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Therapeutic Potential of Moringa Oleifera Leaves in Chronic Hyperglycemia and Dyslipidemia: A Review
Therapeutic Potential of Moringa Oleifera Leaves in Chronic Hyperglycemia and Dyslipidemia: A Review
Edited by: Moringa oleifera (M. oleifera) is an angiosperm plant, native of the Indian subcontinent,
Adolfo Andrade-Cetto, Universidad
where its various parts have been utilized throughout history as food and medicine. It is
Nacional Autónoma de México,
Mexico now cultivated in all tropical and sub-tropical regions of the world. The nutritional, pro-
Reviewed by: phylactic, and therapeutic virtues of this plant are being extolled on the Internet. Dietary
Adolfo Andrade-Cetto, Universidad consumption of its part is therein promoted as a strategy of personal health preserva-
Nacional Autónoma de México, tion and self-medication in various diseases. The enthusiasm for the health benefits of M.
Mexico
oleifera is in dire contrast with the scarcity of strong experimental and clinical evidence
Rene Cardenas, Universidad Nacional
Autónoma de México, Mexico supporting them. Fortunately, the chasm is slowly being filled. In this article, I review cur-
*Correspondence: rent scientific data on the corrective potential of M. oleifera leaves in chronic hyperglycemia
Majambu Mbikay , Ottawa Hospital and dyslipidemia, as symptoms of diabetes and cardiovascular disease (CVD) risk. Reported
Research Institute, Civic Campus, 725 studies in experimental animals and humans, although limited in number and variable in
Parkdale Avenue, Ottawa, ON,
design, seem concordant in their support for this potential. However, before M. oleifera
Canada K1Y 4E9.
e-mail: mmbikay@ohri.ca leaf formulations can be recommended as medication in the prevention or treatment of
diabetes and CVD, it is necessary that the scientific basis of their efficacy, the therapeu-
tic modalities of their administration and their possible side effects be more rigorously
determined.
Keywords: Moringa oleifera, cardiovascular disease, diabetes, phytotherapy, natural products
The review includes five sections. The first two sections are con-
cerned with the scientific evidence of M. oleifera efficacy at correct-
ing chronic hyperglycemia or dyslipidemia. They each begin with
a brief description of main aspects of glucose or lipid homeostasis
and its pathogenic disruption, so that the therapeutic efficacy of
the plant could be subsequently evaluated based on current bio-
medical understanding. The third section attempts to correlate
the observed therapeutic effects with the presence in the leaves
of physiological properties or chemical constituents experimen-
tally proven to offer such metabolic benefits. The fourth section
briefly examines what is known of the possible toxicity of M.
oleifera leaves. The final section identifies obvious gaps in current
knowledge and proposes potential avenues for future investigation.
METHODOLOGY
Two biomedical literature databases were searched: PubMed and
FIGURE 1 | Chronological trend of scientific publications on M. Google Scholar (subsections: Biology, Life Science, Environmen-
oleifera. The bibliographic search was conducted online in the PubMed tal Science, Medicine, Pharmacology, and Veterinary Science). The
database at www.pubmed.ncbi.nlm.nih.org/, using moringa, drumstick, or
search was conducted using moringa or drumstick as a keyword
malunggay as title keywords. Article abstracts were reviewed for content
and those unrelated to M. oleifera were discarded. Of the 163 PubMed within the title of the article. Articles dealing with Moringa vari-
articles retained, 64 (39.3%) were about the physiological effects of M. eties other than oleifera were excluded; as were articles in which
oleifera preparation in experimental animals, 30 (18.4%) on their the word drumstick referred to other subject matters (e.g., medical
water-cleansing properties as toxic metal absorbent or flocculent, 23 conditions or transcription factor) than the plant. All the remain-
(14.1%) about their chemical composition, 22 (13.5%) about their
antimicrobial efficacy, 5 (3.1%) about their antioxidant properties in vitro, 5
ing articles, including reviews, were critically read. Peer-reviewed
(3.1%) about their effects on cellular physiology ex vivo, 6 (3.1%) on their articles presenting results of experimental studies, in animals or
nutritional values, 3 (1.8%) about their therapeutic effects in humans, and 6 humans, on the therapeutic potential of M. oleifera leaf extract
about various matters (review, genetics, biofuel, animal feed). or powder in chronic hyperglycemia or hyperlipidemia were ana-
lyzed for inclusion in this review. The analysis focused on therapy
subjects, galenic formulation, mode of administration, dosage,
respectively. Clearly, in spite of the widely held “belief ” in the treatment duration, and measurable biochemical outcomes.
