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Mexican Antidiabetic Herbs: Valuable Sources of Inhibitors ofGlucosidases

Rachel Mata,* Sol Cristians, Sonia Escandon-Rivera, Krutzkaya Jua rez-Reyes, and Isabel Rivero-Cruz

Facultad de Qumica, Universidad Nacional Autonoma de Me xico, Me xico DF 04510, Me xico

ABSTRACT: Type II-diabetes mellitus (TII-DM) has been regarded as one of themost important public health problems in all nations in the 21st century. Althoughallopathic therapies remain the most important for the initial management of TII-DM, herbal remedies have gained wide acceptance for treating this condition. Thesealternative therapies are particularly valued in countries such as Mexico, rich inmedicinal plants strongly attached to the cultural values of the population. Medicinalplants are prized sources of-glucosidase inhibitors, which delay the liberation ofglucose from complex carbohydrates, retarding glucose absorption, and thuscontrolling the characteristic hyperglycemia of TII-DM. Among the plant speciesused for treating diabetes in Mexico only 38 have been analyzed for their inhibitoryactivity of-glucosidases. Most of these studies, reviewed in the present work, havefocused on the evaluation of different types of extracts on the activity of -glucosidases from diverse sources. Four species have been thoroughly analyzed inorder to discover novel -glucosidase inhibitors, namely, Hintonia latiflora and Hintonia standleyana (Rubiaceae), Ligusticum

porteri (Apiaceae), and Brickellia cavanillesii (Asteraceae). Their ethnomedical uses, pharmacological and toxicological studies,chemical composition, and antihyperglycemic principles with -glucosidase inhibitory activity are summarized.

INTRODUCTION

Diabetes mellitus (DM) is a polygenic complex metabolicdisorder characterized by hyperglycemia. Many people sufferfrom diabetes mellitus type II (TII-DM), which is associated

with low insulin production or insulin resistance due to geneticand/or epigenetic causes. TII-DM has been regarded as one ofthe most important public health problems in all nations in the21st century, since the disease leads to serious complicationsresulting in increasing disability and reduction of life expect-ancy.1,2 The best treatment for TII-DM involves hyperglycemiccontrol using appropriate therapies and a healthy lifestyle.

Although metformin remains the most important oral agent forthe initial management of TII-DM, there are increasingnumbers of second- and third-line pharmacological agents forthis condition.3 These include sulfonylureas, thiazolidinediones,incretin-based therapies, and -glucosidase inhibitors. Fre-quently, these drugs are combined to make the treatment moreefficient due to synergistic effects.4 The most recent incretin-

based therapies are unable to halt the progression of TII-DM,possibly because they do not increase secretion of endogenousinsulin analogue glucagon-like peptide-1 (GLP-1). However,recent evidence suggests that G-protein-coupled receptor(GPCR) agonists, inhibitors of -glucosidases, peroxisomeproliferator-activated receptor (PPAR) agonists, metformin,

bile acid mimetics, and bile acid sequestrants represent newapproaches to the management of TII-DM via modification ofendogenous GLP-1 secretion.5

-Glucosidases are membrane-bound enzymes of the GH31family that hydrolyze larger carbohydrate molecules to glucoseand related monosacharides.3 Most of these enzymes arelocated in the brush border of the small intestine, where they

catalyze the final step in the digestive process of carbohydrates.Hence, -glucosidase inhibitors can delay the liberation ofglucose from dietary complex carbohydrates, retarding glucoseabsorption and lowering the postprandial blood glucose peak.

Consequently,

-glucosidase inhibitors are useful to prevent theprogression of the disease and for treating prediabeticconditions.4

The best known -glucosidase inhibitors are acarbose andmiglitol; the former is a natural product isolated initially froman Actinoplanes strain, and the second is the N-hydroxyethylanalogue of 1-deoxynojirimycin, isolated from Morus spp.35

Unfortunately, these products produce gastrointestinal com-plaints.3 In recent years many efforts have been made toidentify effective inhibitors of -glucosidases from naturalsources in order to find lead compounds for the developmentof new drugs or herbal preparations useful for the treatment ofdiabetes.6,7 As a result of this endeavor, a few natural products

with inhibitory properties against -glucosidases have been

isolated from plants, mostlyfl

avonoids and alkaloids, but alsoincluding some terpenoids and anthocyanin glycosides.610

