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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 3  |  Page : 192-198

Effect of administration of flavonoid-rich extract from Hibiscus sabdariffa to lactating rats on plasma glucocorticoid, leptin, and postnatal growth of offspring


1 Department of Physiology, Reproductive and Developmental Programming Research Group, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Enugu, Nigeria
2 Department of Physiology, Reproductive and Developmental Programming Research Group, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Enugu; Department of Human Physiology, Faculty of Basic Medical Sciences, College of Medical Sciences, Rivers State University, Port Harcourt, Rivers State, Nigeria
3 Department of Physiology, Reproductive and Developmental Programming Research Group, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Enugu; Department of Physiology, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex Ekwueme Federal University Ndufu Alike, Abakaliki, Ebonyi State, Nigeria
4 Department of Physiology, Reproductive and Developmental Programming Research Group, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Enugu; Physiology Unit, College of Health Sciences, Evangel University, Akaeze, Ebonyi State, Nigeria

Date of Submission07-Aug-2021
Date of Decision22-Aug-2021
Date of Acceptance24-Aug-2021
Date of Web Publication30-Nov-2021

Correspondence Address:
Sandra Ugonne Ugwu
Reproductive and Developmental Programming Research Group, Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Enugu
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_33_21

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  Abstract 


Introduction: Flavonoids are a group of natural substances with variable phenolic structures well-known for their beneficial effects on health. Flavonoids are now considered an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal, and cosmetic applications because of their anti-oxidative, anti-inflammatory, anti-mutagenic, and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Aim: This study was aimed at investigating the effect of administration of flavonoids from Hibiscus sabdariffa (HS) to lactating rats on plasma glucocorticoids, leptin, and postnatal weights of the offspring. Materials and Methods: Forty pregnant female Sprague − Dawley rats weighing 150 g–200 g were used for this study. Flavonoids were extracted from HS following standard procedures. On the day of delivery, the rats were divided basically into four groups of 10 dams per group. Group A received tap water; Group B received low dose of flavonoid (5 mg/kg body weight daily); Group C received medium dose of flavonoid (10 mg/kg body weight daily); and Group D received high dose of flavonoid (20 mg/kg body weight daily). Flavonoid administration commenced on day 1 of lactation and ended at weaning. Dams from each group had their blood withdrawn from the orbital sinus on days 1, 7, and 21 for assay of plasma glucocorticoids and leptin. Food intake of the dams and body weight of the offspring was measured. Results: There was a progressive dose-dependent decrease (P < 0.05) in maternal plasma glucocorticoids and leptin with the most decrease seen in the high dose group and PND 21. Low dose flavonoid caused a progressive decrease in maternal food consumption when compared with the control group (P < 0.05). Low dose extract caused a progressive decrease in the body weight of the offspring, whereas the high dose caused a progressive increase in the body weight of the offspring (P < 0.05). Conclusion: Flavonoids from HS caused a progressive decrease in glucocorticoids and leptin with a resultant progressive increase in maternal food intake and body weights of the offspring.

Keywords: Flavonoids, glucocorticoids, Hibiscus sabdariffa, lactation, leptin, postnstal growth


How to cite this article:
Ugwu SU, Adeniyi DB, Katchy NA, Nwannadi V, Ugwu PI, Amadi O, Iloabachie CR, Emelike CU, Chukwu OO, Iyare CO. Effect of administration of flavonoid-rich extract from Hibiscus sabdariffa to lactating rats on plasma glucocorticoid, leptin, and postnatal growth of offspring. Niger J Exp Clin Biosci 2021;9:192-8

How to cite this URL:
Ugwu SU, Adeniyi DB, Katchy NA, Nwannadi V, Ugwu PI, Amadi O, Iloabachie CR, Emelike CU, Chukwu OO, Iyare CO. Effect of administration of flavonoid-rich extract from Hibiscus sabdariffa to lactating rats on plasma glucocorticoid, leptin, and postnatal growth of offspring. Niger J Exp Clin Biosci [serial online] 2021 [cited 2022 Jan 21];9:192-8. Available from: https://www.njecbonline.org/text.asp?2021/9/3/192/331559