health benefits of M. oleifera, the interest of the international bio-
medical community in the medicinal potential of this plant has THERAPEUTIC POTENTIAL OF M. OLEIFERA IN CHRONIC
been rather tepid. HYPERGLYCEMIA
This report is a review of current data on the therapeutic poten- GLUCOSE HOMEOSTASIS
tial of M. oleifera in chronic hyperglycemia and dyslipidemia. Glucose is a major fuel for animal cells. It is supplied to the organ-
Chronic hyperglycemia is an indicator of diabetes mellitus (DM), ism through dietary carbohydrates and, endogenously, through
and chronic dyslipidemia a risk factor for cardiovascular disease hepatic gluconeogenesis and glycogenolysis. Glucose absorption
(CVD). These metabolic disorders are global epidemics (Yusuf from the gastrointestinal tract (GIT) into blood is regulated by a
et al., 2001; Wild et al., 2004). In developing countries, they are on variety of neuronal signals and enterohormones (incretins), as well
the way to becoming as major causes of morbidity and mortality as as by meal composition and the intestinal flora. Glucose homeosta-
infectious diseases, due to the progressive transition in these coun- sis reflects a balance between glucose supply and its utilization.
tries to a lifestyle characterized, among other aspects, by greater Physiologically, this balance is determined by the level of circulat-
access to dietary calories and less demand for calorie expenditure ing insulin and tissue responsiveness to it. Insulin is secreted by
(Hossain et al., 2007; Aje and Miller, 2009). Geographically, many pancreatic islet β cells. It stimulates glucose uptake and utilization
of developing countries are located in the tropical and sub-tropical by tissues, especially by liver, skeletal muscle, and adipose tissue. It
regions of the world where M. oleifera grows and is cultivated. If also suppresses gluconeogenesis in hepatocytes, while stimulating
validated by medical science, dietary consumption of this plant lipogenesis and inhibiting lipolysis in adipocytes (Gerich, 2000).
could be advocated in these and other countries as an inexpensive
prophylactic strategy against DM and CVD. HYPERGLYCEMIA
The review covers peer-reviewed studies of the therapeutic An individual is diagnosed as diabetic when his blood glucose level
potential of M. oleifera in these pathologies. It focuses on stud- is chronically ≥126 mg/dL after an overnight fast, and ≥200 mg/dL
ies involving experimental animal models and human subjects, 2 h after an oral glucose load of 75 g (oral glucose tolerance test,
in which leaves were used as the medicinal parts of the plant. OGTT; Alberti and Zimmet, 1998). Age, genetics, environment,
Leaves were generally administered per os (p.o.) as powders or and lifestyle influence the development of this pathology. The rela-
aqueous or organic extracts thereof, and, for experimental animals, tive importance of these factors and their combinatorial effects are
at body weight-adjusted doses. A therapeutic effect was defined as not yet fully understood. Two types of DM are commonly recog-
a beneficial change in specific biochemical parameters of disease. nized: type 1 DM (T1DM) results from autoimmune destruction
of pancreatic β cells and represents only 5% of all cases; type-2 half-life in circulation. These particles are prone to oxidation and
DM (T2DM) is the most common form of the disease and the are potent initiators of atherogenesis and its vascular damages
primary concern of this review. (discussed in more detail below). Diabetes-associated neuropathy,
In its early stages, T2DM is characterized by chronic hyper- retinopathy, and nephropathy are some of the consequences of
glycemia and hyperinsulinemia, due to loss of tissue sensitivity to these damages (Dokken, 2008).
insulin, and compensatory secretion of the hormone by islet β cells. Underlying these complex physiological changes are mole-
Its progression involves a complex network of interacting cellular cular alterations in the relative levels of expression and post-
and physiological alterations leading to β cell failure. Glucotoxicity translational modifications of a wide variety of gene products,
and lipotoxicity are the most commonly invoked mechanisms for including surface receptors, second messengers and transcrip-
this failure (Robertson et al., 2004). tional factors.
