CC BY
33RESEARCH RESULT
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Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
Rus.
UDC 528.675.1:547.915:615.322/.076.9:616.12-008.46
DOI: 10.18413/2313-8971-2017-3-4-89-99
Marina P. Efremova1 2
Aelita V. Ivasheva Mikhail V. Korokin3
STUDY OF PHARMACOLOGICAL ACTIVITY OF NIGELLA DAMASCENA FIXED OIL IN EXPERIMENT
1 Pyatigorsk Medical Pharmaceutical Institute of Volgograd Medical State University of the Ministry of Health Care of Russia. 11, Kalinin Av., Pyatigorsk, 357532, Russia
interregional center of vocational postgraduate training and professional development of experts "Development". 178, Mira St., Pyatigorsk, 357532, Russia
3Belgorod National Research University. 85, Pobedy St., Belgorod, 308015, Russia Corresponding author, 1e-mail: [email protected]
Abstract
Introduction: Literature data, rich chemical macro-microelement composition set the stage for experimental pharmacological study of adaptogene and lipid protective activity of Nigella damascena essential oil.
Objectives: study of pharmacological activity of Nigella damascena essential oil while simulating pathology on laboratory animals.
Methods: irritant action - HET-CAM test and DRAIZE-test, acute toxicity, open field test, simulated hypoxia method, swimming with the load, No-way-out and Rotating-rod tests, acute lipid pathology under Tween 80 (tween lipid pathology), vitamin D2 hyperlipidemia, simulated chronic heart failure (CHF).
Results and Discussion: Nigella damascena essential oil have low irritant effect along with almost non-toxicity. Nigella oil increase life duration with the presence of hypoxia and endurance while swimming-with-the-load test. Course administration of Nigella oil normalize hormone-mediatore metabolism on the background of acute stress. Course administration of Nigella damascena essential oil normalize lipids on the background of CHF, acute tween and subchronic vitamin D2 hyperlipidemias.
Conclusion: stress protective, actoprotective and adaptogene properties of Nigella damascena essential oil was pharmacologically proved. It was substantiated experimentally that Nigella damascena essential oil has an impact on lipid metabolism on the background of chronic heart failure (CHF), acute tween, subchronic vitamin D2 lipid pathologies and blood serum lipoprotein lipase (LPL) activity. Keywords: Nigella damascena essential oil, actoprotector, adaptogene, hyperlipidemia.
Introduction
According to variety of literature data Nigella damascena seed essential oil contain: essential oil (31-42%); essential oil with nigellon and thymoquinone as main components (0.37 - 0.5%); sum of alkaloids (damascene and damascenine 0.1-0.3% respectively); flavonoids; sesquiterpene compounds; tocopherols; steroids; triterpenoid saponins; coumarins; quinones
(thymoquinone); lipase enzyme; macro-(potassium, calcium, magnesium, ferrum) and microelements (manganese, magnesium, zinc, copper, molybdenum, strontium, selenium, chrome, lead, boron, iodine) [1, 2, 3, 4, 5].
Literature data, rich chemical, macro- and microelement composition set a base for experimental pharmacological research of Nigella damascena essential oil adaptogene and lipid protective activity [6, 7].
Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
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Objectives: study of pharmacological activity of Nigella damascena essential oil while simulating pathology on laboratory animals.
Methods
The research was conducted in accordance with the policy of Declaration of Helsinki. Experiments were carried out with 246 white male Wistar rats 180-200 g weight, 12 white mice 30-33 g weight, 4 guinea pigs 600-700 g weight and 12 Leggron chicken embryo 9-10 days.
Experiment started with oil irritant effect on chicken embryo - HET-CAM test. Fixed oil was applied on chorioallantoic membrane at a dose of 0.3 ml and monitored for 120 sec. DRAIZE-test was conducted on guinea pigs during 2 min. Sunflower oil GOST R 524652005 was used as a control (solvent).
Mice were administered once by Nigella damascena essential oil at a dose of 8.5 mg/kg as the rats at a dose of 30 mg/kg intragastrically to determine acute toxicity. Animals were monitored for 14 days.
