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Pre-clinical toxicology of garcinielliptone FC, a tautomeric pair of polyprenylated benzophenone, isolated from Platonia insignis Mart seeds.

ABSTRACT

Background: Garcinielliptone FC (GFC) is a tautomeric pair of polyprenylated benzophenone, which has proven to have antiepileptic, cytotoxic and antioxidant activity.

Purpose: The aim of this study was to investigate the biochemical, hematological and pathological effects of the acute toxicity study as well as to assess the locomotor activity and motor coordination in mice treated with GFC.

Methods: Swiss mice of both sexes weighing 25-30 g divided into three separate groups of five animals matched by weight and size. GFC was aseptically suspended in 0.05% Tween 80, dissolved in 0.9% saline (vehicle) and administered orally (p.o.) and intraperitoneally (i.p.) (500, 1000 and 2000 mg/kg). The acute toxicity study was performed in compliance with the Anvisa regulations.

Results: Behavioral manifestations of toxicity, such as state of consciousness, coordination, muscle tone, reflexes, the activity on the central nervous system (shake, seizures, Straub tail reaction and anesthesia) and the activity of the autonomic nervous system (lacrimation, ptosis, urination, piloerection, hypothermia, breathing and hyperemia) were not seen in any of the animals treated with doses of 500, 1000 and 2000 mg/kg. Additionally, no significant difference in body weight, food and water intake, excreta production or macroscopic changes in the organs of treated animals were detected in comparison with control group. GFC did not affect the locomotor activity and motor coordination of the animals.

Conclusion: The acute toxicity study indicated that GFC treatment, at selected doses given orally and intraperitoneally, showed relatively low risk of toxicity in all test animals, suggesting that it is safe for further investigation.

Keywords:

Acute toxicity

Garcinielliptone FC

Polyprenylated benzophenone

Introduction

In the hexane extract of seeds of Platonia insignis Mart (known as "bacuri") has been isolated a tautomeric form polycyclic polyprenylated acylphloroglucinol called garcinielliptone FC (GFC, Fig. 1/1a). This compound is little known in the genus Platonia belonging to the family Clusiaceae, in which was observed occurrence of polyprenylated benzophenones. This class of compounds has demonstrated antidepressant activity, antifungal, cytotoxic, antiretroviral, antibacterial, antioxidant and vasorelaxant effect on mesenteric artery of rats (Costa Junior et al. 2011a; Costa Junior et al. 2011b; Costa Junior et al. 2011c and Costa Junior et al. 2013).

In spite of promising pharmacological activities, there are no studies analyzing toxicological profile of GFC in animals. In this context, this study aimed to evaluate the toxicity after administration of garcinielliptone FC at doses of 500, 1000 and 2000 mg/kg in male and female Swiss mice treated orally and- intraperitoneally.

Materials and methods

Plant material

The seeds were obtained from fruits of specimens located in the city of Bars, Piaui, Brazil, harvested in March 2012. After collecting one voucher specimen was stored in the Herbarium Graziella Barroso of the Federal University of Piaui (UFPI) under no ICN TEPB 27164.

Extract preparation from P. insignis seeds

The seeds of P. insignis were dried at 55[degrees]C and ground in order to obtain the powder. In the extraction apparatus, powder (848.2 g) was extracted with hexane (63%, v/v). The hexane extract was then subjected to saponification methylation reaction and a small (saponifiable and unsaponifiable) product of the crude extract reaction was analyzed by chromatographic methods (Costa Junior et al. 2011a).

Identification and structural determination of garcinielliptone FC (GFC)

Chemical structure was confirmed by comparing [sup.1]H- and [sup.13]C-nuclear magnetic resonance (NMR) data after previously analyzed and purified by chromatographic methods (column and thin layer) (Supplementary material) (Costa Junior et al. 2011a). Garcinielliptone FC (Fig. 1/la) is a tautomeric pair of polyprenylated benzophenone with a core (diphenyl methanone) substituted by isoprenyl (s) (3-methyl-2-butenyl) and isopropenyl-2-hex-5-enyl group (s). This polyprenylated benzophenone is a yellow oil and its molecular formula and structure (m/z 603.3; [C.sub.38][H.sub.50][O.sub.6]) was confirmed by ESI (+)/MS and NMR, EIMS m/z (%): 602 [[M].sup.+] (1), 465 (6), 341 (8), 231 (10), 177 (3), 137 (20), 109 (11), 69 (100).

