Medicinal uses, pharmacology, and phytochemistry of convolvulaceae plants with central nervous system efficacies: a systematic review
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This systematic review summarizes evidence on Convolvulaceae plants with central nervous system (CNS) activities. 54 Convolvulaceae species have been historically used for CNS effects, and 46 have been pharmacologically evaluated. 67 compounds from 16 species are recognized to have CNS effects. While progress has been made in pharmacology and phytochemistry studies, more research is needed to better understand the CNS activities of this plant family.
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Medicinal uses, pharmacology, and phytochemistry of convolvulaceae plants with central nervous system efficacies: a systematic review
- 1. R E V I E W Medicinal uses, pharmacology, and phytochemistry of Convolvulaceae plants with central nervous system efficacies: A systematic review Guang‐Tong Chen | Yun Lu | Min Yang | Jian‐Lin Li | Bo‐Yi Fan School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China Correspondence Bo‐Yi Fan and Jian‐Lin Li, School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province, 226001, China. Email: fanboyi@ntu.edu.cn; jianlinli1980@163. com Funding information Postdoctoral Science Foundation of China, Grant/Award Number: 2016M591897; Natu- ral Science Project of Nantong Science and Technology Board, Grant/Award Number: MS12016038; National Natural Science Foundation of China, Grant/Award Number: 21402100 Central nervous system (CNS) disorders play a major impact on individual lives and place a severe strain on health care resources. Convolvulaceae is a family comprising approximately 1,600–1,700 species grouped in 55–60 genera, and many species are reported to have an effect on CNS functions. A systematic review of the literature studies was carried out to summarize available evidences on Convolvulaceae plants with CNS efficacies. This review is based on various data sources such as Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. A total of 200 related articles were included in this review. According to the research result, 54 Convolvulaceae species are suggested to display CNS efficacies historically, and 46 species have been evaluated for their CNS efficacies. In addition, 67 compounds from 16 Convolvulaceae species are recognized to possess CNS efficacies. Despite great progress made through pharma- cology and phytochemistry studies on CNS active Convolvulaceae species, more exploratory research is needed to gain a better understanding of the CNS efficacies of this plant family. KEYWORDS CNS efficacies, Convolvulaceae, ethnopharmacology, pharmacology, phytochemistry 1 | INTRODUCTION The central nervous system (CNS) is the control center of the body. It integrates information received to coordinate and influence the body's activity. Central nervous system disorders, such as neuralgia, dementia, epilepsy, anxiety, and insomnia, profoundly debilitate human behavioral, social, and cognitive functions (Ajetunmobi, Prina‐Mello, Volkov, Corvin, & Tropea, 2014). Besides accounting for 12% of deaths worldwide, CNS disorders also result generally in poor quality of life (Reddy et al., 2016). Moreover, CNS disorders place a severe challenge on health care systems. An extensive study by the European Brain Council estimated the total cost of brain dis- orders across Europe at 798 billion pounds in 2010 (Gustavsson et al., 2011). Despite the significant impact of CNS disorders on individual and society, new drug development in this field of medi- cine remains limited. Treatments for CNS disorders, such as depres- sion and schizophrenia, are still largely based on substances identified in the 1950s (Brandon & Sawa, 2011). Therefore, novel and active chemical substances for the treatment of CNS disorders are to be discovered. Plants have been used by humans since immemorial times to cure disorders and to promote relief from ailments (Carlini, 2003). The tra- ditional usage of medicinal plants by indigenous healers has been valu- able for community health care in many cultures (Cheikhyoussef et al., 2011). Medicinal plants are valuable sources of alternative therapy per se, but a wide range of secondary metabolites can also be potentially used for treatment and prevention of disorders. Nearly 51% of approved drugs directly or indirectly originated from natural products since 1980 (Newman & Cragg, 2016). Among plant medicines used in CNS disorder treatments historically, many are proven effective by modern pharmacological studies (Chen et al., 2017; da Costa et al., 2017; Dong et al., 2016; Hosseinkhani, Sahragard, Namdari, & Zarshenas, 2017). Meanwhile, plenty of natural metabolites identified from medicinal plants have demonstrated efficacy in in vivo or in vitro models, suggesting their therapeutic potential on CNS disor- ders (Nabavi et al., 2015; Z. Y. Wang et al., 2017). However, a large Abbreviations: 5‐HT, serotonin; AChE, acetylcholinesterase; AD, Alzheimer's disease; Aβ, amyloid β‐protein; CNS, central nervous system; CQA, caffeoylquinic acid; ERK, extracellular regulated protein kinase; GABA, γ‐aminobutyric acid; i.p., intraperitoneal; IC50, 50% inhibitory concentration; ICR, Institute of Cancer Research; LPS, lipopolysaccharide; LSA, lysergic acid amide; LSD, lysergic acid diethylamide; MDA, malondialdehyde; MPP+ , 1‐methyl‐4‐phenyl‐pyridinium ion; NO, nitric oxide; PD, Parkinson's disease; PSPC, purple sweet potato color; ROS, reactive oxygen species; SOD, superoxide dismutase Received: 23 July 2017 Revised: 17 November 2017 Accepted: 18 December 2017 DOI: 10.1002/ptr.6031 Phytotherapy Research. 2018;32:823–864. Copyright © 2018 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/ptr 823