As elsewhere, the incidence of diabetes in Mexico is veryhigh, with the number of cases also increasing rapidly.11Asignificant segment of the population believes that treatment

with plants is safer and less expensive than with allopathicmedicine. Furthermore, some patients stop their conventionaltreatments and begin using plants. This situation is not unusual

Special Issue: Special Issue in Honor of Lester A. Mitscher

Received: December 14, 2012Published: February 11, 2013

Review

pubs.acs.org/jnp

2013 American Chemical Society andAmerican Society of Pharmacognosy 468 dx.doi.org/10.1021/np300869g | J. Nat. Prod. 2013, 76, 468483
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in a country like Mexico that is rich in medicinal plants stronglyattached to the cultural values of the population.12,13

According to recent reviews, in Mexico there are at least 383plant species employed for the treatment of TII-DM, but only afew of these have been investigated for their preclinical orclinical efficacy.12,1420 With this in mind, it is important topursue the pharmacological research of a few of these species tosupport their rational use and to discover new herbal-basedtherapies for the treatment of diabetes.

FROM PLANTS TO -GLUCOSIDASE INHIBITORS

Among the plant species highly prized for treating diabetes inMexico only 38 have been analyzed for their inhibitory activityof -glucosidases. Most of these studies have focused on theevaluation of different types of extracts (organic or aqueous) onthe activity of -glucosidases from different sources (e.g.,

bakers yeast, murine, Bacillus stearothermophilus, and pigintestine crude enzymatic preparation). Table 1 summarizesthese studies and includes the plant species, the part of theplant used, the sample tested, and the inhibitory activity of-glucosidase found by means of enzymatic testing and by in vivo

tests, when performed.

2146

Only six of these studies have ledto the isolation of new inhibitors of-glucosidases,30,33,37,4446

and only three were conducted on plants grown inMexico.4446 Thus, this review aims at describing theethnomedical uses, preclinical pharmacological studies, andantidiabetic principles of the latter group of plants, inclusive ofHintonia latiflora (Sesse & Moc. ex DC.) Bullock (Rubiaceae),Hintonia standleyana Bullock (Rubiaceae), Ligusticum porteriCoult. & Rose (Apiaceae), and Brickellia cavanillesii (Cass.) A.Gray (Asteraceae).4448

For conducting studies focused on the isolation of -glucosidase inhibitors from H. latiflora, H. standleyana, L.

porteri, and B. cavanillesii, first potential preclinical toxicity usingthe Lorke procedure was assessed.49 This method measuresacute toxicity for 14 days in mice using a range of doses

between 10 and 5000 mg/kg, in two phases. Those plantslacking acute toxicity effects were then tested for theirantidiabetic potential in vivo by means of well-known animalmodels; this issue is relevant since the initial bioassays selectedshould hold the potential to measure a reduction on bloodglucose levels. For the antidiabetic action in vivo two sets ofexperiments are employed.5052 In the first of these, the acutehypoglycemic activity in normoglycemic and diabetic animals(ICR mice or Wistar rats) is assessed. If feasible, subchronic (14days) or chronic (30 days) experiments are also performed.50

The second group of assays is used to measure theantihyperglycemic action of the extracts or compounds after aglucose [1 g/kg; oral glucose tolerance test, OGTT], sucrose [2g/kg; oral sucrose tolerance test, OSTT], or starch [2 g/kg;

oral starch tolerance test, OStarchTT] challenge, using normaland diabetic animals. These tests provide relevant informationregarding peripheral utilization or absorption of glucose.52 Inparticular, the last two types of experiments are useful to detectinhibitors of-glucosidases. In all tests, the animals are madediabetic with streptozotocin (STZ, 100 mg/kg for mice and 50mg/kg for rats), after previous protection with nicotinamide(NA, 40 mg/kg for mice and 65 mg/kg for rats). Thispreliminary treatment with NA provokes partial protectionagainst the oxidant action of STZ, leading to a diabeticsyndrome much more like TII-DM.53 After 7 days of NA-STZadministration, the animals were generally diabetic andincluded in the studies conducted subsequently. Glybenclamide

(Gly, 10 mg/kg) and acarbose (AC, 5 mg/kg) are used aspositive controls, depending on the type of experiment.Percentage variation of glycemia for each group of animals iscalculated with respect to the initial values at different periodsof time. The results are plotted indicating blood glucose valuesor percentage of variation versus time at several doses.