NMR spectra description of [sup.1]H is [sup.1]H NMR (CD[Cl.sub.3], 500 MHz) [delta]H (1) 17.84 (OH-2); 6 ([alpha] 2.04 (bd, 13.5), [beta] 2.32 (bd, 13.5)); 7 (1.46 (m)); 12 (7.02 (d, 4.5)); 13 (7.52 (OH)); 14 (7.69 (OH)); 15 (6.57 (d, 8.4)); 16 (6.99); 17 ([alpha] 2.63 (bd, 13.8), [beta] 2.71 (bd, 13.8)); 18 (5.36 (t)); 20 (1.88 (s)); 21 ((1.73 (s)); 22 [alpha] 1.95 (15, 7.2), [beta] 2.16 (14.5, 8.0)); 23 (4.97 (t, 7.2)); 25 (1.67 (s)); 26 (1.53 (s)); 27 (1.88 (2H, m)); 28 (2.64 (bd, 13.8)); 30 (4.30 (2H, s)); 31 (1.53 (s)); 32 ([alpha] 1.88 (m) [beta] 1.96 (m)); 33 (1.88 (2H, m)); 35 (4.64 (s), 4.66 (s)); 36 (1.73 (s)); 37 (0.98 (s)); 38 (1.18 (s)). (la) 17.78 (OH-2); (1H, H-3); 3.06 (1H, H-2); 3.23 (1H, H-6); 2.12 (3H, H-12'); 134 (3H, H-7); 1.43 (2H, H-2'); 2.47 (2H, H-10'); 1.29-1.33 (14 H, H-3'-H-9'); NMR spectra description of [sup.13]C is [sup.13]C NMR (CD[Cl.sub.3], 500 MHz) [delta]c-58.8 (CH, C-2); 66.1 (CH, C-3); 31.3 (CH2, C-4); 23.8 (CH2, C-5); 57.7 (CH, C-6); 16.1 (CH3, C-7); 34.8 (CH2, C-l'); 26.4 (CH2, C-2'); 30.5-30.9 (CH2, C-3'-8'); 25.0 (CH2, C-9'); 44.4 (CH2, C-10'); 212.4 (C, C-ll'); 29.9 (CH3, C-12').

Reagents and experimental protocols

GFC was prepared and emulsified in 0.05% Tween 80 (Sigma Chem. Co., St. Louis, MO, USA), diluted in 0.9% saline (vehicle) and given orally and intraperitoneally at selected doses (500, 1000, 2000 mg/kg) for acute toxicity study. For the assessment of locomotor activity and motor coordination, the animals were treated at GFC doses of 25, 50 and 75 mg/kg. Control groups were given vehicle at the same volume (10 ml/kg).

Animals and behavioral tests

Swiss mice were 2 months old of both sexes weighing 25-30 g (Central Animal Laboratory of the Federal University of Piaui). All animals were maintained under controlled temperature (26 [+ or -] 1[degrees]C) and a 12-h light/dark cycle. Animals had free access to water and food. All behavioral tests were performed in quiet rooms under the same conditions mentioned above and isolated from external noise. All experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals, Department of Health and Human Services, Washington DC, 1985. The project was approved by the Ethics Committee for Experimental Animals from the Federal University Piaui (ECEA/UFPI # 078/2012).

Acute toxicity study

The acute toxicity study was performed in accordance with Anvisa regulations (Brazil 2013). GFC or vehicle was administered only once orally (p.o.) and intraperitoneally (i.p.) at dose levels of 500, 1000 and 2000 mg/kg. Mice were divided into 4 groups of 5 animals matched by weight and size. Symptoms of toxicity related to autonomic and neurobehavioral changes (Hippocratic screening) were monitored continuously for 1 h after dosing, periodically during the first 24 h (with particular attention during the first 3h) and then, daily for a total of 14 days of observation (Almeida et al. 2012).

Behavioral toxicity

For the assessment of locomotor activity and motor coordination, the animals were treated with GFC (25, 50 and 75 mg/kg) and diazepam (2 mg/kg). Mice were divided into 5 groups of 10 animals matched by weight and size. Effect of GFC was also studied on muscular relaxation and locomotor activity using the rota rod test and open field test, respectively (Almeida et al. 2012). Parameters observed during open field test were the number of squares crossed (considering crossed when the four legs of each animal passed the previous square), the number of times the animal had a self-cleaning behavior (grooming) and the number of surveys (rearing). Parameters observed during rota rod test were the number of falls (up to three falls) and the time of permanence on the bar.

Physiological analysis

Physiological data were observed and recorded daily (weight, water consumption, food consumption and excreta production).

Macroscopic analysis and organ weight

After the 14th day, animals were anesthetized with ketaminexylazine as described by Flecknell (1996) and Wixson and Smiler (1997) according to protocol by Cornell University/Cornell Center for Animal Resources and Education. After euthanasia, a detailed necropsy was carried out in all animals and the criteria for gross pathological examination were based on position, shape, size, color, and consistency of the internal organs. In addition, the absolute weight of the following organs was determined: brain, lungs, liver, heart, spleen and kidneys.

Biochemical and hematological parameters

After 14 days of acute treatment, animals were anesthetized and blood was collected into polypropylene Eppendorf tubes. The blood was placed in two different types of tube: one with EDTA anticoagulant for determination of hematological parameters, and another without anticoagulant in order to obtain serum for biochemical analysis.

Statistical analysis

Results were expressed as mean [+ or -] standard error of mean (S.E.M.). Data were analyzed using analysis of variance (ANOVA) followed by t-Student and Newman-Keuls as post hoc test (p < 0.05).

Results

Acute toxicity study

The results showed that GFC at doses of 500, 1000 and 2000 mg/kg produced no toxic effects as evidenced by the absence of signs of toxicity or mortality in the animals during the experimental period (data not shown). Additionally, no significant difference in body weight, food and water intake, excreta production or macroscopic changes in the organs of treated animals were detected in comparison with control group (data not shown). There were no treatment-related changes in organ weights (lungs, liver, heart, spleen and kidneys) (data not shown).