- 2. majority of medicinal plants have not been investigated for their phar- macological activities and represent a potential source for providing new lead compounds for CNS disorder treatments (Gomes, Campos, Órfão, & Ribeiro, 2009). Convolvulaceae, known commonly as bindweed or morning glory family, is a family comprising approximately 1,600–1,700 spe- cies grouped in 55–60 genera. The family is nearly cosmopolitan in distribution, but its members are primarily tropical plants (Stefanović, Austin, & Olmstead, 2003). Convolvulaceae plants are commonly present as herbaceous vines, but some plants are also trees, shrubs, or herbs. Many species of the Convolvulaceae have been reported to possess CNS efficacies throughout the world. The seeds of Turbina corymbosa and Ipomoea violacea are known as ololiuhqui and tlitliltzin, respectively, in the Aztec language and were used to attain a state of mind suitable for divination in religious ceremonials in ancient Mexico (Meira, Silva, David, & David, 2012). Convolvulus pluricaulis and Evolvulus alsinoides, two important sources of Indian medicine Shankhpushpi, were used to treat several CNS disorders, including insanity, epilepsy, nervous debility, and memory impair- ment (Agarwa, Sharma, Fatima, & Jain, 2014; Sethiya, Nahata, Mishra, & Dixit, 2009). Cuscuta chinensis Lam., a traditional Chinese medicine used to tonify the livers and kidneys, is used as a CNS depressant in India (Akbar, Nisa, & Tariq, 1985). Recently, extensive studies have been conducted on the CNS efficacies of Convolvulaceae species, such as Argyreia nervosa (Meher & Padhan, 2011), C. pluricaulis (Agarwa et al., 2014; Sethiya et al., 2009), and Ipomoea batatas (J. K. Kim, Choi, et al., 2011). A number of reviews were published on some specific Convolvulaceae species or genus (Al‐Snafi, 2016; Austin, 2007; Chan, Baba, Chan, Kainuma, & Tangah, 2016; Meira et al., 2012). However, a systematical and comprehensive review on the ethnopharmacology and pharmacology properties of the CNS active Convolvulaceae species has not been performed. Originally, ergoline alkaloid derivatives were isolated from lower fungi and were shown to exhibit diverse and remarkable CNS activi- ties, especially in the treatment of migraine or Parkinson's disease (PD; Leistner & Steiner, 2009). In 1960s, Hofmann and Tscherter defined ergoline alkaloids in higher plants, specifically in some Convolvulaceae plants (Chao & Dermarderosian, 1973). Since then, a large number of genera belonging to Convolvulaceae, including Argyreia (Chao & Dermarderosian, 1973), Ipomoea (Amor‐Prats & Harborne, 1993), and Stictocardia (Lee, Chao, & Der Marderosian, 1979), have been searched for the existence of ergoline alkaloids, based on the idea that ergoline alkaloids are the main bioactive constit- uents responsible for the psychotomimetic effects of Convolvulaceae plants. In recent years, with the development of phytochemical research, other CNS active compounds have been identified from Convolvulaceae plants, including flavonoids, coumarins, lignans, and resin glycosides, greatly enriching the understanding of the CNS efficacies of Convolvulaceae plants. This review study not only focuses on the medicinal uses and pharmacological studies of CNS active Convolvulaceae plants but also summarizes the isolated biological compounds from several Convolvulaceae species. In addition, the crosstalk among the medicinal uses and pharmacological and phytochemical studies provides a theoretical guidance for the medicinal utilization of Convolvulaceae plants and might lead to the discovery of novel active chemical sub- stances for the CNS disorder treatments. 2 | MATERIALS AND METHODS The study design followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (Moher, Liberati, Tetzlaff, Altman, & PRISMA Group 2009). 2.1 | Search strategy A number of electronic databases were searched, including Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. The relevant term Convolvulaceae was paired with psychotomimetics, central nervous, CNS disorder, neuroinflammation, stroke, depression, pain, anal- gesic, antinociceptive, neurodegenerative disease, Parkinson, Alzheimer, Huntington, memory, learning, cognitive, epilepsy, seizure, anticonvulsant, stress, anxiety, anxiolytic, sedative, and schizophrenia. The databases were queried for articles published up to June 2017. The ultimate goal of this search was to explore articles that investigated the Convolvulaceae species with CNS efficacies, including medicinal uses and pharmacological and phytochemical studies. Inclusion and exclusion criteria of evidences found in databases are listed below. Inclusion criteria included the following: 1. Studies carried out in vitro, in animal and clinical studies 2. Studies utilizing the fresh, dried, juice version or extracts of Convolvulaceae species 3. All studies on Convolvulaceae species assessing the CNS efficacies Exclusion criteria included the following: 1. Studies on Convolvulaceae species assessing other than CNS efficacies 2. Phytochemical studies on Convolvulaceae species not related to CNS efficacies 3. Duplication of data and titles and/or abstracts not meeting the inclusion criteria The course of action of this study is shown in Figure 1. 2.2 | Study selection The shortlisted and relevant studies (200 articles) were indepen- dently assessed by two authors (B. Y. F. and G. T. C.) of this study. In addition, a third independent review was performed by one of the authors (J. L. L.) for studies containing nonconsensus features. 824 CHEN ET AL.