Glucotoxicity arises from excessive uptake of glucose by islet β
cells. The excess sugar drives glycation reactions and the mito- EVIDENCE OF ANTI-HYPERGLYCEMIC PROPERTIES OF M. OLEIFERA
chondrial electron transport chain, producing macromolecule- Moringa oleifera parts have been used in folk medicine for the
damaging reactive oxygen species (ROS), at levels beyond the treatment of diabetes (Dieye et al., 2008). Five studies aimed at ver-
antioxidation capacity of the cell. The ensuing oxidative stress ifying these properties using leaves were identified in the scientific
impairs insulin synthesis and secretion, and initiates a cascade literature: two were conducted in experimental animals (Ndong
of cellular events that ultimately lead to apoptosis (Kaneto et al., et al., 2007b; Jaiswal et al., 2009) and three in T2DM patients
2007). (William et al., 1993; Kumari, 2010; Ghiridhari et al., 2011). They
Lipotoxicity, on the other hand, results in part from the unre- are summarized in Table 1.
sponsiveness of adipocytes to insulin, negating the ability of this
hormone to stimulate uptake by these cells of non-esterified fatty Animal studies
acids (NEFA) that result from triglycerides (TG) lipolysis in cir- In the study by Ndong et al. (2007b), Goto-Kakizaki (GK) Wistar
culation, and to inhibit lipolysis of endogenous TG to NEFA. rats were used as model of DM. GK rats spontaneously develop
Excess plasma NEFA impairs insulin secretion by β cells, stimulates early glucose intolerance associated with impaired insulin secre-
gluconeogenesis by liver, and inhibits glucose disposal by skele- tion (Bisbis et al., 1993; Abdel-Halim et al., 1995). In an OGTT,
tal muscle, further exacerbating hyperglycemia (Stumvoll et al., overnight fasted Wistar controls or GK male rats were given 2 g/kg
2005). NEFA accumulation in the bloodstream is further aggra- of body weight (kg-bw) glucose by oral gavage, without or with
vated by obesity, a condition characterized by an expanded adipose 200 mg/kg-bw of M. oleifera leaf powder. To determine blood glu-
mass. Furthermore, adipose tissues, especially the visceral and deep cose levels, vein blood was collected before gavage and at different
subcutaneous ones, secrete pro-inflammatory cytokines such as times afterward up to 120 min. Areas under the curves (AUC)
interleukin 6 (IL-6) and tumor necrosis factor α (TNFα), which were derived from the time courses of these levels. In the absence
also contribute to tissue insensitivity to insulin. of treatment, fasting plasma glucose levels (FPG) and their post-
Impaired TG storage into adipocytes facilitates the forma- prandial levels (PPPG) at 120 min were greater (∼1.4× and 2.2×,
tion in the bloodstream of small, cholesterol ester-poor, TG-rich respectively) in GK rats than in control rats. Treatment with M.
low-density lipoprotein (LDL) particles. Hyperglycemia promotes oleifera leaf powder resulted in a lower glycemic response in GK
glycation of these particles, a modification that extends their and control rats. However, in GK rats, the treatment reduced
A. ANIMAL MODELS
Species Inducer Plant part (extract) Protocola Corrective outcomes Reference
Rat STZ Leaf (water) 100–300 mg/kg-bw; p.o., single dose; 8 h ↓FPG; ↑glucose tolerance Jaiswal et al. (2009)
(OGTT)
Rat (GK) – Leaf 200 mg/kg-bw; p.o., single dose; 2 h ↑glucose tolerance (OGTT); Ndong et al. (2007b)
↑stomach content
B. HUMAN T2DM PATIENTS (FPG > 9 mmol/L)
Exper. N Contr. N Plant part (formulation) Protocol Corrective outcomes Reference
(in the experimental group)
Exper. N, number of subjects in the experimental (treated) group; Contr. N, number of subjects in the control (untreated) group. The other abbreviations are explained
in the text.
a
The protocol brief description is given in three lines: line 1, dose; line 2, mode of administration and frequency; line 2, duration of treatment before assessment.
AUC values by 23% (P < 0.05); it did not significantly affect More recently, Ghiridhari et al. (2011) studied a group of 60
these values in control rats. These observations suggested that M. T2DM patients, age 40–58 years, BMI 20–25 kg/m2 , on sulfony-
oleifera treatment improves plasma glucose disposal only in the lurea medication and a standardized calorie-restricted diet. The
diabetic rats. patients were equally divided into an experimental and a control
In the study by Jaiswal et al. (2009), prediabetes and diabetes groups. Patients in the experimental group were prescribed two
were induced in Wistar rats by intraperitoneal (i.p.) injection M. oleifera leaf tablets/day, one after breakfast, the other after din-
of 55 mg/kg-bw of streptozotocin (STZ), a cytotoxic drug that ner for 90 days. M. oleifera leaf powder constituted 98% (w/w)
selectively destroys islet β cells (Like and Rossini, 1976). Based of the tablet content, but the average weight of tablets was not
on FPG (mg/dL), STZ-treated rats were classified as sub-diabetic specified, making the total daily dose unclear. Blood glycated
(∼88 mg/dL), mildly diabetic (∼190 mg/dL), and severely dia- hemoglobin (HbA1c ) was measured before and after the regi-
betic (∼300 mg/dL). A M. oleifera aqueous extract was admin- men. PPPG was determined before the regimen and every 30 days
istered to overnight fasted animals by oral gavage, at 100, 200, or afterward. In the control group, HbA1c and PPPG progressed
300 mg/kg-bw. FPG was determined before treatment (baseline) downwardly with time, but the change was not significant. In the
and at various time points post-treatment. An OGTT was con- experimental group, in contrast, relative to the baseline, HbA1c
ducted 90 min after the last time point. In normal rats, M. oleifera decreased by 0.4% point (from 7.8 ± 0.5 to 7.4 ± 0.6; P < 0.01).