Effects of GFC on hematological and biochemical parameters

Female animals treated with 2000 mg/kg of GFC (i.p.) showed lower MCHC compared to control (p<0.05) (Table 2). Lower triglyceride levels were found in male and female animals treated at doses of 1000 and 2000 mg/kg (p.o. and i.p.) when compared to control (p < 0.05) (Tables 3 and 4). Male mice treated with 1000 and 2000 mg/kg (p.o. and i.p.) showed lower total cholesterol when compared to control (p < 0.05). No significant differences were found in other hematological or biochemical parameters in treated animals compared to control groups (p > 0.05) (Tables 1-4).

Behavioral toxicity

Animals treated with GFC at doses of 25, 50 and 75 mg/kg (p.o. and i.p.) showed no changes in locomotor activity and motor coordination as shown by open field test and rota rod test, respectively, when compared with the control group (data not shown).

Discussion

This study is relevant, since GFC is a potential product for the development of new pharmaceutical formulations in need to have their safety initially investigated by non-clinical studies. The difficulty to find data in the literature to evaluate and discuss the acute toxicity of GFC reinforces the need for this kind of study to provide support for non-clinical studies in order to ensure the safe use of this compound for humans and animals.

In this study, GFC, at doses of 500, 1000 and 2000 mg/kg, did not show any mortality or toxicity signs, when administered only once orally and intraperitoneally. 2000 mg/kg can be considered as the non-observed adverse effect dose (Alexeeff et al. 2002). GFC [LD.sub.50] for mice treated orally and intraperitoneally is higher than 2000 mg/kg, which falls in category 5 of substances with relatively low acute toxicity (2.000-5.000/kg) (OECD 2001). For GFC isolated from P. insignis seed, there are no data in the literature to determine [LD.sub.50] in mice, by any route of administration, which reinforces the need for this study and suggests that GFC is slightly toxic.

The results of the hippocratic screening showed good tolerability of GFC in rodents, without any clinical toxicity sign observed throughout the observation period. Furthermore, the absence of mortality in this study is also considered a positive aspect to support a safe use of this substance in animals, favoring its use in non-clinical studies at repeated doses and, subsequently, in clinical trials with formulations to be developed of this substance. With regard to food and water intake, there were no significant differences over the 14 days of observation and, the intake volume was proportional to excreta output in both groups administered orally and intraperitoneally, which indicates that GFC does not interfere with these parameters. Similar results were observed by Abdullah and Ismail (2009) and Khan et al. (2011) who studied other natural compounds using the same toxicological study method.

After administration of GFC at doses of 500, 1000 and 2000 mg/kg, the body weight of animals treated with GFC did not change in relation to the control group during the observation period (p > 0.05). As a rule, most investigators consider the weight gain or weight loss of toxicological importance if the reduction is at least 10% less than the initial body weight (Hayes 2008). In addition, there are no comparative studies in mice studying the effects of different GFC doses on their body weight, which reinforces the need for this study.

The hematopoietic system is an important indicator to assess the physiological and pathological status of both animals and humans, since this system is very sensitive to toxic compounds. Although female mice treated with 2000 mg/kg (GFC, i.p.) showed reduced MCHC, it is unclear whether there is a disorder in the hematopoietic system, since other erythrocyte indicators (MCV and MCH) did not differ significantly when compared to control group (Table 1).

No biochemical changes were identified in liver transaminases (ALT and AST) and urea and creatinine levels, which are indicators of liver and kidney function, respectively. In contrast, significant reduced levels of total cholesterol and triglycerides in GFC-treated animals indicate the need for further pharmacological study regarding a potential lipid-lowering effect of GFC, since the doses used in this study were aimed to investigate its toxicity (Tables 3 and 4).

As for the macroscopic morphological analysis, there was no change in the shape or weight of the organs studied (brain, lungs, liver, heart, spleen and kidneys) in the GFC animals, which reinforces the findings of low toxicity with this compound. The investigation of toxic effects, whether in single dose or repeated doses, potentially caused by drug substances, is of great importance, since it can interfere in various biological mechanisms, including blood cell production, or cause harm to major organs playing an important role to the vital functions of the body.

Open field test is used to evaluate the exploratory activity of the animals, as emotionality measure in rodents. Literature data show that the reduction in spontaneous exploratory activity gives an indication of the excitation level of the CNS (Almeida et al. 2012), and this reduction may be related to depression resulting from CNS sedation. GFC at the doses studied did not affect the psychomotor activity, suggesting that GFC is not able to produce changes in the CNS, which supports the safety of this compound for non-clinical studies. In rota rod test, the difference in the length of stay and number of falls between GFC-treated and vehicle-treated groups was used as a muscle relaxation index. Thus, GFC at the tested doses (25, 50 and 75 mg/kg) showed no psychomotor changes, suggesting potential safety of this substance, and providing further information on the toxicity of this natural compound.