- 3. 2.3 | Data extraction The data were collected and examined by the authors using standard procedures. The information from the chosen articles on study substances, cell lines, animal models, strains, doses or concentrations, route of administrations, biochemical assays, and molecular mecha- nisms studied was extracted and assessed. 2.4 | Data analysis Pooling statistics was not considered due to methodological heterogeneities between animal studies. Hence, meta‐analyses have not been performed for the accessed data. 3 | RESULTS A total of 32,777 published articles were found in the aforementioned databases. Among them, 200 met the criteria after the exclusion of 32,577 evidences by reading the title (31,206), checking for data duplication (403), and reading the contents (968). Among the included articles, 49 mentioned the medicinal uses of Convolvulaceae species, 144 referred to pharmacological studies on the Convolvulaceae species with CNS efficacies, and 31 described the CNS active compounds from Convolvulaceae species. 4 | MEDICINAL USES Table 1 lists the ethnobotanical information such as genera, species, medicinal parts, route of administration, medicinal properties and dis- orders cured, and country or region of usage of Convolvulaceae plants. As shown in Table 1, a total of 54 species belonging to 19 genera are recorded to possess CNS efficacies historically. Here, we introduce some important species or genera. 4.1 | Argyreia nervosa A. nervosa (syn. Argyreia speciosa) is native to the Indian subcontinent and was introduced to numerous areas worldwide, including Hawaii, Africa, Deccan, and the Caribbean. Although its seeds are now recog- nized as a hallucinogen and are found to contain the highest concen- tration of ergoline alkaloids in the entire family, its roots are the traditional medicinal parts used in India since ancient times. The roots have been regarded as a nervine tonic, which was used to improve the intellect and prevent the effects of age (Meher & Padhan, 2011). 4.2 | Convolvulus species and Evolvulus species Shankhpushpi is considered as one of the best brain tonics in Ayurvedic pharmacopoeia (Sethiya et al., 2009). C. pluricaulis (syn. Convolvulus microphyllus) and E. alsinoides, two medicinal plants belonging to different genera in Convolvulaceae, are the main sources of Shankhpushpi. C. pluricaulis is mostly used in North India, whereas E. alsinoides is used in South India. Despite belonging to different genera, they share similar therapeutical effects on CNS disorders including insanity, epilepsy, nervous debility, and memory impairment (Agarwa et al., 2014; Sethiya et al., 2009). Evolvulus nummularius, another Evolvulus plant morphologically similar to E. alsinoides, is also regarded as a substituent source of Shankhpushpi to improve memory according to literature (Karthik et al., 2016; Sethiya et al., 2012). In addition, Convolvulus arvensis was traditionally used to treat epilepsy in north Pakistan (Murad et al., 2011). 4.3 | Cuscuta species Chinese Dodder or Tu Si Zi, the seed of Cuscuta australis and C. chinensis, is a commonly used traditional Chinese medicine for improving sexual function, tonifying the livers and kidneys, and reduc- ing urination (Fan, Luo, Gu, & Kong, 2014). It is also used to treat cog- nitive impairment in many Chinese formulations, such as Five Seeds Combo and Zuo Gui Wan pill (Shen et al., 2016). Moreover, the whole plant of C. chinensis has been used widely as CNS depressant in tradi- tional Indian medicine to treat various brain disorders such as epilepsy, insanity, mania, and melancholy for several centuries (Akbar et al., 1985). Cuscuta reflexa is a substitute of C. chinensis in China, the seeds of which are also used as Tu Si Zi (S. Patel et al., 2012). In India, the seeds of C. reflexa are reported to possess a sedative effect, and the whole plant is used for the treatment of mental disorders such as mel- ancholy, insanity, and epilepsy (J. Sharma et al., 2013). Moreover, the stem of Cuscuta epithymum is recorded to treat epilepsy in Iran (Sahranavard et al., 2014). 4.4 | Ipomoea species The genus Ipomoea, with approximately 500–600 species, comprises the largest number of species within Convolvulaceae. Due to the hallucinogenic content of ergoline alkaloids in the seeds, a lot of Ipomoea species were used by ancient people to attain a state of mind suitable for divination during religious ceremonies and magical rituals in Central America and Africa. For instance, the seeds of I. violacea, known as tlitliltzin in the Aztec language, are FIGURE 1 Search and selection of published articles CHEN ET AL. 825