treatment lowered FPG at all doses in time- and concentration- Compared to the starting levels (210 ± 49 mg/dL), PPPG in the
dependent manners. Six hours after administration, 200 mg/kg-bw experimental group progressively decreased with treatment dura-
of M. oleifera extracts lowered FPG by about 26% (P < 0.05), tion, by 9% after 30 days, 17% after 60 days, and 29% after
compared to baseline levels or the levels in untreated mice. In 90 days (P < 0.01), indicating that M. oleifera medication can
an OGTT, at the same dose, a 30% fall in PPPG was observed after induce with time better glucose tolerance. However, it should
3 h, in normal, sub-diabetic, and mildly diabetic rats. A 21-day be noted that treatment allocation to patients appear to have
treatment of severely diabetic rats with the M. oleifera extract at not been randomized as baseline values for the two parameters
a daily dose of 300 mg/kg-bw reduced FPG and PPPG by 69 and were higher in the experimental group than in the control group,
51%, respectively, relative to untreated controls. In all the above 7.8 ± 0.5 vs. 7.4 ± 0.6% for HbA1c , 210 ± 49 vs. 179 ± 36 mg/dL
experiments, the hypoglycemic effect of the plant extract was com- for PPPG.
parable to that of the anti-diabetic drug Glipizide administered at
2.5 mg/kg-bw. THERAPEUTIC POTENTIAL OF M. OLEIFERA IN DYSLIPIDEMIA
LIPID HOMEOSTASIS
Human studies Lipids constitute a major class of hydrophobic constituents of the
In a controlled study with untreated T2DM patients, William et al. body. Their main forms are cholesterol, phospholipids (PL), and
(1993) examined how M. oleifera addition to a standardized meal, triglycerides (TG). Lipids are involved in a variety of biologi-
taken after an overnight fast, affected the 1- and 2-h PPPG, rel- cal processes, including membrane formation, intracellular and
ative to the standard meal alone or a 75-g oral glucose load. M. intercellular signaling, as well as energy storage and production.
oleifera was compared to bitter gourd (Momordica charantia) and The body derives its lipids from de novo cellular biosynthesis and
curry leaves (Murraya koenigii). Compared to the glucose load, from nutrition. Cellular biosynthesis of lipids is regulated at the
standard meals with or without vegetable supplements induced transcriptional level by sterol-regulated element-binding proteins
a significantly lower rise in PPPG (glycemic response) as derived (SREBPs) 1 and 2. SREBP-1 promotes the biosynthesis fatty acids
from AUCs. However, when leaf-supplemented meals were com- and TG, SREBP-2 that of cholesterol (Horton, 2002).
pared to standard meals, only the M. oleifera leaf-supplemented Intestinal and plasma lipids are transported by lipoproteins par-
meal elicited a lower response (−21%, P < 0.01). Plasma insulin ticles. Apolipoproteins (Apo) constitute the protein components
AUCs did not differ significantly between the two meals, suggesting of these particles. Lipoproteins vary in density and, depending on
that the hypoglycemic effect of M. oleifera leaf supplementation their relative contents in TG, cholesterol, and PL, are identified as
was not due to increased insulin secretion. chylomicrons, very low-density lipoprotein (VLDL), LDL, inter-
Kumari (2010) examined the hypoglycemic effect of M. oleifera mediate density lipoprotein (IDL), and high-density lipoprotein
leaf dietary consumption over a 40-day period in T2DM patients, (HDL). Lipids are transported by chylomicrons in the intestinal
30–60 years of age, not on anti-hyperglycemic medication. The lymphatic system; and, in the bloodstream, by chylomicron rem-
experimental group included 46 subjects, 32 men, and 14 women; nants, VLDL, LDL, IDL, and HDL (Abeles et al., 1992; Havel and
the control group of 9 subjects included 4 men and 5 women. Daily Kane, 2001).
