Anti-seizure activity of African medicinal plants: The identification of bioactive alkaloids from the stem bark of Rauvolfia caffra using an in vivo zebrafish model
Anti-seizure activity of African medicinal plants: The identification of bioactive alkaloids from the stem bark of Rauvolfia caffra using an in vivo zebrafish model
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DOI：
10.1016/j.jep.2021.114282
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发表时间：
2021-06-24
影响因子：
5.4
通讯作者：
Enslin, Gill M.
中科院分区：
文献类型：
--
作者：
Chipiti, Talent;Viljoen, Alvaro M.;Enslin, Gill M.
民族药理学相关性：癫痫是一种主要的慢性疾病，目前尚无治愈方法。使用现有的抗癫痫药物（AEDs）也报告了药物不良反应，这些药物仅对三分之二的患者有效。因此，鉴定具有有希望的抗癫痫活性的支架仍然是开发新的抗癫痫疗法的重要的第一步，具有改善的功效和减少的不良反应。草药在发展中国家被广泛使用，包括用于治疗癫痫，但几乎没有科学证据证明这种用途。在寻找新的癫痫治疗方案的过程中，斑马鱼已经成为一种基于化学惊厥剂的癫痫模型，主要是因为斑马鱼幼虫提供的许多优势使其非常适合高通量药物筛选。研究目的：在这项研究中，南非传统上用于治疗癫痫的20种药用植物使用斑马鱼幼虫模型筛选抗癫痫活性。材料与方法：对120种粗提取物、44种馏分和3种分离化合物进行毒性分类，以确定每种提取物、馏分或化合物的最大耐受浓度（MTC）。MTC值用于指导生物活性研究中的浓度范围选择。对萝芙木粗提物、级分和分离化合物的药效进行了研究。在6-dpf斑马鱼幼虫模型中，使用戊四唑（PTZ）测定来测量戊四唑（PTZ）诱导的类寄生虫行为的抑制。结果如下：经过初步的毒性分类和生物活性筛选的粗提取物，从20个非洲植物传统上用于治疗和管理癫痫，甲醇提取物的萝芙木caffra Sond。被鉴定为在斑马鱼幼虫模型中最有希望抑制PTZ诱导的类寄生虫行为。随后的生物活性导向分馏和光谱结构解析导致两种tryptoline衍生物的分离和鉴定;一种以前未报道的生物碱，我们将其命名为rauverine H（1）和已知的生物碱pleiocarpamine（2）。Pleiocarpamine被发现以剂量依赖性方式减少PTZ诱导的癫痫发作。结论：因此，多果芸香胺代表了一个有前途的支架开发新的抗癫痫治疗化合物。此外，本研究的结果提供了初步的证据，以支持萝芙木的传统用途。癫痫的治疗和管理。这些发现证明了萝芙木抗癫痫潜力的进一步研究。使用其他模型。
Ethnopharmacological relevance: Epilepsy is one of the major chronic diseases that does not have a cure to date. Adverse drug reactions have been reported from the use of available anti-epileptic drugs (AEDs) which are also effective in only two-thirds of the patients. Accordingly, the identification of scaffolds with promising antiseizure activity remains an important first step towards the development of new anti-epileptic therapies, with improved efficacy and reduced adverse effects. Herbal medicines are widely used in developing countries, including in the treatment of epilepsy but with little scientific evidence to validate this use. In the search for new epilepsy treatment options, the zebrafish has emerged as a chemoconvulsant-based model for epilepsy, mainly because of the many advantages that zebrafish larvae offer making them highly suitable for high-throughput drug screening. Aim of the study: In this study, 20 medicinal plants traditionally used in South Africa to treat epilepsy were screened for anti-epileptic activity using a zebrafish larvae model. Materials and methods: Toxicity triaging was conducted on 120 crude extracts, 44 fractions and three isolated compounds to determine the maximum tolerated concentration (MTC) of each extract, fraction or compound. MTC values were used to guide the concentration range selection in bioactivity studies. The effectiveness of crude extracts, fractions and isolated compounds from Rauvolfia caffra Sond. in suppression of pentylenetetrazole (PTZ) induced seizure-like behaviour in a 6-dpf zebrafish larvae model was measured using the PTZ assay. Results: Following a preliminary toxicity triage and bioactivity screen of crude extracts from 20 African plants used traditionally for the treatment and management of epilepsy, the methanolic extract of Rauvolfia caffra Sond. was identified as the most promising at suppressing PTZ induced seizure-like behaviour in a zebrafish larvae model. Subsequent bioactivity-guided fractionation and spectroscopic structural elucidation resulted in the isolation and identification of two tryptoline derivatives; a previously unreported alkaloid to which we assigned the trivial name rauverine H (1) and the known alkaloid pleiocarpamine (2). Pleiocarpamine was found to reduce PTZ-induced seizures in a dose-dependent manner. Conclusions: Accordingly, pleiocarpamine represents a promising scaffold for the development of new antiseizure therapeutic compounds. Furthermore, the results of this study provide preliminary evidence to support the traditional use of Rauvolfia caffra Sond. in the treatment and management of epilepsy. These findings warrant further studies on the anti-epileptic potential of Rauvolfia caffra Sond. using other models.