  Introduction Top


The discipline of ethnopharmacology, the study of biologically active agents traditionally employed or observed by man, has in recent years received increased attention, and there is presently a widespread interest in the medicinal plants used by different cultures.[1] Nigeria has a rich source of medicinal herbs, with high potential for a holistic system of medicines. There are many species which is spread over a vast area, but only a few have been studied to prove their potential medicinal value. Traditional medicines based on herbal remedies have always played a key role in the health system of many countries which Nigeria is not an exception. Varieties of herbal products are exploited in Nigeria and other developing countries for the effective management of various ailments. The plant parts used, the methods of preparation, and administration of the extracts vary from one place to another. Moreover, the knowledge of herbal medicine is gradually perishing, although some of the traditional herbal practitioners are still practicing the art of herbal healing effectively.[2]

Among all the herbs used in folk medicine, Hibiscus sabdariffa (HS) is one of the effectively used historical herbs which has been widely used in medicine by cultures mostly in African continent in treating many types of ailments ranging from diabetes to hypertension and hypercholesterolemia mostly because of its high flavonoid content.[3],[4],[5]

Lactation is the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all postpregnancy female mammals, although it predates mammals. In humans, the process of lactation is also called breastfeeding or nursing. In most species, milk comes out of the mother's nipples; however, the monotremes, egg-laying mammals, lack nipples, and release milk through ducts in the abdomen.[6]

From the 18th week of pregnancy (the second and third trimesters), a woman's body produces hormones that stimulate the growth of the milk duct system in the breasts: Series of hormones contributes to milk production and lactation, these hormones include progesterone, estrogen, prolactin, human placental lactogen, follicle-stimulating hormones, luteinizing hormone, and human chorionic gonadotropin, growth hormone, thyroid-stimulating hormone, thyrotropin-releasing hormone, oxytocin and glucocorticoids such as cortisol have an important lactation inducing function in several animal species, including humans. Glucocorticoids play a complex regulating role in the maintenance of tight junctions.[7]

Flavonoids are a group of natural substances with variable phenolic structures which are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea, and wine. These natural products are well known for their beneficial effects on health. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal, and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic, and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also the prevention of coronary heart disease. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. The current trends of research and development activities on flavonoids relate to isolation, identification, characterization, and functions of flavonoids and finally their applications on health benefits.[8],[9],[10]

Flavonoids can be used as potential steroid-genesis modulators against three enzymes 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, and aromatase of the steroid-genesis pathway.[11] The virtual screening experiment indicated higher affinity for flavonones than their respective chalcones. The flavonones possess consistent binding affinity to all the three enzymes used and are better steroidogenesis modulators in hormone-dependent cancer.[12],[13] The present study was aimed at investigating the effect of administration of flavonoids from HS to lactating rats on plasma glucocorticoid and leptin levels and offspring's weight.


  Materials and Methods Top


Materials, reagents, and equipment

The materials that were used for this study were the following: Whatman No. 1 filter paper, water bottles and normal rat chow, 2, 5, and 10 ml syringes, 21G needles, 100 ml measuring cylinder, orogastric cannula, plain sample bottles, disposable hand groves, test tubes of various sizes, urine bottles, dissecting set, dissecting board, water bath, distilled water, rotary evaporator, column chromatograph, cotton wool, medicated soap, chloroform anesthesia, desiccator bottle, bucket centrifuge machine (B-Bran Scientific and Instrument Company, England), pipettes, light microscope (B-Bran Scientific and Instrument Company, England), slides and cover slips, electronic weighing balance (weighs up to 0.1 g), potassium, calcium assay kits (by Teco diagnostics company), and creatinine and urea reagents.

Preparations of extract

Matured dry dark red calyces of HS were collected from a local market in Ogbete, Enugu State and were identified and authenticated by a taxonomist at herbarium unit of Department of Plant Science and Biotechnology, University of Nigeria, Nsukka, Enugu State.