meals were comparable among these groups in terms of relative The liver plays a pivotal role in lipid metabolism. It extracts
content of food types (e.g., cereals, green leafy vegetables, fruits, cholesterol from intestinal chylomicrons and excretes it back into
etc.) and nutrients (e.g., proteins, fat, fiber, minerals, etc.) as well the intestines with bile acids. It biosynthesizes TG and cholesterol
as calories. The experimental group received a daily dose of 8 g and packages them as VLDL, that it secretes into the bloodstream.
M. oleifera leaf powder. FPG and PPPG at the end of the protocol Through the LDL receptor (LDLR), it clears up plasma LDL as
(final) were compared to baseline levels. Final values did not differ well as IDL from VLDL or HDL catabolism. HDL mediates the
much from baseline in the control group. They were significantly reverse transport of cholesterol from extra-hepatic tissues to the
reduced in the experimental group (FPG: −28%, P < 0.01; PPPG: liver (Havel and Kane, 2001). Liver LDLR levels and its capacity
−26%, P < 0.05). to clear blood LDL are down-regulated by proprotein convertase
subtilisin/kexin-type 9 (PCSK9), a plasma protein secreted by this coronary artery disease (CAD), myocardial infarction, thrombo-
organ (Horton et al., 2009). embolic stroke, and peripheral artery disease (Steinberg, 2002;
Libby et al., 2011).
Over the years, there has been a vigorous debate over the pre-
DYSLIPIDEMIA
dictive value of plasma LDL-C level as a marker of CVD risk in
Dyslipidemia is a disorder characterized by alterations in the levels
humans. An emerging view is that the level of non-HDL lipopro-
and composition of plasma lipids. According to Adult Treatment
teins, also captured in the TC/HDL-C or HDL-C/non-HDL-C
Panel III (2001), plasma levels ≥200 mg/dL for TC, ≥130 mg/dL
ratio, may constitute a better marker, and its reduction a more
for LDL-C, <40 mg/dL for HDL-C, and ≥150 mg/dL for TG are
cogent measure of the efficacy of anti-dyslipidemia therapies
dyslipidemic. Dyslipidemia may result from inborn defects of
(Sniderman et al., 2010; Manickam et al., 2011).
lipoprotein production or metabolism; but in most cases, it is
secondary to an unhealthy lifestyle (e.g., excessive cigarette smok-
ing or alcohol consumption), other health disorders (e.g., obesity, EVIDENCE OF ANTI-DYSLIPIDEMIC PROPERTY OF M. OLEIFERA
diabetes, infection, obstructive liver disease), or medication (e.g., Five studies were identified in the scientific literature: three were
β blockers, steroids). conducted with experimental animals (Ghasi et al., 2000; Chu-
Besides hypertension, chronic dyslipidemia is a major cause of mark et al., 2008; Jain et al., 2010), two with human subjects
atherosclerosis, a vascular disease affecting blood circulation in (Kumari, 2010; Nambiar et al., 2010). They are summarized in
the coronary, central, and peripheral arteries. The pathology is Table 2.
initiated by irritation of the arterial endothelium by high level of
circulating LDL-C, which leads to overexpression of adhesion and Animal studies
chemoattraction molecules (e.g., vascular cell adhesion molecule- Chumark et al. (2008) examined the therapeutic potential of M.
1, intercellular adhesion molecule, P and E selectins, monocyte oleifera leaves on dyslipidemia induced in rabbits on a high-
chemoattractant protein-1) to injured sites, and the recruitment cholesterol (5%) diet (HCD) for 12 weeks. By the end of the
and capture of circulating monocytes to these sites. These immune regimen, relative to rabbits on a normal diet, HCD-fed rabbits
cells penetrate into the sub endothelium and differentiate into experienced several-fold (×) increases in the plasma levels of total
tissue macrophages, which take up oxidized LDL (oxLDL) via cholesterol (TC, 55×), HDL-C (17×), LDL-C (131×), and TG
scavenger receptors (e.g., CD36, scavenger receptor-A), becoming (4×). The diet also caused extensive plaque formation in carotid
the lipid-laden foam cells characteristic of atheromatous plaques. arteries. When these HCD rabbits were concomitantly fed a M.