In conclusion, this acute toxicity study indicated that GFC, given orally and intraperitoneally at the selected doses, was well tolerated in all animals, suggesting that it is safe for further toxicity studies using repeated doses.

http://dx.doi.org/10.1016/j.phymed.2016.02.013

ARTICLE INFO

Article history:

Received 3 July 2015

Revised 3 February 2016

Accepted 14 February 2016

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; CNS, central nervous system; GFC, garcinielliptone FC; LD50, median lethal dose; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration.

Conflict of interest

The authors declare that there is no conflict of interest.

Acknowledgment

We would like to thank the Research Supporting Foundation of the State of Piaui (FAPEPI/Brazil) for the financial support. The authors are grateful for the support provided by the researchers of Laboratory of Research in Experimental Neurochemistry (LAPNEX/UFPI).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.phymed.2016.02.013.

References

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Alexeeff, G.V., Broadwin, R., Liaw, J., Dawson, S.V., 2002. Characterization of the LOAEl-NOAEL uncertainty factor for mild adverse effects from acute inhalation exposure. Regulat. Toxic. Pharma. 36, 96-105.

Almeida, A.A.C., Costa, J.P., Carvalho, R.B.F., Sousa, D.P., Freitas, R.M., 2012. Evaluation of acute toxicity of a natural compound (+)-limonene epoxide and its anxiolytic-like action. Brain Res. 1448, 56-62.

Brazil, Ministry of Health, 2013. National Health Surveillance Agency--ANV1SA. Guide for conducting non-clinical studies of toxicology and safety pharmacology required to drug development (Version 2). Management of Safety and Efficacy Assessment - GESEF. Ministry of Health, Brasilia.

Costa Junior, J.S., Ferraz, A.B.F., Filho, B.A.B., Feitosa, C.M., Cito, A.M.G.L, Freitas, R.M., Saffi, J., 2011. Evaluation of in vitro antioxidant effects of garcinielliptone FC (GFC) isolated from Platonia insignis Mart. J. Med. Plant Res. 5, 293-299.

Costa Junior, J.S., Almeida, A.A., Costa, J.P., Gracas, L.C.A.M., Saffi, J., Freitas, R.M., 2011. Superoxide dismutase and catalase activities in rat Hippocampus pretreated with garcinielliptone FC from Platonia insignis. Pharma. Biol. 50, 455-457.

Costa Junior, J.S., Almeida, A.A.C., Tome, A.R., Cito, A.M.G.L, Saffi, J., Freitas, R.M., 2011. Evaluation of possible antioxidant and anticonvulsant effects of the ethyl acetate fraction from Platonia insignis Mart. (Bacuri) on epilepsy models. Epil & Beh 22, 678-684.

Costa Junior, J.S., Almeida, A.A.C., Ferraz, A.B.F., Rossatto, R.R., Silva, T.G., Silva, P.B.N., Militao, G.C.G., Cito, A.M.G.L., Santana, L.C.L.R., Carvalho, F.AA, Freitas, R.M., 2013. Citotoxic and leishmanicidal properties of garcinielliptone FC, a prenylated benzophenone from Platonia insignis. Nat. Prod. Res. 27, 470-474.

Hayes, A., 2008. Principles and Methods of Toxicology, 5th edition..

Khan, M.I., Denny, K.M., Muralidhara, J., Ramesh, H.P., Giridhar, P., Ravishankar, G.A., 2011. Acute, subacute and subchronic safety assessment of betalains rich Rivina humilis L. Berry juice in rats. Food Chem. Toxicol. 49, 3154-3157.

OECD, 2001. (Organization of Economic Cooperation and Development's). The OECD Guideline for Testing of Chemicals: 423 Acute Oral Toxicity - Acute Toxic Class Method. OECD, Paris. 1-14.

Ana Paula dos Santos C. L da Silva (a), *, George Laylson da Silva Oliveira (a), Shirlene Cesario Medeiros (a), Allyson Martins Lopes Sousa (a), Luciano da Silva Lopes (b), Jorge M. David (c), Joaquim S. da Costa Junior (a), Rivelilson Mendes de Freitas (a)

(a) Department of Phamacy. Laboratory of Research in Experimental Neurochemistry (LAPNEX), Federal University of Piaui, Teresina, CEP 64049-550, Piaui, Brazil

(b) Department of Biophysics and Physiology, Federal University of Piaui, CEP 64000-040, Teresina, Piaui, Brazil

(c) Institute of Chemistry, CEP 40170-290, Federal University of Bahia, Salvador, Bahia, Brazil

* Corresponding author at: Campus UniversitSrio Ministro PetrSnio Portella, Curso de Farmicia, Universidade Federal do Piaui, Bairro Ininga, 64049-901, Teresina, Piaui, Brazil. Tel.: +55 86 3237 1240/+55 86 9498 7766.

E-mail addresses: apaulasantoslima@gmail.com (A.P.d.S.C.L. da Silva), georgenotalO@hotmail.com, georggeoliveira@outlook.com (G.Ld.S. Oliveira).

Table 1
Effects of garcinielliptone FC on hematological parameters of male and
female mice after treatment of 14 days by oral administration.