The extraction procedure used was as described previously.[14] 30 g of the calyces of HS was brewed in 400 ml of boiled tap water for 45 min. The resulting decoction was filtered using Whatman No. 1 filter paper to obtain a pure filtrate of aqueous extract of the HS calyx. The extract was concentrated using rotary evaporator at 40°C and Column chromatography was used to extract, purify and quantify flavonoids from the aqueous extract of HS using the method of Javed et al.[15] The extract was stored under 40°C before use and was reconstituted in distilled water to give required doses of flavonoid using the method of Nakahara et al.,[16] The doses were prepared fresh on the day of experiment before the administration to the rats by oral gavage.

Animal preparation and experimental design

A total of 40 in-bred virgin female Sprague–Dawley rats weighing 150 g–200 g were used for this study. The animals were obtained from the Faculty of Basic Medical Sciences' Animal House, University of Nigeria, Enugu Campus. The animals were given access to normal rat chow and clean water ad libitum and were placed under a normal standard laboratory condition of 12/12 h light/dark cycle and were allowed to acclimatize for 7 days. The rats' estrous cycle was monitored daily and male rats of proven fertility were introduced into the cages of the female rats that were expected to get into the estrous phase within 12 h (proestrous) to allow for mating in the ratio of 1 male to 2 female rats. Day 1 of pregnancy was taken as the day sperm was seen in the vaginal smear of the rats.[17] On the day of delivery, the rats were divided basically into four groups of ten dams per group as follows:

  • Group A (Control group): This group only received clean water at the dose of 5 ml/kg body weight per os as a vehicle to subject them to the same handling stress with other groups
  • Group B (Low dose flavonoid): This group received low dose of flavonoid fraction of HS extract per os at the dose of 5 mg/kg body weight daily
  • Group C (Medium dose flavonoid): This group received medium dose of flavonoid fraction of HS extract per os at the dose of 10 mg/kg body weight daily
  • Group D (High dose flavonoid): This group received high dose of flavonoid fraction of HS extract per os at the dose of 20 mg/kg body weight daily.[18]


Flavonoid administration commenced on day-1 of lactation and ended at weaning. From birth to weaning, two dams from each group had their blood withdrawn from the orbital sinus on days 1, 7, and 21 for assay of plasma glucocorticoids and leptin.

Measurement of body weight

The body weight of the animals was measured and recorded weekly using an electronic weighing balance.

Measurement of food intake

The daily food intake was calculated by giving each of the rats a known weight of feed after which the remaining feed was weighed the next day and was subtracted from the amount of feed given to the rat the previous day.

i.e.,; Food intake (g) = Amount given (g) − amount remaining (g).

Measurement of plasma glucocorticoid and leptin levels (hormonal assay)

Blood samples were collected from the orbital sinus into a heparinized sample bottle and spun in a centrifuge at 3000 revolutions per minute for 5 min to obtain the plasma samples. The plasma samples were assayed for corticosteroid and leptin using enzyme immunoassay kits specific for corticosteroid and leptin (Cayman Chemicals, Ann Arbor, MI) according to the manufacturer's instructions.

Statistical analysis

All the results were presented as mean ± standard deviation. All the data were analyzed using the one-way analysis of variance and values of P < 0.05 were taken as statistically significant. All the analyses were carried out using the SPSS software version 20.0 for Windows (IBM SPSS version 23, Chicago, USA).


  Results Top


The result of the study on the effect of administration of flavonoids from HS to lactating rats on plasma glucocorticoid and leptin levels and offspring's weight is presented in this section.

Maternal food intake (g)

The result shows in [Table 1] that the values for maternal food intake significantly decreased (P < 0.05) in the low dose group than other groups throughout the study duration. The medium dose group maintained a significantly lower (P < 0.05) maternal food intake value than the control and the high dose group maintained a significantly higher (P < 0.05) maternal food intake value than other groups throughout the study duration.
Table 1: Effect of flavonoid administration during lactation on maternal food intake (g)

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Maternal glucocorticoids level (nmol/l)

[Table 2] summarizes the maternal plasma glucocorticoids level (in nanomole per liter) at Post Natal Day 1 (PND 1), PND 7 and PND 21. The low dose group (Group 2) shows no significant difference when compared with the control group (Group 1) throughout the study duration and a significant increase (P < 0.05) throughout the study when compared with the high dose group (Group 4) and also a significant increase (P < 0.05) at PND 7 and 21 without a significant change at PND1 when compared with the medium dose group (Group 3). The medium dose group shows a significant decrease (P < 0.05) in mean maternal plasma glucocorticoids level against the control group throughout the study duration and only significantly lower (P < 0.05) than the high dose group at PND 7 and 21 while the high dose group (Group 4) shows a significantly lowest (P < 0.05) value than other groups throughout the study duration.
Table 2: Effect of flavonoid administration during lactation on maternal glucocorticoids level