In response to growth factors, resident vascular smooth muscle oleifera aqueous leaf extract, at the daily dose of 100 mg/kg-bw
cells (VSMC) proliferate and form a fibrous cap overlying the for the duration of the protocol, these increases were reduced: for
plaques. The oxidative process that leads to oxLDL production also TC and lipoprotein-cholesterol by about 50%, for TG by 75%,
contributes to atherogenesis, as this modified lipoprotein and its and for carotic plaque formation by 97%. This protective effect
by-products (oxysterols and oxPL) act as monocyte chemoattrac- was comparable to that of the anti-cholesterol drug simvastatin,
tants and VSMC mitogens. Clinical complications of this process given p.o., at a daily dose of 5 mg/kg-bw. Similar results were also
include a narrowing of the arterial lumen, plaque rupture, and for- obtained with HCD rabbits fed an aqueous extract of M. oleifera
mation of circulating thrombi. These complications could lead to fruits (Mehta et al., 2003).
A. ANIMAL MODELS
Species Inducer Plant part (extract) Protocola Corrective outcomes Reference
Rabbit HCD Leaf (water) 5 mg/kg-bw; p.o., daily; 12 weeks ↓TC; ↓LDL; ↓HDL; ↓TG; Chumark et al. (2008)
↓carotid plaque formation
Rat HFD Leaf (water) 1 g/kg-bw; p.o., daily; 30 days ↓TC Ghasi et al. (2000)
Rat HFD Leaf (methanol) 150–600 mg/kg-bw; p.o., daily; 30 days ↓TC; ↓LDL; ↑HDL; ↓VLDL; Jain et al. (2010)
↓TG; ↑fecal cholesterol;
↓atherogenic index
B. HUMAN HYPERLIPIDEMICS (TC > 180 mg/dL or TG > 140 mg/dL)
Exper. N Contr. N Plant part (formulation) Protocol Corrective outcomes Reference
(in the experimental group)
17 18 Leaf (tablet) 4.6 g/day; p.o., daily; 50 days ↓TC; ↑HDL-C; ↓non-HDL-C Nambiar et al. (2010)
46 9 Leaf (tablet) 8 g/day; p.o., daily; 40 days ↓TC; ↓LDL-C; ↓VLDL-C Kumari (2010)
Exper. N, number of subjects in the experimental (treated) group; Contr. N, number of subjects in the control (untreated) group. The other abbreviations are explained
in the text.
a
The protocol brief description is given in three lines: line 1, dose; line 2, mode of administration and frequency; line 2, duration of treatment before assessment.
translocase in rat liver, reducing hepatic gluconeogenesis and period), or sub-acute (daily doses, except the highest, for 21 days
glycogenolysis (Hemmerle et al., 1997; Karthikesan et al., 2010a). followed by hematological profiling). Acute treatment caused no
It was found to lower PPBG in obese Zucker rats (Rodriguez death at 400 or 800 mg/kg-bw; it caused 1/6 and 2/6 deaths at 1600
de Sotillo and Hadley, 2002). In OGTT experiments performed and 2000 mg/kg-bw, respectively. At these high doses, surviving
on rats or humans, it reduced the glycemic response in both rats exhibited transient dullness for up to 5 h. Sub-acute treat-
species (van Dijk et al., 2009; Tunnicliffe et al., 2011); in rodents, ment with 400 mg/kg-bw caused a modest (10%), but significant
it also reduced the glucose AUC (Tunnicliffe et al., 2011). Its (P < 0.05) increase in packed cell volume (PCV) and white-blood
anti-dyslipidemic properties are more evident as its dietary sup- cell (WBC) count; with 800 mg/kg-bw, it lowered the PCV, but
plementation has been shown to significantly reduce plasma TC increased the WBC; with 1600 mg/kg-bw, it lowered both para-
and TG in obese Zucker rats or HFD mice (Rodriguez de Sotillo meters. The WBC changes affected lymphocytes, neutrophils, and
and Hadley, 2002; Cho et al., 2010) and to reverse STZ-induced monocytes, but not eosinophils. Blood levels of aspartate amino-
dyslipidemia in diabetic rats (Karthikesan et al., 2010b). transferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) were also examined as surrogate indicators of
Moringinine hepatic function. The results were inconsistent: treatment with 400
The alkaloid moringinine was initially purified from M. oleifera and 1600 mg/kg-bw increased AST and ALT levels by 40–50%; with
root bark (Ghosh et al., 1935) and later chemically identified as 800 mg/kg-bw, it lowered it by about 50%. A 70% increase in ALP
benzylamine (Chakravarti, 1955; Figure 3C). It is also present in levels was observed only after treatment with 1600 mg/kg-bw. His-
leaves. This substance was suspected to mediate the hypoglycemic tological examination of tissue sections stained with hematoxylin
effect of the plant. An early study showed that Wistar rats provided and eosin revealed no alteration in testis or kidney; a diffuse tissue