                         Orally

Parameters                 Control (Vehicle)         [GFC.sub.500]
                                                      (500 mg/kg)

Male
  RBCs ([mm.sup.3])        9.97 [+ or -] 0.25      9.23 [+ or -] 0.35
  Hemoglobin (g/dl)       15.39 [+ or -] 0.29     15.62 [+ or -] 1.78
  Hematocrit (%)          43.28 [+ or -] 1.37     43.34 [+ or -] 2.27
  VCM (fL)                49.69 [+ or -] 0.07     47.89 [+ or -] 3.45
  HCM (pg)                17.67 [+ or -] 0.05     17.34 [+ or -] 3.46
  MCHC (g/[dl.sup.3])     38.95 [+ or -] 0.39     38.54 [+ or -] 3.25
  Platelets              310.80 [+ or -] 16.92   312.47 [+ or -] 12.19
    ([mm.sup.3])
  Leukocytes total         4.92 [+ or -] 0.35      4.34 [+ or -] 2.55
    ([mm.sup.3])
  Neutrophils (%)          8.40 [+ or -] 0.89      9.58 [+ or -] 3.14
  Lymphocytes (%)         71.19 [+ or -] 2.51     69.89 [+ or -] 3.98
Females
  RBCs ([mm.sup.3])        9.97 [+ or -] 0.25      9.83 [+ or -] 0.12
  Hemoglobin (g/dl)       15.39 [+ or -] 0.09     15.10 [+ or -] 2.26
  Hematocrit (%)          43.28 [+ or -] 1.37     44.25 [+ or -] 2.75
  VCM (fL)                49.69 [+ or -] 0.07     50.25 [+ or -] 2.24
  HCM (pg)                17.67 [+ or -] 0.05     17.20 [+ or -] 2.28
  MCHC (g/[dl.sup.3])     38.95 [+ or -] 0.39     38.23 [+ or -] 2.16
  Platelets              310.80 [+ or -] 16.92   313.15 [+ or -] 12.16
    ([mm.sup.3])
  Leukocytes total         4.92 [+ or -] 0.35      4.31 [+ or -] 2.24
    ([mm.sup.3])
  Neutrophils (%)          8.40 [+ or -] 0.89      8.31 [+ or -] 2.28
  Lymphocytes (%)         71.19 [+ or -] 2.51     72.43 [+ or -] 2.39

                         Orally

Parameters                  [GFC.sub.1000]          [GFC.sub.2000]
                             (1000 mg/kg)            (2000 mg/kg)

Male
  RBCs ([mm.sup.3])        9.45 [+ or -] 0.23     10.64 [+ or -] 0.45
  Hemoglobin (g/dl)       15.56 [+ or -] 1.46     16.12 [+ or -] 2.05
  Hematocrit (%)          43.67 [+ or -] 2.56     44.87 [+ or -] 2.23
  VCM (fL)                48.56 [+ or -] 2.47     49.26 [+ or -] 2.41
  HCM (pg)                17.90 [+ or -] 3.23     17.87 [+ or -] 3.23
  MCHC (g/[dl.sup.3])     37.76 [+ or -] 2.27     36.19 [+ or -] 2.16
  Platelets              313.59 [+ or -] 13.26   312.35 [+ or -] 10.58
    ([mm.sup.3])
  Leukocytes total         4.56 [+ or -] 4.73      3.79 [+ or -] 3.55
    ([mm.sup.3])
  Neutrophils (%)          9.37 [+ or -] 1.39      8.47 [+ or -] 2.95
  Lymphocytes (%)         70.78 [+ or -] 3.48     69.49 [+ or -] 3.82
Females
  RBCs ([mm.sup.3])        9.74 [+ or -] 0.20      9.91 [+ or -] 0.95
  Hemoglobin (g/dl)       15.50 [+ or -] 1.78     16.38 [+ or -] 1.24
  Hematocrit (%)          45.28 [+ or -] 3.09     45.60 [+ or -] 2.25
  VCM (fL)                50.46 [+ or -] 1.37     51.34 [+ or -] 1.87
  HCM (pg)                17.91 [+ or -] 3.67     16.71 [+ or -] 2.22
  MCHC (g/[dl.sup.3])     37.08 [+ or -] 3.39     37.40 [+ or -] 2.85
  Platelets              313.18 [+ or -] 13.29   313.50 [+ or -] 13.26
    ([mm.sup.3])
  Leukocytes total         4.16 [+ or -] 3.26      4.61 [+ or -] 2.80
    ([mm.sup.3])
  Neutrophils (%)          8.56 [+ or -] 3.20      7.35 [+ or -] 3.26
  Lymphocytes (%)         69.18 [+ or -] 3.53     70.25 [+ or -] 2.59

MCV, mean corpuscular volume: HCM, mean corpuscular hemoglobin; MCHC,
mean corpuscular hemoglobin concentration: Control, vehicle; GFC,
garcinielliptone FC 500 mg-kg, 1000 mg-kg and 2000 mg-kg. Values
represent mean [+ or -] S.E.M. (n = 10). P < 0.05 versus control
(ANOVA followed by t-Student-Newman-Keuls test as post hoc test).