- 6. still used even today by certain natives in Mexico (Meira et al., 2012). In Latin American countries, the seeds and leaves of some Ipomoea species, such as Ipomoea alba, Ipomoea pes‐caprae, and Ipomoea purpurea, are also used during religious ceremonies (Meira et al., 2012). Two to four seeds of I. alba crushed in water and taken at night result in vivid dreams as reported in Zimbabwe (Sobiecki, 2002). In addition to their use as a hallucinogenic, Ipomoea species are also used in the treatment of nervous disorders. Ipomoea aquatica and I. batatas, two important consumed foods, are used to treat nervous debility and madness in India and Zimbabwe, respectively (K. N. Prasad et al., 2008; Sobiecki, 2002). The smoke of burned roots of Ipomoea leptophylla is used in the treatment of nervousness (Pereda‐Miranda et al., 2010). The roots of Ipomoea tyrianthina (syn. Ipomoea orizabensis) and Ipomoea stans were used to treat convulsions and epilepsy in Mexico (Pereda‐Miranda et al., 2010). The roots of Ipomoea ommaneyi are used to treat convulsions and epilepsy in Zimbabwe (Sobiecki, 2002). Moreover, the whole plants of Ipomoea eriocarpa are used to treat epilepsy in India (Jain & Verma, 2016). 4.5 | Merremia species Merremia dissecta was first discovered in the Caribbean islands. As a medicine, the crushed leaves of M. dissecta are recommended by Cubans as a sedative for use in tisanes (Austin, 2007). Merremia emarginata, which is also called Convolvulus reniformis, Evolvulus emarginatus, Ipomoea reniformis, or Merremia gangetica, is the twining herb therapeutically used to treat neuralgia and epilepsy in India (Mohan & Subramani, 2014). In addition, the fruits of Merremia tridentata are used to treat epilepsy in India (Jain & Verma, 2016). 4.6 | Operculina turpethum Operculina turpethum is a well‐known medicinal herb traditionally used in the Unani system of medicine to treat various disorders. During the flowering season, the roots of the plants are shed to be used as a drug. It is reported to possess a number of neurological effects in the Unani system of medicine, such as brain evacuant and brain tonic, and to be used to treat CNS disorders such as insanity, epilepsy, and pain (Ahmad et al., 2017). 4.7 | Pharbitis nil The seed of Pharbitis nil (syn. Ipomoea nil), with the common Chinese name of Qian Niu Zi, is one of the most powerful purgative drugs used in China and Japan. Although there are no related records on the utilization of P. nil in CNS disorders in China, it is used to treat Alzheimer's disease (AD) in Unani. Eminent Unani scholars believed that P. nil as a purgative agent could be used to slow the progression of AD by removing deranged material from the brain tissue (Ahmer & Khan, 2015). 4.8 | Turbina corymbosa T. corymbosa, also called Rivea corymbosa or Ipomoea corymbosa, is a large scandent twining woody vine distributed throughout Latin Amer- ica from Mexico to as far south as Peru. The seeds are known as ololiuhqui and are used as a narcotic by the Aztecs and neighboring Indians (Taber et al., 1963). In addition, ololiuhqui is also used to attain a state of mind suitable for divination during religious ceremonies and magical healing practices (Meira et al., 2012). According to our research, a total of eight species are suggested to possess the hallucinogenic effects as a part of their traditional usage. Meanwhile, 21 species are used to treat head or body pain; about 14 species are used to treat epilepsy; about 11 species are suggested to possess a CNS depressant effect that could be used to treat madness, insanity, or nervousness; about nine species are regarded as brain tonic. Other plants are used for senselessness, brain evacuant, nar- cotic, and some other mental distributions. 5 | PHARMACOLOGY A total of 144 published articles referred to the CNS efficacies of 46 Convolvulaceae species. According to their curative effects, the CNS efficacies of Convolvulaceae species can be categorized as fol- lows: analgesic, antidementia, anxiolytic or antistress, antiepileptic, sedative–hypnotic, neuroprotective, and other effects. Tables 2–8 list the pharmacological studies of Convolvulaceae species according to different curative effects. Table 9 summarizes the researched Convolvulaceae species and their corresponding CNS efficacies. 5.1 | Analgesic effect Pain is an unpleasant sensory and emotional feeling accompanying existing or impending tissue damage (Świeboda, Filip, Prystupa, & Drozd, 2013). Pain sensation involves the active regulation by excit- atory and inhibitory circuits in the CNS, controlled primarily by nuclei in the brainstem that can either diminish or exaggerate pain depending on mood, cognitive function, and memories (Woolf, 2010). On the basis of our research, 28 species belonging to 12 genera have been investigated for analgesic effects (Table 2). Most of the studies investigated the in vivo analgesic effects of Convolvulaceae species using mouse or rat models, with the exception of an in vitro study evaluating the antimigraine effect of Ipomoea pes‐tigridis. The methanol extract of the stems of Argyreia argentea was evalu- ated for its analgesic effect against pain induced by acetic acid and for- malin in Swiss albino mice. The extract at the doses of 1.0, 1.5, and 2.0 g/kg produced an inhibition of 12.66%, 16.04%, and 23.60% in acetic‐acid‐induced pain and 19.3%, 24.5%, and 31.0% in formalin‐ induced pain (Dina et al., 2010). The roots, leaves, and aerial parts of A. nervosa are all investigated for the analgesic effect in tail‐flick test, acetic‐acid‐induced writhing test, or hot‐plate test, which showed pos- itive results (George et al., 2016; Jeet et al., 2012; Lalan et al., 2015). Tang et al. (2009) reported that the ethanol extract of the fruits of Calonyction aculeatum showed remarkable analgesic activity, which they suggest to be related to the malondialdehyde and prostaglandin E2 reduction and superoxide dismutase level increase. 828 CHEN ET AL.