Open field test was conducted 24 hours since mice were administrated with 0.17 ml of Nigella damascena essential oil to examine motion behavior features and emotional state. The experiment lasted for 3 min. Amount of center and squares crossing, postures, grooming (washing), defecation, diuresis served as indexes of behavior [8]. Experimental dose was defined during active rat swimming. Mature male rats were divided into 7 groups of 6 animals which were selected on the base of bodyweight and swimming ability. Oil had been administered intragastrically once a day before the experiment for 14 days at the doses of 1, 5, 10, 15, 20, 25 mg/kg in accordance with groups. Control animals received distilled water [9, 10].
The aim of the second stage was to determine adaptogene activity of Nigella damascena essential oil. The aim was gained by a series of experiments. Antihypoxic effect was modeling by normobaric normocapnic hypoxia. Rats were placed into hermetic chamber 1.5 l vol. Carbon dioxide was eliminated by soda lime. Animals life duration indicated the hypoxia impact resistance. Nigella damascena
essential oil was administered intragastrically at the doses of 1mg/kg and 10mg/kg one time 40 min before experiment or as a course during 2 weeks. Control animals received distilled water [11, 12].
For examination of actoprotective activity of Nigella damascena essential oil were used: forced swimming in 33-35oC water, with load -7.5% of rat bodyweight to refusal and rotating rod tests with mice (animals were placed on horizontal rod, rotating at a rate of 10 rpm) [13,
14].
Stress has been evoked by fixation rats on its back for 6 hours resulting in development of pain-emotional stress type of No-way-out situation. Stress resistance was determined by following values: thymus and adrenal glands weight, gastric mucosal ulceration and ulceration rate. Biochemical values were studied by spectrofluorometric
(spectrofluorometer "Hitachi" MPF-4) and colorimetric (photoelectric colorimeter KOK-2 - YX^4,2) methods. Rat's blood, hearts, cerebral cortex were analyzed and homogenized. Concentration of adrenalin (AD), noradrenaline (NAD), dopamine (DA), 11-oxycorticosteroid, serotonin (S) and histamine (H) [15, 16, 17, 18, 19].
Pharmacological effect of Nigella damascena essential oil was studied on the background of simulated hyperlipidemia by setting acute tween lipid pathology. Were studied two types of Nigella damascena essential oil administration schedule at the background of "tween" model of hyperlipidemia: one-time administration and a course administration. In a course oil was administered oral using tube for 14 days. Untreated animals and animals who got physiological solution at a dose of 1mg/100g were used as a control. After 14 days Tween-80 was administered intraperitoneally and 12 hours after that decapitation was performed [20]. Subchronic vitamin model was simulated by course administration of vitamin D2 along with everyday administration of cholesterol alimentary and mercazolilum for metabolism inhibition. Vitamin model of hyperlipidemia was induced using Vsilenko's method [21]. Experimental animals' blood serum and liver were examined for biochemical values to make
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Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
a judgment about lipid metabolism. Those values are: rat's blood serum cholesterol, blood serum triglyceride, blood serum beta- and pre-beta-lipoproteins, blood serum lipoprotein lipase, liver cholesterol, liver triglyceride [22, 23].
Right ventricular chronic heart failure was simulated by intermittent admission of silicone oil into each pleural cavity at a dose of 1.5ml/100g rat weight according with the method of N. Pyatnitskiy and Y. Blinkov. Oil administration was performed under hexenalum anesthesia. After 30 days oil administrations were repeated at a dose of mg/100g of rat weight. Course of Nigella damascena essential oil has been administered for 14 days 24 hours after second administration [24, 25].
Results and Discussion
First step was to determine irritant effect. Chicken embryo coat was intact, clear, thin, with blood vessel and capillaries system
functioning properly. Next was local irritating action. DRAIZE-test showed hyperemia and chemosis score <2. Results obtained allows for the conclusion that Nigella damascena essential oil has low irritant effect.
Animals' survival ability after injection of Nigella damascena essential oil for acute toxicity determination was 100% in 2 weeks monitoring. According with K. Sidorov's classification essential oil refers to 5 class as non-toxic compound.
Thereby while valuing using safety low irritating effect was determined along with practically non-toxic features.
Open field test administration showed 42.9% mood increase after Nigella damascena administration resulting in defecation, diuresis and posturing. Physical activity had a tendency to increase up to 9.5% resulting in center, squares crossing and grooming amount (Figure 1).
%
160 140 120 100 80 60 40 20 0
100
4 2.3
2.338
10(
110
3.
3
100
100
18.
59.3 * 2
59.3
10.8
20 * 0.3 0. 0.5
142.9
10100 100
0.