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Maternal leptin level (ng/dl)

In [Table 3], result for the effect of maternal consumption of flavonoid during lactation on maternal leptin level (in nanogram per deciliter) shows that the test groups (low dose, medium dose and high dose groups) had a significant decrease (P < 0.05) in the mean leptin level throughout the study (from PND 1 to PND 21) when compared with the control group. However, the high dose group (Group 4) shows a significantly lowest (P < 0.05) leptin level throughout the study duration when compared with other groups, low dose group maintained a significantly higher (P < 0.05) leptin values throughout the study than Group 3 and Group 4 while the medium dose group (Group 3) shows a significantly lower (P < 0.05) leptin level than control and low dose group but significantly higher (P < 0.05) than that of high dose group throughout the study duration.
Table 3: Effect of administration of flavonoid during lactation on maternal leptin level

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Body weight of the offspring (g)

[Table 4] shows the effect of maternal consumption of flavonoid during lactation on body weight of the offspring from birth to postnatal day 21 (PND 1–PND 21) with the mean body weights (in gram) of pups in the low dose group significantly lower (P < 0.05) than that of pups in other groups except at PND 1 where it showed no significant difference when compared with the control group pups. The medium group pups had no significant difference in their body weights against that of the control group except on PND 21 where it had a significant decrease (P < 0.05) in mean body weight of pups when compared with the control group while pups in the high dose group maintained a significantly higher (P < 0.05) body weight than that of other groups throughout the study duration.
Table 4: Effect of administration of flavonoid during lactation on body weight (g) of offspring from birth to weaning (postnatal day 1–postnatal day 21)

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  Discussion Top


In this study, we investigated the effect of administration of flavonoids from HS to lactating rats on maternal food intake, plasma glucocorticoids, leptin levels, and offspring's body weight.

Maternal food intake (g)

This study shows that the animals in the high dose group had the highest weekly value of food intake. Animals in the medium dose group had values smaller than those in the high dose group but were significantly higher than that of animals in the low dose group and normal control except during the 3rd week when there was no difference in food intake between the medium dose animals and the normal control animals. However, the animals in the low dose group had the lowest food intake throughout the study duration. Considering the result for the glucocorticoid concentrations, the finding of this present study is not in agreement with previous findings[19],[20],[21] which revealed that in normal male rodents, adrenalectomy reduces daily food intake (by 10%–20%), fat stores, and the rate of ponderal weight gain in a glucocorticoid-reversible manner. This is evidence that reduction in the adrenal glucocorticoid concentration reduces food intake by 10%–20% but this reduction in food intake is reversible with the administration of exogenous glucocorticoid. In a like manner, the findings of Udden et al.,[22] also stated that food intake was elevated after glucocorticoid administration as observed with an objective, quantitative method, in spite of increased levels of circulating leptin. Surprisingly, in the present study, the group of animals that had the lowest glucocorticoid concentration also had the highest food intake and that is the group treated with high dose of flavonoids from HS. This could have been caused by the high dose flavonoids as it also reflected in the same manner but less evident in low dose and medium dose groups or more aptly due to the leptin concentration as the animals in the three experimental groups (groups administered with flavonoids from HS) had a lower leptin level than the control group animals but a significantly higher food intake. Leptin regulates energy balance by inhibiting hunger[23] as a result increase in leptin level results to stimulation of the satiety center and consequently inhibition of hunger which will result to an evident reduction in food intake. Conversely, decrease in leptin level results to an opposite effect which is inhibition of the satiety center and stimulation of the feeding center and consequently increase in appetite.[24],[25] This however could be the reason for the increased food intake observed in the flavonoid administered groups.