- 18. Huang and Feng (2010) and Tan et al. (2012) have compared the analgesic effects of the aqueous and ethanol extracts of the whole plants of Calystegia soldanella. Their results showed that both extracts exhibited analgesic effects, with a better activity for the ethanol extract. With the systematic solvent method, the acetoacetate fraction of the ethanol extract of C. soldanella was considered as the valid tar- get for the analgesic effect (Tan et al., 2012). Awaad et al. (2011) and Atta and El‐Sooud (2004) have reported that the ethanol and methanol extracts of the aerial parts of Convolvu- lus fatmensis both exhibited analgesic activities in vivo. Agarwal et al. (2014) reported that the ethanol extract of the leaves of C. pluricaulis showed significant analgesic activity in the tail‐flick and hot‐plate tests in male Wistar rats. Cressa cretica L. (Convolvulaceae), popularly known as Rudanti in Hindi, is a useful medicinal plant. The aqueous and methanol extracts of the whole plants of C. cretica both showed analgesic activities in male albino mice, which reduced the number of writhing induced by acetic acid (Abdallah et al., 2017). In the genus Cuscuta, the whole plants of Cuscuta arvensis (Koca et al., 2011), Cuscuta campestris (Agha et al., 1996; Ghule et al., 2011), and C. chinensis (Akbar et al., 1985); the seeds of C. chinensis (Liao et al., 2014); and the stems of C. reflexa (Pal et al., 2003) all show analgesic effects in different animal models. Koca et al. (2011) reported that the methanol extract of Cu. arvensis whole plants showed the strongest analgesic effect among different extraction methods. The Caulis of Erycibe obtusifolia and Erycibe schmidtii are officially recorded in the Chinese Pharmacopoeia under the same name, Erycibes Caulis. Both plants reduce the number of contortions induced by acetic acid and inhibit the second phase of the formalin‐ induced licking response in Institute of Cancer Research mice (Z. Chen et al., 2013). As the largest genus in Convolvulaceae, a total of 12 Ipomoea species were reported to possess analgesic effects. Among them, the different parts of I. pes‐caprae, including aerial parts (da Silva Barth et al., 2017; de Souza et al., 2000; Vieira et al., 2013), leaves (Bragadeeswaran et al., 2010), and whole plants (Ji et al., 2008), all showed in vivo analgesic effects. In addition, Rogers et al. (2000) found that the methanol extract of the whole plants of I. pes‐caprae could potently inhibit adenosine‐diphosphate‐induced platelet aggregation and [14 C]‐serotonin ([14 C]5‐HT) release in vitro, suggesting a potential utilization in migraine and tension‐type headache. M. emarginata (Purushoth et al., 2012), M. tridentata (Arunachalam et al., 2011), O. turpethum (Ezeja et al., 2015; M. N. Islam, Nyeem, Taher, & Awal, 2015; Prabhavathi et al., 2012; V. Sharma & Singh, 2013), Porana sinensis (Z. Chen et al., 2013), and Rivea hypocrateriformis (Brahmbhatt et al., 2010; Godipurge et al., 2015; Jyothirmai et al., 2014) also show analgesic effects in various pain models in vivo. Among them, Prabhavathi et al. (2012) reported that the extract of the whole plant of Operculina exhibited a remarkable activity similar to that of the standard drug diclofenac sodium. Jyothirmai et al. (2014) reported that the ethanol extract of R. hypocrateriformis showed 35.76% and 80.47% inhibition of writhing movements, respectively, compared to standard drug ibuprofen. TABLE4(Continued) GenusSpecies Medicinal parts Pharmacological activitiesExtractorfractionTypesTestingsubjectsDoseanddurationPositivecontrolNegativecontrolEffectsReference EvolvulusEvolvulus alsinoides Aerial parts anxiolytic activity Ethylacetatefraction ofethanolextract InvivoElevatedplusmazetest inSprague‐Dawleyrats Oral,100and 200mg/kg Diazepam, i.p.,1mg/kg 0.2%Tween‐80, oral Increaseinthetimespentin openarmsandthenumber ofopen‐armentries Nahataetal. (2009) WholeplantsAnxiolytic activity MethanolextractInvivoElevatedplusmazetestOral,10and 20mg/kg Diazepam, 2mg/kg 3%Tween‐80, oral ShowedanxiolyticactivityMaliketal. (2011) Antistress activity EthanolicextractInvivoChronicunpredictable stressinadultmale Sprague‐Dawleyrats Oral,200mgkg−1 day−1 ,7days Melatonin,i.p., 20mg/kg 1% carboxymethyl cellulose Normalizedstressinduced oxidativealterationswith anefficacysimilartothat ofmelatonin M.Kumaretal. (2010) IpomoeaIpomoea aquatica LeavesAnxiolytic activity Methanol:acetone (70:30)extract InvivoElevatedplusmaze,light– darkapparatus,hole boardapparatusin Swissalbinomice Oral,200and 400mg/kg Diazepam,i.p., 1mg/kg —Increasedthetimespentin openarmandlitarea; increasednumberof headpoking Khan,Saini,Bhati, Karchuli,and Kasture(2011) Ipomoea carnea LeavesAnxiolytic activity Petroleumether, alcohol,and waterextract InvivoSwissalbinomiceand Wistaralbinorats Oral,100– 400mg/kg Diazepam,oral, 4mg/kg —Prolongedthecumulative timespentintheopenarms RoutandKar (2013) Ipomoea stans RootsAnxiolyticactivityEthylacetateextractInvivoMaleInstituteofCancer Researchmice i.p.,2.5– 40.0mg/kg Diazepam,i.p., 1mg/kg 2.5%Tween‐ 20,i.p. ProducedananxiolyticeffectHerrera‐Ruiz etal.(2007) 840 CHEN ET AL.