Table 2
Effects of garcinielliptone FC on hematological parameters of male and
female mice after treatment of 14 days by intraperitoneal
administration.

Parameters              Intraperitoneally

                               Control              [GFC.sub.500]
                              (Vehicle)              (500 mg/kg)

Male
  RBCs ([mm.sup.3])       9.97 [+ or -] 0.25      9.46 [+ or -] 0.67
  Hemoglobin (g/dl)      15.39 [+ or -] 0.09     61.14 [+ or -] 3.92
  Hematocrit (%)         43.28 [+ or -] 137      43.76 [+ or -] 2.46
  VCM (fL)               49.69 [+ or -] 0.07     49.34 [+ or -] 2.35
  HCM (pg)               17.67 [+ or -] 0.05     17.50 [+ or -] 3.34
  MCHC (g/[dl.sup.3])    38.95 [+ or -] 0.39     37.56 [+ or -] 2.67
  Platelets             310.80 [+ or -] 16.92   311.47 [+ or -] 12.38
    ([mm.sup.3])
  Leukocytes total        4.92 [+ or -] 0.35      3.73 [+ or -] 3.45
    ([mm.sup.3])
  Neutrophils (%)         8.40 [+ or -] 0.89      8.47 [+ or -] 2.48
  Lymphocytes (%)        71.19 [+ or -] 2.51     70.52 [+ or -] 2.49
Females
  RBCs ([mm.sup.3])       9.97 [+ or -] 0.25      9.51 [+ or -] 0.48
  Hemoglobin (g/dl)      15.39 [+ or -] 0.09     13.46 [+ or -] 3.34
  Hematocrit (%)         43.28 [+ or -] 1.37     44.31 [+ or -] 3.18
  VCM (fL)               49.69 [+ or -] 0.07     48.23 [+ or -] 2.56
  HCM (pg)               17.67 [+ or -] 0.05     17.27 [+ or -] 3.16
  MCHC (g/[dl.sup.3])    38.95 [+ or -] 0.39     37.54 [+ or -] 3.17
  Platelets             310.80 [+ or -] 16,92   314.34 [+ or -] 14.38
    ([mm.sup.3])
  Leukocytes total        4.92 [+ or -] 0.35      4.64 [+ or -] 4.17
    ([mm.sup.3])
  Neutrophils (%)         8.40 [+ or -] 0.89      8.24 [+ or -] 3.47
  Lymphocytes (%)        71.19 [+ or -] 2.51     70.20 [+ or -] 4.35

Parameters              Intraperitoneally

                           [GFC.sub.1000]           [GFC.sub.2000]
                             (1000mg/kg)             (2000 mg/kg)

Male
  RBCs ([mm.sup.3])       9.57 [+ or -] 0.48     9.73 [+ or -] 0.89
  Hemoglobin (g/dl)      61.12 [+ or -] 2.45    61.67 [+ or -] 2.65
  Hematocrit (%)         43.56 [+ or -] 1.86    43.45 [+ or -] 1.23
  VCM (fL)               48.39 [+ or -] 1.67    48.38 [+ or -] 2.45
  HCM (pg)               16.92 [+ or -] 234     16.76 [+ or -] 3.14
  MCHC (g/[dl.sup.3])    38.29 [+ or -] 1.87    38.39 [+ or -] 3.35
  Platelets             312.54 [+ or -] 11.55  313.50 [+ or -] 12.57
    ([mm.sup.3])
  Leukocytes total        4.52 [+ or -] 1.28     4.62 [+ or -] 2.49
    ([mm.sup.3])
  Neutrophils (%)         9.40 [+ or -] 2.33     9.52 [+ or -] 1.49
  Lymphocytes (%)        69.12 [+ or -] 3.31    69.30 [+ or -] 3.20
Females
  RBCs ([mm.sup.3])       9.32 [+ or -] 0.49     9.78 [+ or -] 0.71
  Hemoglobin (g/dl)      15.10 [+ or -] 2.23    15.39 [+ or -] 3.14
  Hematocrit (%)         44.23 [+ or -] 2.54    43.84 [+ or -] 3.95
  VCM (fL)               49.35 [+ or -] 2.61    50.42 [+ or -] 4.16
  HCM (pg)               17.54 [+ or -] 3.16    17.29 [+ or -] 2.17
  MCHC (g/[dl.sup.3])    37.29 [+ or -] 3.38    34.34 [+ or -] 4.14 (a)
  Platelets             314.21 [+ or -] 13.35  314.34 [+ or -] 14.27
    ([mm.sup.3])
  Leukocytes total        4.25 [+ or -] 3.41     3.74 [+ or -] 4.57
    ([mm.sup.3])
  Neutrophils (%)         8.36 [+ or -] 3.49     8.24 [+ or -] 4.01
  Lymphocytes (%)        69.41 [+ or -] 2.38    69.37 [+ or -] 4.09

MCV, mean corpuscular volume; HCM, mean corpuscular hemoglobin; MCHC,
mean corpuscular hemoglobin concentration; Control, vehicle; GFC,
garcinielliptone FC 500mg-kg, 1000mg-kg and 2000mg-kg. Values
represent mean [+ or -] S.E.M. (n = 10). (a) p < 0.05 versus control
(ANOVA followed by t-Student-Newman-Keuls test as post hoc test).