1.0
square center posture grooming diuresis defecation
Untreated
NDEO 8.5 mg/kg
Fig. 1. The influence of Nigella damascena essential oil on nervous system. Note: NDEO - Nigella damascena essential oil, * - p>0.05 reliable relatively to untreated animals
Experimental dose of Nigella damascena essential oil was chosen by the results of the research on dose addiction depended on dynamic performance rising. As the result was determined that in a 10mg/kg dose of Nigella damascena essential oil swimming time
increased in comparison with swimming time of control group. What is more, increase had linear character from 1 to 15 mg/kg. Following dose escalation had no valued dynamic performance rising (Figure 2) [8].
•k
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Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
Fig. 2. Ergotropic effect escalation after Nigella damascena essential oil administration
at the doses from 1 to 25 mg/kg. Note: NDEO - Nigella damascena essential oil, min - minutes
Thereby according to results of 2 weeks' oil administration research there were chosen experimental groups with 1 mg/kg and 10 mg/kg one-time and course administration.
For the second stage of the research the aim was to determine adaptogene Nigella damascena essential oil activity. The adaptogene medications tend to combine at least three types of activity - actoprotective, antihypoxic and stress protective [26].
Antihypoxic effect showed in rat's life duration increase up to 63.5 ± 3 min with both types of administration - one-time and course in comparison to control group. However reliable data became available for Nigella damascena essential oil at a dose of 10 mg/kg, which increased rat's life duration on the background of hypoxia up to 35% in acute experiment and up to 26% after course administration (Fig. 3).
Actoprotective activity of Nigella damascena essential oil resulted in forced swimming with the load and Rotating rod test.
Experimental data gathered while swimming shows that one-time administration of Nigella damascena essential oil at a dose of 10 mg/kg 2 times increases rat's performance in the comparison to control group and 3 times increases performance after course administration. Rotating rod test showed increase in mice' muscular load tolerance up to 81.1% after one-time administration and up to 209.1% after course administration (Figure 3).
Stress tolerance experiment showed that Nigella oil at a dose of 10 mg/kg prevents thymus involution, decreasing its presence up to 35% after one-time administration and normalizing this value after course administration. Adrenal gland examination showed prevention of gland hypertrophy accumulation after one-time and course Nigella oil administration up to 28.78% and 38.85% respectively. Gastric mucosa erosion reduced 2.6 times after one-time administration and 7.8 times after course administration in comparison with control (Figure 4).
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Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
100 80 60 40 20 0
min., sec.
86.8*
82.2*
70.5*#
75.1*#
Control NDEO 10mg/kg NDEO 10mg/kg NDEO 1mg/kg NDEO 1mg/kg
one-time
course
one-time
course
Hypoxia/min.
Swimming/min.
Rotating rod/sec
Fig. 3. The influence of Nigella damascena essential oil 10 mg/kg on muscular load and hypoxia. Note: NDEO - Nigella damascena essential oil; min. - minutes; sec. - seconds; * - p>0.05 reliable relatively to control animals; # - p>0.05 reliable relatively to animals who got NDEO 10mg/kg
one-time
180 % 167.47 160 140 120 100 80 60 40 20 0
148.88#
Control NDEO 10mg/kg NDEO 10mg/kg NDEO 1mg/kg NDEO 1mg/kg Buckthorn oil 2.0 Buckthorn oil 2.0 one-time course one-time course mg/kg 1-time mg/kg cour.
■ Thymus ■ Adrenal gland ■ GM damage level
- - Untreated animals
Fig. 4. Stress protective activity of Nigella damascena essential oil at a dose of 10 mg/kg and 1 mg/kg. Note: NDEO - Nigella damascena essential oil; cour - course administration; GM - gastric mucosa;
# - p>0.05 reliable relatively to control animals
Stress resistance reflected in changings of biochemical values: adrenalin (AD), noradrenaline (NAD), dopamine (DA), serotonin (S), histamine (H) and protective effect index (PEI) in blood, heart, cerebral cortex.
Blood plasma showed 2.23 times reducing concentration of DA mediator at the background of increasing AD 1.74 times and NAD 2.24 times. There was an increasing of concentration of NAD and DA in heart muscle
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Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
of stressed animals 2.03 and 1.62 times respectively. Adrenalin level in heart truly 1.77 times reduced in comparison to untreated rats. In cerebral cortex was seen truly increasing of adrenalin concentration - 1.87 times, noradrenaline - 6.1 times and dopamine - 1.56 times compared with the normal range.