- 24. TABLE 9 Summary of pharmacological evaluation on the central nervous system efficacies of Convolvulaceae species Genus Species Parts of plants Central nervous system efficacies References Argyreia Argyreia argentea Stems Analgesic Dina et al. (2010) Argyreia nervosa (Burm. F.) Bojer Roots, leaves, aerial parts Analgesic, antidementia, antistress, anxiolytic, antiepileptic, sedative Bodhankar and Vyawahare (2008); Galani and Patel (2011a, 2011b); George et al. (2016); Habbu, Mahadevan, Kulkarni, et al. (2010); Habbu, Mahadevan, Shastry and Chilakwad (2010); Hanumanthachar et al. (2007); Jeet et al. (2012); Joshi et al. (2007); A. Kumar et al., 2015; Lalan et al. (2015); Neeraj et al. (2009); N. Patel et al. (2011); Vyawahare and Bodhankar (2009a, 2009b) Argyreia populifolia Choisy Leaves Sedative Ratnasooriya and Dharmasiri (2011) Calonyction Calonyction aculeatum Fruits Analgesic Tang et al. (2009) Calystegia Calystegia soldanella (L.) R. Br Whole plants Analgesic Huang and Feng (2010); Tan et al. (2012) Convolvulus Convolvulus arvensis Linn. Aerial parts, flowers Antiepileptic, sedative Awaad et al. (2006); Quintans Júnior et al. (2008) Convolvulus fatmensis G.Kunze. Aerial parts analgesic Atta and El‐Sooud (2004); Awaad et al. (2011) Convolvulus hirsutus Aerial parts Antiepileptic Quintans Júnior et al. (2008) Convolvulus pilosellaefolius Aerial parts Antidementia Gholamhoseinian et al. (2009) Convolvulus pluricaulis Choisy Leaves, aerial parts, roots, whole plants, flowers Analgesic, antidementia, anxiolytic, antiepileptic, sedative, neuroprotective, antidepressant, anti‐ Huntington's disease Agarwal et al. (2014); Amin and Sharma (2015); Amin et al. (2014); Bihaqi et al. (2009, 2011, 2012); Dhingra and Valecha (2007a, 2007b); Dhuna et al. (2012); Kaur et al. (2016); R. Kumar (2014); L. F. Liu et al. (2012); Malik et al. (2015, 2011); Mathew and Subramanian (2012, 2014); Nahata et al. (2008, 2009); Pawar et al. (2001); Quintans Júnior et al. (2008); Rawat and Kothiyal (2011); K. Sharma et al. (2009, 2010); Siddiqui et al. (2014); Verma et al. (2012) Convolvulus suendermannii Aerial parts Antiepileptic Quintans Júnior et al. (2008) Cressa Cressa cretica L. Whole plants Analgesic, antidementia Abdallah et al. (2017); Khare, Chaudhary, et al. (2014); Khare, Yadav, et al. (2014) Cuscuta Cuscuta arvensis Whole plants Analgesic Koca et al. (2011) Cuscuta campestris Yuncker Whole plants Analgesic Agha et al. (1996); Ghule et al. (2011) Cuscuta chinensis Lam. Seeds, whole plants, aerial parts Analgesic, antidementia, antiepileptic, sedative, neuroprotective, anti‐ Parkinson's disease, neuronal differentiation effects Akbar et al. (1985); S. Y. Kang, Jung, et al. (2014); Lan and Du (2010); Li et al. (2006); Liao et al. (2014); S. in et al. (2013); J. H. Liu et al. (2003); Saeedi et al. (2017); Yang et al. (2013); M. Ye et al. (2014); Zhen et al. (2006) Cuscuta japonica Choisy Seeds Antidementia Moon et al. (2016) Cuscuta planiflora Ten. Whole plants Antiepileptic, antidepressant Firoozabadi et al. (2015); Mehrabani et al. (2007) Cuscuta reflexa Roxb. Stems, whole plants, leaves Analgesic, antidementia, anxiolytic, antiepileptic, sedative Borole et al. (2011); Hiremath and Handral (2016); Pal et al. (2003); Thomas et al. (2015) Erycibe Erycibe obtusifolia Benth. Caulis Analgesic Z. Chen et al. (2013) Erycibe schmidtii Craib Caulis Analgesic Z. Chen et al. (2013) Evolvulus Evolvulus alsinoides Linn Aerial parts, leafy shoots, leaves, whole plants Antidementia, anxiolytic, antiepileptic, sedative, neuroprotective, antidepressant Abubakar et al. (2013); Andrade et al. (2012); Auddy et al. (2003); A. Gupta, Singh Karchuli, and Upmanyu (2013); M. Kumar et al. (2010); L. F. Liu et al. (2012); Malik et al. (2011); Mathew and Subramanian (2014); Mehla et al. (2012); Mukherjee et al. (2007); Nahata et al. (2009, 2010); Nag (Continues) 846 CHEN ET AL.