Table 3
Effects of garcinielliptone FC on biochemical parameters of male and
female mice after treatment of 14 days by oral administration.

                          Orally

Parameters                 Control (Vehicle)        [GFC.sub.500]
                                                     (500 mg/kg)

Male
  Glucose (mg/dl)         90.15 [+ or -] 1.45    90.23 [+ or -] 1.25
  Urea (mg/dl)            60.85 [+ or -] 0.82    61.34 [+ or -] 1.76
  Creatinine (mg/dl)       0.37 [+ or -] 0.02     0.35 [+ or -] 0.07
  Uric acid (mg/dl)        2.45 [+ or -] 0.35     2.47 [+ or -] 0.78
  Triglycerides (mg/dl)   95.68 [+ or -] 3.22    95.00 [+ or -] 4.96
  Total Cholesterol       85.60 [+ or -] 2.85    83.34 [+ or -] 3.17
    (mg/dl)
  ALT (U/ml)              50.34 [+ or -] 1.46    51.23 [+ or -] 2.15
  AST (U/ml)              85.10 [+ or -] 1.27    86.13 [+ or -] 3.61
Females
  Glucose (mg/dl)         90.15 [+ or -] 1.45    91.30 [+ or -] 3.07
  Urea (mg/dl)            60.85 [+ or -] 0.82    61.31 [+ or -] 3.58
  Creatinine (mg/dl)       0.37 [+ or -] 0.02     0.36 [+ or -] 0.04
  Uric acid (mg/dl)        2.45 [+ or -] 0.35     2.43 [+ or -] 0.22
  Triglycerides (mg/dl)   95.68 [+ or -] 3.22    95.10 [+ or -] 2.96
  Total Cholesterol       85.60 [+ or -] 2.85    85.33 [+ or -] 2.15
    (mg/dl)
  ALT (U/ml)              50.34 [+ or -] 1.46    50.05 [+ or -] 2.04
  AST (U/ml)              85.10 [+ or -] 1.27    85.60 [+ or -] 2.61

                          Orally

Parameters                    [GFC.sub.1000]
                                (1000mg/kg)

Male
  Glucose (mg/dl)         89.74 [+ or -] 1.33
  Urea (mg/dl)            61.56 [+ or -] 2.46
  Creatinine (mg/dl)       0.36 [+ or -] 0.03
  Uric acid (mg/dl)        2.47 [+ or -] 0.56
  Triglycerides (mg/dl)   94.51 [+ or -] 3.78
  Total Cholesterol       75.45 [+ or -] 3.18 (a)
    (mg/dl)
  ALT (U/ml)              49.18 [+ or -] 2.45
  AST (U/ml)              86.33 [+ or -] 2.56
Females
  Glucose (mg/dl)         89.60 [+ or -] 2.35
  Urea (mg/dl)            60.85 [+ or -] 3.82
  Creatinine (mg/dl)       0.37 [+ or -] 0.02
  Uric acid (mg/dl)        2.45 [+ or -] 0.35
  Triglycerides (mg/dl)   79.68 [+ or -] 1.72 (a)
  Total Cholesterol       85.45 [+ or -] 2.85
    (mg/dl)
  ALT (U/ml)              49.40 [+ or -] 1.46
  AST (U/ml)              86.50 [+ or -] 1.42

                          Orally

Parameters                    [GFC.sub.2000]
                               (2000 mg/kg)

Male
  Glucose (mg/dl)         91.42 [+ or -] 2.20
  Urea (mg/dl)            62.45 [+ or -] 1.32
  Creatinine (mg/dl)       0.36 [+ or -] 0.05
  Uric acid (mg/dl)        2.46 [+ or -] 0.51
  Triglycerides (mg/dl)   72.38 [+ or -] 4.12 (a)
  Total Cholesterol       74.62 [+ or -] 3.16 (a)
    (mg/dl)
  ALT (U/ml)              49.34 [+ or -] 1.37
  AST (U/ml)              84.34 [+ or -] 2.78
Females
  Glucose (mg/dl)         90.56 [+ or -] 1.55
  Urea (mg/dl)            60.85 [+ or -] 3.52
  Creatinine (mg/dl)       0.37 [+ or -] 0.02
  Uric acid (mg/dl)        2.51 [+ or -] 0.22
  Triglycerides (mg/dl)   72.48 [+ or -] 2.52 (a)
  Total Cholesterol       83.54 [+ or -] 4.15
    (mg/dl)
  ALT (U/ml)              47.34 [+ or -] 3.26
  AST (U/ml)              84.36 [+ or -] 2.36

AST, aspartate aminotrasaminase; ALT, alanine aminotrasaminase;
Control, vehicle; GFC, garcinielliptone FC 500mg-kg, 1000mg-kg and
2000mg-kg. Values represent mean [+ or -] S.E.M. (n = 05). (a)
p < 0.05 versus control (ANOVA followed by t-Student-Newman-Keuls test
as post hoc test).

Table 4
Effects of garcinielliptone FC on biochemical parameters of male and
female mice after treatment of 14 days by intraperitoneal
administration.