with drinking water containing 2.9 g/L of benzylamine for 7 weeks degeneration was noted in liver. Interestingly, a dose-dependent
exhibited a reduced hyperglycemic response in an intraperitoneal reduction of body weight gain was noted at the term of the sub-
glucose tolerance test (IPGTT), suggesting improved glucose tol- acute treatment with M. oleifera extract: whereas untreated rats
erance (Bour et al., 2005). More recently, the effect was further gained 53% more weight, those treated with 400, 800, 1600 mg/kg-
explored using HFD-fed, insulin-resistant C57BL/6 mice taking an bw of extract gained only 37, 27, and 18%, more, respectively. It
estimated daily dose 386 mg/kg-bw in drinking water for 17 weeks. is unclear whether this effect is symptomatic of an underlying
Compared to untreated controls, these mice gained less weight, pathology or indicative of a potential anti-obesity property of
had reduced FPG and plasma TC, and were more glucose tolerant the plant. Considering the alterations induced by the sub-acute
(Iffiu-Soltesz et al., 2010). treatment to be mild, the investigators concluded that nutritional
and therapeutic consumption of M. oleifera leaves at doses below
Niaziminin
2 g/kg-bw is safe.
Niaziminin (Figure 3D) is a mustard oil glycoside initially isolated
Other investigators have examined the effects of hexane extracts
(along with other glycosides such as niazinin and niazimicin) from
of M. oleifera leaves on the reproductive organs of male mice after
ethanolic extracts of M. oleifera leaves, based on their hypotensive
an oral gavage at 17, 170, and 1700 mg/kg-bw/day for 21 days.
properties on Wistar rats. At 1 mg and 3 mg/kg-bw, these com-
They observed a dose-dependent significant increase in testis and
pounds caused a 16–22 and a 40–65% fall of mean arterial blood
epididymis weights, in seminiferous tubule diameter and in epi-
pressure (MABP), respectively (Faizi et al., 1992). Other active
didymal epithelium thickness, but no change in the plasma levels
isothiocyanate glycosides and thiocarbamates were isolated from
of gonadotropins. They concluded that these changes reflected
the plant using the same bioassay (Faizi et al., 1994, 1998; Saleem,
enhanced spermatogenesis (Cajuday and Pocsidio, 2010).
1995).
Several studies using experimental rodent models have shown
Aurantiamide acetate that M. oleifera leaf extracts can protect the liver from chemi-
This compound was isolated from M. oleifera roots and struc- cally induced damage (Pari and Kumar, 2002; Ndong et al., 2007a;
turally identified as N -benzoylphenylalanyl phenylalinol acetate Fakurazi et al., 2008; Buraimoh, 2011).
(Figure 3E). At 25 μM, this unusual dipeptide derivative
inhibited by nearly 90% the secretion TNFα and IL-2 from CONCLUSION AND PERSPECTIVES
lipopolysaccharide-stimulated peripheral blood lymphocytes in Collectively, the studies described in this review provide com-
culture. It had no effect on IL-6 secretion (Sashidhara et al., 2009). pelling, albeit very preliminary, experimental evidence of a thera-
This inhibitory activity may contribute to the anti-inflammatory peutic potential of M. oleifera leaves in chronic hyperglycemia and
properties of the plant. dyslipidemia. No report contradicting this evidence was found in
the scientific literature. A common weakness of all the human
TOXICOLOGY OF M. OLEIFERA THERAPY LEAVES studies reviewed herein was the fact that none was randomized
In the studies reviewed in this report, no acute or sub-acute toxic- and double-blind, raising the possibilities of bias in the allocation
ity was reported following treatment with M. oleifera leaves at the of patients to control and experimental groups.
dosage used. The toxicology of this phytotherapy was specifically In spite of converging results, a comparative analysis of these
addressed in two studies. Using rats, Adedapo et al. (2009) exam- studies is made difficult by variations in agro-climatic conditions
ined the safety of an aqueous extract of M. oleifera taken orally at of plant growth and harvesting, in leaf processing methods, in
400, 800, 1600, and 2000 mg/kg-bw (n = 6 rats/dose). The treat- final galenic formulations, and in therapeutic protocols. The phy-
ment was either acute (single dose followed by a 48-h observation tochemical composition of M. oleifera parts have been shown to
vary significantly among regions and seasons (Iqbal and Bhanger, metabolomics), combined with the equally powerful algorithms
2006; Juliani et al., 2009). Leaf extraction solvents determine the of modern bioinformatics (Zhang et al., 2010).