Alternatively, the area under the curve, integrated values over

time at diff

erent doses, can be plotted.

50

For those extracts showing antihyperglycemic action in theOSTT, an in vitro inhibition test for -glucosidases is carriedout using a well-known spectrophotocolorimetric procedure.54

This assay measures the ability of bakers yeast -glucosidasesto hydrolyze a suitable substrate (p-nitrophenyl--D-glucopyr-anoside) in the presence of the potential inhibitor; AC is alsoused as positive control.

Finally, extracts with evident activity in the OSTT andenzymatic assay then are subjected to activity-guidedfractionation to isolate the active principles. Once thecompounds are obtained and characterized, they are tested in

vitro for their -glucosidase inhibitory activity. If the quantity ofthe active compounds is sufficient, in vivo antihyperglycemic

studies using the OSTT are conducted. In addition, otherrelevant assays might be carried out.Hintonia latif lora and H. standleyana. H. latiflora

belongs to the Mexican medicinal plant complex known ascopalchi. This complex comprises several species of the genusCroton in the Euphorbiaceae family as well as several Rubiaceaeof the genera Coutarea, Exostema, and Hintonia. There are threecommon features of species belonging to this plant complex:the first is their extremely bitter stem bark; second, their long-term use as a substitute of cinchona bark for healing feversassociated with malaria; and finally, their recent use for thetreatment of TII-DM.55 Owing to their employment ascinchona bark substitutes, the copalchi species of theRubiaceae, namely, H. latiflora, H. standleyana, and Exostema

caribaeum, are also known asfalsas quinas

(false cinchonabarks).55

H. latiflora and H. standleyana are endemic to Mexico andNorthern Guatemala.56 Many authors have treated H. stand-leyana as a synonym ofH. latiflora.57 However, morphologicaland molecular studies have demonstrated recently that the twoplants should be recognized within the genus Hintonia asindependent species.58 Regarding their morphological differ-ences, the flowers and leaves of H. latiflora are hairless and theleaves possess domatia on the back side; in contrast, the flowersof H. standleyana are white-pubescent and the leaves are hairy

without domatia.59 On the other hand, analysis of certainregions of ribosomal and chloroplast DNA has revealed low butimportant divergences in the base sequences of the two species.

Thus, these findings provide genetic support for the segregationof the two Hintonia taxa.56,58

In modern day Mexico, H. latiflora is used for the treatmentof gastritis, urinary infections, pain, malaria, and diabetes.15,16

Owing to its antidiabetic effect, Mexican and several Europeandrug companies have commercialized herbal products contain-ing the stem bark of H. latiflora for more than ninedecades.60,61 It is worth mentioning that the hypoglycemicproperties of this plant were discovered in Mexico City at theInstituto Medico Nacional (IMN) at the beginning of the 20thcentury.62 When this institution closed in 1913, Dr. AntoniNovellas introduced Mexican copalchi to Spain for treatingdiabetes.63

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The first written report on the medicinal use of H. latifloraappeared in the 16th century in the Florentine Codex ofBernardino de Sahagun,64which is perhaps the major source of

Aztec life in the years before the Spanish Conquest. Theoriginal source materials were records of conversations andinterviews with indigenous populations in central Mexico. Inthis codex, a bitter stem bark is referred to by the local peopleas chichic patli, which means in Nahualt bitter medicine.The drug was used as a eupeptic and diuretic agent. Severalauthorities have identified chichic patli of the Florentine Codexas H. latiflora.65

In the 16th century, Francisco Hernandez, the personalphysician to King Philip II, in his bookPlants and Animals of the

New Spain and its Vir tue s described a plant namedcopalxihuitl, which resembled H. latiflora in appeareance.66

Next, in 1802, when the Royal Scientific Expedition to NewSpain ended, two copalchi plants were described as beingamong the most important medicinal plants of New Spain. Onecopalchi was from Guadalajara and turned out to be H.latiflora, and the second was Croton niveus, a species of theEuphorbiaceae family. Both copalchi species were valued fortheir antiseptic and antipyretic properties.67 The best testimonyto the value of these two plants was their inclusion in theTorner Collection paintings, which were part of thedocumentation of the work of the Royal expeditioncommanded by Sesse and Mocino.