                          Intraperitoneally

Parameters                      Control              [CFC.sub.500]
                               (Vehicle)              (500 mg/kg)

Male
  Glucose (mg/dl)         90.15 [+ or -] 1.45   91.34 [+ or -] 2.45
  Urea (mg/dl)            60.85 [+ or -] 0.82   61.14 [+ or -] 3.92
  Creatinine (mg/dl)       0.37 [+ or -] 0.02    0.36 [+ or -] 0.05
  Uric acid (mg/dl)        2.45 [+ or -] 0.35    2.46 [+ or -] 0.75
  Triglycerides (mg/dl)   95.68 [+ or -] 3.22   93.60 [+ or -] 6.82
  Total Cholesterol       85.60 [+ or -] 2.85   71.34 [+ or -] 3.27 (a)
    (mg/dl)
  ALT (U/ml)              50.34 [+ or -] 1.46   50.35 [+ or -] 2.48
  AST (U/ml)              85.10 [+ or -] 1.27   84.24 [+ or -] 3.67
Females
  Glucose (mg/dl)         90.15 [+ or -] 1.45   91.37 [+ or -] 1.70
  Urea (mg/dl)            60.85 [+ or -] 0.82   60.35 [+ or -] 2.41
  Creatinine (mg/dl)       0.37 [+ or -] 0.02    0.36 [+ or -] 0.01
  Uric acid (mg/dl)        2.45 [+ or -] 0.35    2.24 [+ or -] 0.26
  Triglycerides (mg/dl)   95.68 [+ or -] 3.22   93.46 [+ or -] 3.42
  Total Cholesterol       85.60 [+ or -] 2.85   84.34 [+ or -] 4.07
    (mg/dl)
  ALT (U/ml)              50.34 [+ or -] 1.46   49.34 [+ or -] 2.45
  AST (U/ml)              85.10 [+ or -] 1.27   83.33 [+ or -] 3.56

                          Intraperitoneally

Parameters                    [GFC.sub.1000]
                                (1000mg/kg)

Male
  Glucose (mg/dl)         90.67 [+ or -] 2.38
  Urea (mg/dl)            61.12 [+ or -] 2.45
  Creatinine (mg/dl)       0.37 [+ or -] 0.08
  Uric acid (mg/dl)        2.47 [+ or -] 0.34
  Triglycerides (mg/dl)   72.12 [+ or -] 2.61 (a)
  Total Cholesterol       68.10 [+ or -] 2.15 (a)
    (mg/dl)
  ALT (U/ml)              50.34 [+ or -] 2.75
  AST (U/ml)              83.62 [+ or -] 1.21
Females
  Glucose (mg/dl)         91.40 [+ or -] 2.73
  Urea (mg/dl)            61.42 [+ or -] 4.65
  Creatinine (mg/dl)       0.36 [+ or -] 0.05
  Uric acid (mg/dl)        2.49 [+ or -] 0.13
  Triglycerides (mg/dl)   75.00 [+ or -] 2.31 (a)
  Total Cholesterol       84.11 [+ or -] 3.14
    (mg/dl)
  ALT (U/ml)              47.34 [+ or -] 3.23
  AST (U/ml)              84.34 [+ or -] 3.56

                          Intraperitoneally

Parameters                    [GFC.sub.2000]
                               (2000 mg/kg)

Male
  Glucose (mg/dl)         89.71 [+ or -] 2.76
  Urea (mg/dl)            61.67 [+ or -] 2.65
  Creatinine (mg/dl)       0.37 [+ or -] 0.10
  Uric acid (mg/dl)        2.47 [+ or -] 0.85
  Triglycerides (mg/dl)   72.45 [+ or -] 3.72 (a)
  Total Cholesterol       65.89 [+ or -] 4.15 (a)
    (mg/dl)
  ALT (U/ml)              49.70 [+ or -] 2.37
  AST (U/ml)              83.71 [+ or -] 2.66
Females
  Glucose (mg/dl)         90.56 [+ or -] 1.55
  Urea (mg/dl)            60.85 [+ or -] 3.52
  Creatinine (mg/dl)       0.37 [+ or -] 0.02
  Uric acid (mg/dl)        2.51 [+ or -] 0.22
  Triglycerides (mg/dl)   72.48 [+ or -] 2.52 (a)
  Total Cholesterol       83.54 [+ or -] 4.15
    (mg/dl)
  ALT (U/ml)              47.34 [+ or -] 3.26
  AST (U/ml)              84.36 [+ or -] 2.36

AST, aspartate aminotrasaminase; ALT, alanine aminotrasaminase;
Control, vehicle. ; GFC, garcinielliptone FC 500mg-kg, 1000mg-kg and
2000 mg-kg. Values represent mean [+ or -] S.E.M. (n = 05). (a) p <
0.05 versus control (ANOVA followed by t-Student-Newman-Keuls test as
post hoc test).
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Title Annotation:Short communication
Author:da Silva, Ana Paula dos Santos C.L.; Oliveira, George Laylson da Silva; Medeiros, Shirlene Cesario;
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:3BRAZ
Date:May 15, 2016
Words:5684
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