Maternal glucocorticoids level (nmol/l)

Results of this study showed that there was no significant difference in the mean maternal glucocorticoids level between the control and low dose groups throughout the study duration. The medium dose and high dose group decreased significantly throughout the study duration when compared with the control and low dose group, while the medium dose group increased significantly over the high dose group from Post Natal Day 7 (PND7) to PND21. This shows a dose dependent lowering effect of flavonoids from HS on the glucocorticoids level of the dams and this lowering effect is effective from the dose of 20 mg/kg body weight and above as the low dose of 10 mg/kg body weight shows no significant different when compared with the control group that was not treated with flavonoids from HS. This could be through the inhibition of the activities of adrenal steroidogenic enzymes modulating steroid hormones levels by flavonoids which leads to a decrease in adrenal steroid hormone production including glucocorticoids as stated by Schloms and Swart[26] and Ohno et al.[27] However, the result of this finding is also in agreement with the finding of Agbadua and Obi,[28] which discovered that HS aqueous extract may be protective against stressed-induced LDL-cholesterol increase by its ability to reduce the secretion of the stress hormones-corticosteroid hormones like glucocorticoids and the present study has revealed that this characteristic possessed by HS aqueous extract is traceable to its flavonoids composition.

Maternal leptin level (ng/dl)

In this study, all the animals treated with flavonoids from HS showed a significant decrease in their mean leptin level throughout the study when compared with the control group animals. However, the high dose group (Group 4) shows a significantly lowest leptin level throughout the study duration when compared with other groups. The low dose group maintained a significantly higher leptin values than Group 3 and Group 4 throughout the study, while the medium dose group (Group 3) shows a significantly lower leptin level than control and low dose group but significantly higher than that of high dose group throughout the study duration. This is an evidence that flavonoids from HS also have a dose dependent effect on the leptin levels of the dams which is effective from the smallest dose of 10 mg/kg body weight and above unlike its effects on the glucocorticoid level that is effective from the dose of 20 mg/kg body weight, or more aptly, this dose dependent decrease observed in the leptin level of animals in the test groups could be due to the dose dependent decrease also observed in the glucocorticoid level because both in vivo and in vitro studies in rodents and man have shown that glucocorticoids enhance leptin gene transcription and leptin levels and vice versa,[29] this means that the dose dependent decrease in the glucocorticoids level of the animals might have caused the dose dependent decrease also observed in the leptin levels. This is in consonance with the findings of Masuzaki et al.,[30] which revealed that dexamethasone potently induced ob gene expression and leptin secretion in the organ culture of human adipose tissue. The data from the study of Masuzaki et al.,[30] demonstrate that glucocorticoids act, at least in part, directly on the adipose tissue and increase leptin synthesis and secretion in humans. So, in the present study, the decreased glucocorticoids level could have caused the decrease in the leptin level as observed from the results.

Body weight of the offspring (g)

Result for the maternal consumption of flavonoid during lactation on body weight of the offspring from birth to postnatal day 21 showed that pups in the low dose group had the lowest body weight except at the PND 1 where it showed no significant difference when compared with the control group pups. The medium group pups maintained a similar body weight with that of the control pups except on the PND 21 when their body weight decreased significantly against that of the control pups while pups in the high dose group maintained the highest body weight than pups in other groups throughout the study duration. This result shows that administration of flavonoids from HS can result to low offspring's body weight at low dose, high offspring's body weight at high dose and a normal birth weight similar to that of the control at medium dose but a continued administration of flavonoids from HS at medium dose from post natal day 14 and above may result to an increase in the body weight of the offspring. This finding could be as a result of decreased leptin concentration in the experimental dams which caused increase in appetite and consequently increase in food intake. This increase in food intake may have caused increase in nutrients secreted from the dams to the pups through the breast milk which lead to the dose dependent increase in the body weight of the pups as observed from this study because leptin has a critical role on regulation of body weight, body fat mass, appetite, and food intakes as it has been earlier stated by Izadi et al.[25]


  Conclusion Top


The result obtained indicated that flavonoids from HS has a dose dependent decrease in maternal plasma glucocorticoids level and leptin level with a dose dependent increase in maternal food intake and offspring's body weight. These findings suggest that reduced leptin concentration caused increased in appetite and consequently increased food intake.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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