68

Croton niveus was introduced to Europe in 1817, throughHamburg in Germany.60 Ten years later the plant wascommercialized in Europe for the treatment of the feversassociated with malaria, although its virtues were recordedalready in 1802 in the Archivo del Real Jardin Botanico de

Madrid.69 In 1868, the stem bark ofH. latiflora was introducedin Europe as a substitute for C. niveus for the treatment ofmalaria.70

From 1890 to 1913 the stem bark of H. latiflora wassubjected to several chemical, pharmacological, and clinical

investigations in Mexico City at the IMN. The results werepublished in the scientific journal of this center, namely, Analesdel Instituto Medico Nacional.62 The more relevant findings ofthese studies included the isolation of a glycoside that was laterrediscovered by German and French researchers; thecompound was devoid of toxic effects and provoked diuresisand an increment in the body weight of the test animals.62,7173

Most importantly, Landa demonstrated clinically the hypo-glycemic properties of an extract of the plant and a glycosidicconstituent (Figure 1).74 After these investigations, researchersat the IMN recommended the use of copalchi as a diureticand an antidiabetic agent.74 It is notable that in 1913, whenIMN closed in Mexico City, Dr. Antoni Novellas, an eruditeauthority in the field of pharmacy, introduced the Copalchi of

Novellas in Spain for the treatment of diabetes.63Later on, researchers in Germany and France corroborated

the earlier work of these Mexican scientists. Thus, in the 1950sthe stem bark of H. latiflora was investigated chemically andpharmacologically by Kaiser and Geyer (1955), who isolatedtwo flavone glycosides, one of which having similar propertiesto that isolated by Terres in Mexico.75 In 1960, Paris andBastien in France established the antihyperglycemic effect of amethanol extract of H. latiflora in rabbits. In addition, theFrench researchers isolated a glycoside derivative namedcoutareoside, with a molecular formula of C22H24O12, alsoregarded as a flavone glycoside.76 Coutareoside, upon acidhydrolysis, yielded an aglycone (coutareagenin) with similarT

able1.continued

family

plant

crudedrug

extract/compou

nd

sourceof-glucosidases

IC50/%inhibition

invivotest

ID50/%

inhibition

ref(s)

Urticaceae

CecropiaobtusifoliaBertol.

leaves

butanolextract

bakersyeast

14.0g/mL

oralmaltosetolerancetest

activeat96

mg/kg

21,

22

hydroalcoholextract

ratintestinecrudehomogenate28.0

1.9%

UrticadioicaL.

leaves

aqueousextract

bakersyeast

3.7mg/mL

NDa

NDa

25

Zingiberaceae

ZingiberofficinaleRoscoe

rhizomes

aqueousextract

bakersyeast

22.0

2.0%

NDa

NDa

23,

43

ethylacetateextract

bakersyeast

180.1

3g/mL

aND=nodataavailable.

bOSTT:oralsucrosetolerancetest.

cOStarchTT:oralstarchtolerancetest.




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properties to compound 10a. After the earlier contribution ofParis and Bastien, Reher and Kraus reported on the isolation

and structure elucidation of 7-methoxy-5,2,5-trihydroxy-4-

phenylcoumarin (1) and 7-methoxy-4,5-dihydroxy-4-phenyl-5,2-oxidocoumarin (2) in 1984.77

In 1997, an Italian group led by Capasso from the Universityof Palermo analyzed the hypoglycemic effect of the productSucontral in Wistar rats for 30 days.78 Sucontral is produced byHarras Pharma Curarina GmbH as a combination of a bioactiveconcentrate from the Hintonia plant plus antioxidative,

neuroprotective vitamins and trace elements. In 1999, thefirst patent on the hypoglycemic properties of 4-phenyl-coumarins was filed in Germany. In 2005, Vierling in her Ph.D.dissertation demonstrated that Sucontral has vasodilatingeffects in vitro and in vivo. Such activities were attributed tothe inhibition of an intracellular calcium increase regulated byG-coupled proteins.79 In the same year, the hypoglycemicefficacy and safety of Sucontral were tested in a monocenteropen, uncontrolled study in 30 patients with TII-DM. After 12months of therapy, fasting glucose was reduced by 20%,postprandial glucose by 19%, and the mean glycosylatedhemoglobin by 10%. There were no hypoglycemic episodes oradverse events throughout the total treatment period. The