- 25. 5.2 | Antidementia effect Dementia is a chronic condition in which progressive cognitive impair- ment leads to functional disability (Stefaniak & O'Brien, 2016). This condition has become a global health challenge along with an aging world population. AD, the most common type of dementia, represents 60–80% of cases (Tsukamoto, 2015). Pathologically, AD is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits. Altered cholinergic function and induction of neuroinflammation and oxidative stress are also prominent features of AD (Jack et al., 2013). According to our research, 14 species belonging to six genera have been investigated for antidementia effects (Table 3). These researches comprise 31 in vivo studies, 20 in vitro studies, and 3 clinical studies. TABLE 9 (Continued) Genus Species Parts of plants Central nervous system efficacies References and De (2008); Rawat and Kothiyal (2011); Samaradivakara et al. (2016); Siripurapu et al. (2005) Evolvulus nummularius L. Leafy shoots, whole plants Antidementia, antiepileptic Nag and De (2008); Quintans Júnior et al. (2008) Ipomoea Ipomoea aquatica Forsk. Leaves, aerial parts, whole plants Analgesic, antidementia, anxiolytic, antiepileptic, sedative, neuroprotective Choudhury et al. (2008); Datta et al. (2013); Dewanjee et al. (2015); Dhanasekaran et al. (2015); Dwivedi and Tomar (2017); Khan et al. (2011); Sivaraman and Muralidaran (2010a, 2010b); Sivaraman et al. (2015) Ipomoea asarifolia Leaves, aerial parts Analgesic, antidementia Feitosa et al. (2011); Jegede et al. (2009); Lawal et al. (2010) Ipomoea batatas (L.) Lam Roots Analgesic, antidementia, neuroprotective Cho et al. (2003); Choi et al. (2013); H. Kang, Kwak, and Koppula (2014); J. K. Kim, Choi, et al. (2011); Lu et al. (2010, 2012); Sasaki et al. (2013); Shan et al. (2009); Y. J. Wang et al. (2010); Wu et al. (2008); J. Ye et al. (2010) Ipomoea eriocarpa R. Br. Whole plants Analgesic P. S. Prasad et al. (2012) Ipomoea cairica L. Sweet Aerial parts Analgesic Ferreira et al. (2006) Ipomoea carnea Leaves Anxiolytic, antiepileptic, sedative Rout and Kar (2013) Ipomoea fistulosa Leaves Analgesic Alam and Chowdhury (2015) Ipomoea hederaceae Linn Seeds Analgesic S. Kumar et al. (2009) Ipomoea imperati (Vahl) Griseb. Leaves Analgesic De Paula‐Zurron et al. (2010) Ipomoea involucrata Leaves, aerial parts Analgesic, antidementia Elufioye et al. (2010); Ijeoma et al. (2011) Ipomoea mauritiana Jacq. Callus, tubers Analgesic S. Islam, Ahmed, et al. (2015); Monjur‐Al‐Hossain et al. (2013) Ipomoea muricata (Linn.) Jacquin Seeds Antidementia Santiago et al. (2016) Ipomoea pes‐caprae (L.) R. Br. Aerial parts, leaves, whole plants Analgesic Bragadeeswaran et al. (2010); da Silva Barth et al. (2017; de Souza et al. (2000); Ji et al. (2008); Rogers et al. (2000); Vieira et al. (2013) Ipomoea pes‐tigridis Linn. Leaves Analgesic Chowdhury et al. (2014) Ipomoea staphylina Leaves Analgesic Ghosh and Firdous (2014); C. A. S. Kumar et al. (2013) Ipomoea stans Cav. Roots Anxiolytic, antiepileptic, sedative Contreras et al. (1996); Herrera‐Ruiz et al. (2007); Navarro‐Ruiz et al. (1996) Ipomoea tyrianthina Lindl. Roots Sedative León‐Rivera et al. (2011) Jacquemontia Jacquemontia paniculata (Burm.f.) Hallier f. Leaves Sedative Jakaria et al. (2017) Lettsomia Lettsomia setosa Aerial parts Antiepileptic Quintans Júnior et al. (2008) Merremia Merremia emarginata Whole plants Analgesic, antiepileptic Chitra et al. (2014); Purushoth et al. (2012) Merremia tridentate (L.) Hallier. f Roots Analgesic Arunachalam et al. (2011) Operculina Operculina turpethum (L.) Silva Manso Leaves, roots, whole plants Analgesic, sedative Ezeja et al. (2015); M. N. Islam, Nyeem, et al. (2015); Prabhavathi et al. (2012); V. Sharma and Singh (2013) Porana Porana sinensis Caulis Analgesic Z. Chen et al. (2013) Rivea Rivea hypocrateriformis Aerial parts, leaves, roots, fruits Analgesic, antiepileptic, sedative Brahmbhatt et al. (2010); Dhawan et al. (1980); Godipurge et al. (2015); Jyothirmai et al. (2014) CHEN ET AL. 847
- 26. The roots of A. nervosa display antiamnesic effects in different ani- mal models, including scopolamine/diazepam/5‐HT‐treated, aging, and normal Swiss albino mouse models (Bodhankar & Vyawahare, 2008; Habbu, Mahadevan, Shastry, & Chilakwad, 2010; Hanumanthachar et al., 2007; Joshi et al., 2007; Neeraj et al., 2009; Vyawahare & Bodhankar, 2009b). Habbu, Mahadevan, Shastry, and Chilakwad (2010) and Hanumanthachar et al. (2007) have found that the extract of the roots of A. nervosa could reduce the whole‐brain acetylcholines- terase (AChE) activity; Bodhankar and Vyawahare (2008) found that the extract of the roots of A. nervosa could reduce brain dopamine levels, including AChE, dopamine, 5‐HT, and noradrenaline. These results suggested the potential usage of A. nervosa in AD. C. pluricaulis shows antidementia effects in vitro (L. F. Liu et al., 2012; Mathew & Subramanian, 2012, 2014), in vivo (Bihaqi et al., 2011, 2012; Malik et al., 2011; Nahata et al., 2008; Rawat & Kothiyal, 2011; K. Sharma et al., 2010), and in clinical studies (Amin & Sharma, 2015; Amin et al., 2014; R. Kumar, 2014). Bihaqi et al. (2011) reported that C. pluricaulis could improve scopolamine‐induced learning and memory dysfunction by decreasing AChE activity and inhibiting oxida- tive stress in the cortex and hippocampus. Bihaqi et al. (2012) also reported that the C. pluricaulis extract could attenuate scopolamine‐ induced increased protein and messenger RNA levels of tau, β‐amyloid precursor protein levels, amyloid β‐protein (Aβ) levels, and