomes of cluster analysis about the acupoint prescriptions showed that 12 acupoint groups as the SP 6-Hegu (LI 4)-LI 11-SP 10-ST 36, etc. were frequently used. CONCLUSION: The regularity of acupuncture treatment of urticaria can be discovered using data mining technology, resulting in an in-depth understanding and having a solid theoretical basis.

Metabolism, pharmacokinetics, and hepatic disposition of xanthones and saponins on Zhimu treatments for exploratively interpreting the discrepancy between the herbal safety and timosaponin A3-induced hepatotoxicity.

Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.