product manufacturer sponsored this clinical study.80

Figure 1. Hypoglycemic and diuretic effects exerted by a Hintonialatiflora hydroalcohol extract in a clinical trial conducted at IMN,Mexico City (adapted from ref74). Urine volume during a 24 h period(black line); amount of glucose in urine during a 24 h period (greenline); proportion of glucose per liter (red line).

Chart 1




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From 1987 to the present our group has published severalchemical and pharmacological studies on copalchi. Thephytochemical analyses of the stem bark of these plants haveallowed the discovery of cucurbitacins in a plant of the familyRubiaceae as well as the identification of several new 4-phenylcoumarin glycosides, a novel styrene, and desoxycordi-folinic acid (3), an indole alkaloid.44,47,48,8185 The isolatedcucurbitacins are based on dihydrocucurbitacin F and werecharacterized as 23,24-dihydrocucurbitacin F (4), 25-acetyl-

23,24-dihydrocucurbitacin F (5), 3-O--D-glucopyranosyl-23,24-dihydrocucurbitacin F (6), and 25-O-acetyl-3-O--D-glucopyranosyl-23,24-dihydrocucurbitacin F (7).47,48,81 The 4-phenylcoumarins (823) obtained were 5,7,3,4- or 5,7,4-substituted with oxygenated functionalities, with the formerhaving the most common pattern; the sugar portion is usually amonosaccharide (-D-galactose, -D-glucose, 6-acetyl--D-glucose, or 6-acetyl--D-galactose), although a few disacchar-ides were also found (-D-apiofuranosyl-(16)--D-glucopyr-anose or -D-xylopyranosyl-(16)--D-glucopyranose). In allcases, the saccharide unit is attached to the hydroxy group at C-5. According to its spectroscopic and physical properties,compound 10 was found to resemble the glycoside isolated by

Mexican

74

researchers 100 years earlier and then later byGerman75 and French76 researchers. While pursuing theseinvestigations, it was demonstrated that 4-phenylcoumarinsundergo oxidative cyclization under aerobic alkaline conditionsto give oxido-4-phenylcoumarins. Thus, 7-methoxy-5,3,4-trihydroxy-4-phenylcoumarin (10a) was converted to 7-methoxy-4,5-dihydroxy-4-phenyl-5,2-oxidocoumarin (22) bytreatment with potassium hydroxide in methanol. Since thereaction took place only in basic conditions and in the presenceof air, it might proceed via an oxidative phenol couplingprocess. Thus, if oxido-coumarins are natural products, theymight be generated from simple 4-phenylcoumarins via anoxidative phenol coupling reaction.86

More recently, our research group studied H. standleyana andreinvestigated H. latiflora; the preclinical toxicity protocol usedrevealed that none of the extracts of the stem bark of bothHintonia are toxic to mice. Moreover, these extracts did notinduce mutagenic effects using Salmonella typhimurium strains

when assayed by the Ames test.87 The hypoglycemic effects ofthe organic extract and of compounds 5 and 19 from H.standleyana were established in both acute and chronicexperiments.47 Furthermore, the hypoglycemic activity of

cucurbitacin-type compounds was demonstrated for the firsttime. In a different study, the efficacies of extracts and severalisolates from H. latiflora were compared. The extracts (50 mg/kg each time) and compounds 3, 4, 1012, 19, and 20 (15 mg/kg each time) were administered orally twice a day to diabeticrats, for a period of 30 days. The results showed that both theextracts and compounds 4, 1012, 19, and 20 inducedsignificantly more pronounced hypoglycemic effects in diabeticrats than controls, although compound 3 was inactive. Anextract ofH. latiflora and compound 12 restored blood glucoselevels to normal values, with the effect comparable to that ofGly. Compounds 10 and 11 also restored blood glucose levelsto near normal values by the end of the experiment. During thisstudy, it was also demonstrated that the extract of H. latiflora

regulated both hepatic glycogen and plasma insulin levels (p

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