Catalpol in Diabetes and Its Complications: a Review of Pharmacology, Pharmacokinetics, and Safety
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molecules Review Catalpol in Diabetes and its Complications: A Review of Pharmacology, Pharmacokinetics, and Safety Ying Bai 1 , Ruyuan Zhu 1, Yimiao Tian 1, Rui Li 1, Beibei Chen 1, Hao Zhang 1, Bingke Xia 1, Dandan Zhao 1, Fangfang Mo 1, Dongwei Zhang 1,2,* and Sihua Gao 1,* 1 Diabetes Research Center, Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing 100029, China; [email protected] (Y.B.); [email protected] (R.Z.); [email protected] (Y.T.); [email protected] (R.L.); [email protected] (B.C.); [email protected] (H.Z.); [email protected] (B.X.); [email protected] (D.Z.); [email protected] (F.M.) 2 Sino-Canada Anti-Fibrosis Center, Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing 100029, China * Correspondence: [email protected] (D.Z.); [email protected] (S.G.); Tel.: +86-10-64286915 (S.G.) Academic Editor: Lars P. Christensen Received: 5 August 2019; Accepted: 9 September 2019; Published: 11 September 2019 Abstract: This review aimed to provide a general view of catalpol in protection against diabetes and diabetic complications, as well as its pharmacokinetics and safety concerns. The following databases were consulted with the retrieval of more than 100 publications through June 2019: PubMed, Chinese National Knowledge Infrastructure, WanFang Data, and web of science. Catalpol exerts an anti-diabetic effect in different animal models with an oral dosage ranging from 2.5 to 200 mg/kg in rats and 10 to 200 mg/kg in mice. Besides, catalpol may prevent the development of diabetic complications in kidney, heart, central nervous system, and bone. The underlying mechanism may be associated with an inhibition of inflammation, oxidative stress, and apoptosis through modulation of various cellular signaling, such as AMPK/PI3K/Akt, PPAR/ACC, JNK/NF-κB, and AGE/RAGE/NOX4 signaling pathways, as well as PKCγ and Cav-1 expression. The pharmacokinetic profile reveals that catalpol could pass the blood-brain barrier and has a potential to be orally administrated. Taken together, catalpol is a well-tolerated natural compound with promising pharmacological actions in protection against diabetes and diabetic complications via multi-targets, offering a novel scaffold for the development of anti-diabetic drug candidate. Further prospective and well-designed clinical trials will shed light on the potential of clinical usage of catalpol. Keywords: catalpol; diabetes; diabetic complications; pharmacology; pharmacokinetic; safety 1. Introduction Catalpol is an iridoid glucoside widely found in plants belonging to several families of the order Lamiales, such as Plantaginaceae [1], Lamiaceae, and Bignoniaceae [2]. It was named after plants of genus Catalpa, in which it was first discovered in 1962 [3]. In 1971, Kitagawa Hiroshi first isolated catalpol from Rehmannia glutinosa (Figure1) and proved its hyperglycemic e ffect [4]. With its origin distributed widely in the north and central part of China, Rehmannia glutinosa is one of the frequently used herbs in traditional Chinese medicine that was first recorded in Shen Nong’s Herbal Classic and had been clinically used for the management of diabetes for more than 1000 years [5,6]. Therefore, catalpol may assume the anti-diabetic action of Rehmannia glutinosa and has gained increasing attention for its potential contribution in controlling glycolipid metabolism and diabetic complications, making it a very promising scaffold for seeking new anti-diabetic drug candidate [7,8]. Molecules 2019, 24, 3302; doi:10.3390/molecules24183302 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 18 attention for its potential contribution in controlling glycolipid metabolism and diabetic complications,Molecules 2019, 24, making 3302 it a very promising scaffold for seeking new anti-diabetic drug candidate [7,8].2 of 19 ABD C E HO O O O OH O OH HO OH OH IUPAC name of catalpol: (3R,4S,5S,6R)-2-[[(1S,2S,4S,5S,6R,10S)-5- hydroxy-2-(hydroxymethyl)-3,9-dioxatricyclo[4.4.0.02,4]dec-7-en-10- yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol Figure 1. Rehmannia glutinosa, Catalpol, and its chemical structure. (A) Rehmannia glutinosa,(B) Shengdi Figure(dry roots 1. Rehmannia of Rehmannia glutinosa glutinosa, Catalpol,), (C,D )and Crystallized its chemical powder structure. of catalpol, (A) Rehmannia (E) Chemical glutinosa structure, (B) Shengdiof catalpol. (dry Theroots International of Rehmannia Union glutinosa of Pure), (C, and D) AppliedCrystallized Chemistry powder (IUPAC) of catalpol, name (E) of Chemical catalpol: structure(3R,4S,5S ,6ofR )-2-[[(1catalpol.S,2 SThe,4S ,5InternationalS,6R,10S)-5-hydroxy-2-(hydroxymethyl)-3,9-dioxatricyclo[4.4.0.02,4]dec-7- Union of Pure and Applied Chemistry (IUPAC) name of catalpol:en-10-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol. (3R,4S,5S,6R)-2-[[(1S,2S,4S,5S,6R,10S)-5-hydroxy-2-(hydroxymethyl)-3,9- dioxatricyclo[4.4.0.02,4]dec-7-en-10-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol. Diabetes mellitus (DM) [9] is a complex metabolic disorder caused by genetic and/or environmental factors,Diabetes and it ismellitus characterized (DM) by[9] sustainedis a complex hyperglycemia metabolic due disorder to deficient caused insulin by secretiongenetic inand/or islets environmentalor insulin resistance factors, in and the it peripheral is characterized target organsby sustained [9,10]. hyperglycemia DM has now become due to onedeficient of the insulin major secretionepidemics, in andislets there or insulin will be resistance approximately in the 629 peripheral million diabetictarget organs patients [9,10]. around DM the has world now become by 2045 one [11]. ofThe the current major countermeasures epidemics, and forthere DM will may be run approximately into bottlenecks 629 for million the potential diabetic side patients effects, whicharound needs the worldpersisting by 2045 search [11]. for The new current drug candidates countermeasures [12,13]. Forfor thisDM purpose,may run weinto reviewed bottlenecks the currentfor the potential advances sideof catalpol effects, in which the management needs persisting of diabetes search andfor diabeticnew drug complications, candidates [12,13]. its pharmacokinetic For this purpose, profiles, we reviewedand safety the concerns. current advances of catalpol in the management of diabetes and diabetic complications, its pharmacokineticTo accomplish thisprofiles, goal, and weretrieved safety concerns. the following databases, including PubMed (www.pubmed. com),To Chinese accomplish National this Knowledge goal, we Infrastructure retrieved (www.cnki.netthe following), WanFangdatabases, Data including (www.wanfangdata. PubMed (www.pubmed.com),com.cn/), and Web of ScienceChinese (www.isiknowledge.comNational Knowledge Infrastructure). The following (www.cnki.net), words and/ orWanFang phrases Data were (www.wanfangdata.com.cn/),used in various combinations, “catalpol”,and Web of “diabetes”, Science (www.isiknowledge.com). “insulin resistance”, “hyperglycemia”, The following “diabetic words and/ornephrology”, phrases “diabetic were used cardiomyopathy”, in various combinations, “diabetic atherosclerosis”,“catalpol”, “diabetes”, “diabetic “insulin encephalopathy”, resistance”, “peripheral“hyperglycemia”, neuropathy”, “diabetic “diabetic nephrology”, osteoporosis”, “diabetic “diabetic cardiomyopathy”, retinopathy”, “diabetic “diabetic atherosclerosis”, gastroparesis”, “diabeticand “diabetic encephalopathy”, erectile dysfunction”. “peripheral More than neuropathy”, 100 scientific works“diabetic of literatureosteoporosis”, were consulted “diabetic by retinopathy”,June 2019. “diabetic gastroparesis”, and “diabetic erectile dysfunction”. More than 100 scientific works of literature were consulted by June 2019. 2. Physicochemical Properties of Catalpol 2. Physicochemical Properties of Catalpol In addition to mainly sourcing from Radix Rehmanniae, catalpol is also distributed in Lancea tibeticaIn [addition14] and Radix to mainly Scrophulariae sourcing[15 from]. As aRadix kind Rehmanniae of iridoid glycoside, catalpol with is also a polar distributed structure, in catalpol Lancea tibeticais soluble [14] in and water. Radix However, Scrophulariae catalpol [15]. is As unstable a kind of under iridoid high glycosid temperaturee with a [16 polar] and structure, degrades catalpol rapidly isat soluble 100 ◦C (2–6in water. h) [17 However,]. Besides, catalpol catalpol isis unstable less stable under in the high acidic temperature environment [16] and compared degrades to alkalinerapidly atones 100 [ 18°C]. (2–6 h) [17]. Besides, catalpol is less stable in the acidic environment compared to alkaline ones The[18]. content of catalpol depends on different processing and parts of plants [19]. It has been demonstratedThe content that of catalpol catalpol content depends is about on different 3–4% in proc freshessingRehmannia and parts glutinosa of ,plants 1.79–2.28% [19]. inIt has dry roots,been demonstratedand only around that 0.27% catalpol after co steaming.ntent is about Moreover, 3–4% exceptin fresh the Rehmannia roots of Rehmannia glutinosa, glutinosa1.79–2.28%, the in stems dry roots,and leaves and only of this around plant 0.27% are also after rich st ineaming. catalpol Moreover, [20]. Xu etexcept al. [21 the] found roots that of Rehmannia the leaves glutinosa of Rehmannia, the stemsglutinosa andcontained leaves of aroundthis plant 3.81~24.51 are also mgrich/g in of catalpol catalpol. [20]. This Xu discovery et al. [21] provided found that a supplementary the leaves of source for the