histopatho- logical changes in the rat cerebral cortex. In a clinical study, patients treated with Shankhpushpi tablets (made of powder and juice of C. pluricaulis) showed significant result in auditory delayed, visual delayed, auditory recognition, and visual recognition tests compared with the placebo group, suggesting an enhancement in long‐term memory (Amin & Sharma, 2015; Amin et al., 2014). The antidementia mechanism was tested in vitro. L. F. Liu et al. (2012) evaluated a lot of Ayurvedic and traditional Chinese medicines and found that the leaves of C. pluricaulis showed a remarkable inhibition of Aβ40 and Aβ42 productions. Interestingly, C. pluricaulis did not affect the secreted amyloid precursor protein levels, suggesting the extract of C. pluricaulis does not reduce Aβ through amyloid precursor protein modulation. Mathew and Subramanian (2012) reported that C. pluricaulis could prevent the aggregation of Aβ and dissociate preformed Aβ fibrils at a concentration of 100 μg/μl. Mathew and Subramanian (2014) also reported that the ethanol extract of the whole plants of C. pluricaulis could inhibit AChE activity with a 50% inhibitory concentration (IC50) value of 245 ± 32.4 μg/ml. In addition, in a large‐scale screen for activity, the methanol extract of the aerial parts of Convolvulus pilosellaefolius showed an AChE inhibitory ratio of 10.4% at a concentration of 50 μg/ml, suggesting the potential uti- lization of C. pilosellaefolius in the treatment of AD (Gholamhoseinian et al., 2009). According to Khare, Chaudhary, et al. (2014) and Khare, Yadav, et al. (2014), the whole plants of C. cretica reduced whole‐brain malondialdehyde and nitric oxide (NO) levels and decreased whole‐ brain AChE activity, leading to an improvement of memory impairment in scopolamine‐treated mice. In the genus Cuscuta, the three species C. chinensis (Lan & Du, 2010), Cuscuta japonica (Moon et al., 2016), and C. reflexa (Hiremath & Handral, 2016) show memory‐enhancing effects in mouse models. The hydroalcoholic extract of the aerial parts of C. chinensis inhibits the AChE activity with an IC50 value of 478.07 ± 0.42 μg/ml (Saeedi et al., 2017). Similar to C. pluricaulis, E. alsinoides is investigated vigorously for its antiamnetia activities. The aerial parts and whole plants display nootropic and antiamnesic activities in several in vitro and in vivo models (Andrade et al., 2012; A. Gupta, Singh Karchuli, & Upmanyu, 2013; Malik et al., 2011; Mehla et al., 2012; Nahata et al., 2010; Rawat & Kothiyal, 2011; Siripurapu et al., 2005). The leafy shoots and whole plants show AChE inhibitory activities based on several tests (Mathew & Subramanian, 2014; Mukherjee et al., 2007; Nag & De, 2008; Samaradivakara et al., 2016). The leaves of E. alsinoides also show Aβ40 and Aβ42 inhibitory effects at concentrations of 10 and 40 μg/ml (L. F. Liu et al., 2012). Mehla et al. (2012) reported that the hydroalcoholic extract of E. alsinoides dose‐dependently prevented streptozotocin‐induced cognitive impairment by reducing the oxida- tive stress, improving cholinergic function, and preventing the increase in rho kinase expression. In addition, as a substitute of E. alsinoides, the leafy shoots of E. nummularius also showed AChE inhibitory activity with an IC50 value of 232.33 μg/ml (Nag & De, 2008). In the genus Ipomoea, I. aquatica (Dhanasekaran et al., 2015), Ipomoea asarifolia (Feitosa et al., 2011), Ipomea involucrata (Elufioye et al., 2010), and Ipomoea muricata (Santiago et al., 2016) all show AChE inhibitory activities with IC50 values of 49.03, 120, 42.5, and 39.67 μg/ml, respectively. The leaves of I. aquatica have anti‐ AD and nootropic effects in young, old, and Aβ‐treated Swiss albino mice (Dhanasekaran et al., 2015; Sivaraman et al., 2015). J. K. Kim, Choi, et al. (2011) reported that the ethanol extract of I. batatas (sweet potato) roots could exert protective effects against oxidative stress and reverse Aβ‐induced neurotoxicity in vitro and in vivo, suggesting an anti‐AD potential. Purple sweet potato color (PSPC), also called purple sweet potato anthocyanin, is a class of naturally occurring anthocyanin present in I. batatas that can be used to color food. PSPC was reported as being able to enhance the cognitive performance by inhibiting lipid peroxidation initiated in rat brain homogenates (Cho et al., 2003) and to alleviate brain aging by pro- moting neuron survival via the phosphatidylinositol 3‐hydroxy kinase pathway and inhibiting cytochrome‐C‐mediated apoptosis (Lu et al., 2010). PSPC also ameliorates cognition deficits and atten- uates oxidative damage and inflammation in aging mouse brain induced by D‐galactose (Shan et al., 2009), attenuates cognitive def- icits by promoting estrogen receptor‐α‐mediated mitochondrial bio- genesis signaling (Lu et al., 2012), repairs spatial learning and memory impairment by regulating the expression of synaptic proteins (Wu et al., 2008), and protects the PC‐12 cell from Aβ‐induced injury by inhibiting the oxidative damage, intracellular calcium influx, mito- chondria dysfunction, and cell apoptosis (J. Ye et al., 2010). In addition, Sasaki et al. (2013) reported that caffeoylquinic acid (CQA)‐rich purple sweet potato extract, with or without anthocyanin, had a neuroprotec- tive effect on mouse brain and can improve the spatial learning and memory of SAMP8 mice. 5.3 | Anxiolytic and antistress activities Anxiety is a normal reaction simulated by stress. Clinically, excessive anxiety often presents in the form of discrete discomfort, which is very 848 CHEN ET AL.