nature and the relative concentrations of bioactive or medicinal Further exploration of the potentials and the eventual use of
ingredients found in final galenic formulations (Siddhuraju and M. oleifera therapy in humans will require that reference standards
Becker, 2003). be set for its cultivation, the collection of its parts, as well as for
Evaluation of the phytotherapy was often restricted to a nar- their final conditioning under good agricultural and collection
row set of parameters of disease. For examples, most studies of practices (GACP). Such guidelines, specifically directed toward
the anti-diabetic effects were limited to measures of FPG and medicinal plants have been defined by the WHO (2003). Further-
PPPG levels. Fasting and post-OGTT insulin levels were almost more, when the pharmacological basis of the therapeutic effects on
never examined to verify whether the treatment improved the a particular pathology is rationally well circumscribed, standard-
ability of the endocrine pancreas to produce and secrete this hor- ized assays should be required to evaluate all galenic lots for the
mone in response to elevated blood glucose. Insulin clamp studies relevant properties. For example, on the basis of current knowl-
would have clarified whether the treatment increased tissue sensi- edge, it would indicated that the content in fibers, phytosterols
tivity to the hormone. Since the medication was administered p.o., as well in antioxidant and anti-inflammatory activities be evalu-
measures of plasma levels of incretins and other enterohormones ated and documented in M. oleifera galenic formulations destined
would have given insights on how GIT physiology is affected by to the treatment of atherosclerosis or diabetes. The shelf life of
the treatment. these properties under specified storage conditions should also be
In the same vein, it is unclear whether the hypocholesterolemic established.
effect of the therapy was associated with repressed de novo cho- In conclusion, based on the available experimental evidence, M.
lesterol biosynthesis (a statin-like effect), increased hepatic choles- oleifera leaf powder holds some therapeutic potential for chronic
terol clearance (statin-like or anti-PCSK9-like effects) or increased hyperglycemia and hyperlipidemia. However, before it is advo-
intestinal excretion. It might be interesting to find the physiolog- cated in any formulation for the treatment of these metabolic
ical basis of the cardioprotective increase of the TC/non-HDL-C disorders in humans, state-of-the art clinical studies must be con-
ratio following treatment. A more extensive analysis on circulat- ducted to establish the consistency of its medicinal efficacy and
ing biochemical markers of inflammation would be justified, as the the safest modalities of its administration.
balance of pro and anti-inflammatory cytokines could influence
the course of both diabetes and atherosclerosis. ACKNOWLEDGMENTS
Besides a rationalized investigation of the therapeutic effect of The author thanks Drs. Ajoy Basak, Michel Chrétien, Hugues
M. oleifera leaves, it is possible to conduct an unbiased search Loemba, and Teik Chye Ooi for their critical review of the manu-
for the affected physiological pathways. This could be achieved script. He is also grateful to Ms. Denise Joanisse for her invaluable
by globally comparing tissues or fluids of untreated and treated assistance in bibliographical search. The work was supported by
animals or humans, using the powerful techniques of systems grants from the Canadian Institute of Health Research and from
biology, the so-called “omics” (transcriptomics, proteomics, and the Strauss Foundation.
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Proteomics, and Metabolomics in conducted in the absence of any Citation: Mbikay M (2012) Therapeu- Copyright © 2012 Mbikay. This is an
Nutraceuticals and Functional Foods, commercial or financial relationships tic potential of Moringa oleifera leaves in open-access article distributed under the
eds D. Bagchi, F. C. Lau, and M. that could be construed as a potential chronic hyperglycemia and dyslipidemia: terms of the Creative Commons Attribu-
Bagchi (Ames, IA: Wiley-Blackwell), conflict of interest. a review. Front. Pharmacol. 3:24. doi: tion Non Commercial License, which per-
11–22. 10.3389/fphar.2012.00024 mits non-commercial use, distribution,
Received: 05 October 2011; accepted: This article was submitted to Frontiers in and reproduction in other forums, pro-
Conflict of Interest Statement: The 08 February 2012; published online: 01 Ethnopharmacology, a specialty of Fron- vided the original authors and source are
author declares that the research was March 2012. tiers in Pharmacology. credited.