For objective interpretation of gathered data were used protective effect index (PEI), which shows the ability of preparation to increase organism resistance against various interferences and negative effectiveness indicator (NEI). Preparation can be counted as adaptogene if its PEI>0.2 (Figure 5).
Fig. 5. The influence of Nigella damascena essential oil on hormone-mediator metabolism under
simulated acute stress.
Note: U - untreated; O - one-time administration; C - course administration; AD - adrenaline; NAD - noradrenaline; DA - dopamine; H - histamine; S - serotonin; * - p>0.5 reliable relatively untreated animals
Stress protective research would be incomplete without research of adrenal gland activity marker. During the experiment 1.9 times increase of 11-oxycorticosteroids (11-OXY) concentration in blood was determined
in comparison to untreated group. Course administration of Nigella oil at a dose of 10 mg/kg led to complete normalizing of hormone level in blood.
Table 1
The influence of Nigella damascena essential oil 10 mg/kg on 11-OXY metabolism
in rat's blood under acute stress
Value Untreated Control (stress) NDEO 10 ml/kg NDEO 10 ml/kg
_one-time_course._
11-OXY, mkg/ml 0.575+0.041 1.108±0.062* 0.851±0.114* 0.592±0.056#
Note: NDFO - Nigella damascena essential oil, 11-OXY - 11-oxycorticosteroid; * - p>0.05 -reliable relatively untreated animals; # - p>0.05 - reliable relatively control animals.
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H А У Ч IT ЬТ Ii РЕЗУЛЬТАТ
Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
Thereby Nigella oil 10 mg/kg one-time and course administration promoted normalization of catecholamine in all examined tissues. What is more, corrective oil effect became more evident after course administration.
Studying the influence of Nigella damascena essential oil on rat's lipid profile under simulated chronic heart failure (CHF), acute tween and subchronic vitamin D2 lipid pathologies was the next stage of the research.
At the background of simulated CHF pathology Nigella damascena essential oil
administration at a dose of 10 mg/kg prevented lipid metabolism failure and reflected on lipid profile. In experimental rat group normalization of lipid profile was related to reliable reducing of low-density lipoprotein concentration by 68.38% herewith high-density lipoprotein concentration was increased by 22.3% relatively control. At the background of Nigella damascena essential oil administration also total cholesterol reducing by 13.2% was observed (Figure 6).
2,5 2 1,5 1
0,5 0
2.285
1.783
0.234
Untreated
Ch
0.965 0
0.583
2.021*#
1.98*#
829 1
0.661 0.569
001*#
0.453*#
1.
1.762
014*#
0.989
0.572*#
0.394*#
0.582
0.146
Control NDEO 10mgr/kg NDEO 10mg/kg Lipanor® 1-time Cour.
HDLP
LDLP
VLDLP
Fig. 6. The influence of Nigella damascena essential oil on rat's lipid metabolism
under chronic heart failure. Note: NDEO - Nigella damascena essential oil; Ch - cholesterol; HDLP - high-density lipoprotein; LDLP - low-density lipoprotein; VLDLP - very low-density lipoprotein; 1-time - one-time administration; Cour. - course administration; * - p>0.05 reliable relatively untreated animals;
# - p>0.05 - reliable relatively control animals
The cholesterol level reducing was detected in blood serum by 39.6% and by 50.6% after one-time and course administrations respectively as in liver - by 94.1% and 96.2% after one-time and course administrations respectively under acute tween hyperlipidemia. Triglyceride content tended to reduce in blood serum by 36% and 78.5% after one-time and course administration respectively and in liver - by 56.9% (one-time) and 71.5% (course)
(Figure 7).
Same lipid metabolism values changes happened under vitamin D2 hyperlipidemia. Cholesterol in rat's blood serum and liver
reduced by 10.43% and 24.63% respectively after one-time administration and by 22.44% and 22% respectively after course administration. Triglyceride level reduced in blood serum by 25.73% and by 36.73% in liver after course Nigella oil administration (Figure 8).
To improve gathered data lipoprotein lipase (LPL) activity was examined by separate set of experiments. LPL activity increased after Nigella damascena fixed oil administration to rats with acute tween and D2 subchronical intoxication up to 1.321±0.20 lipase unit which in relative units would be 36% relatively control (Figure 9).
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Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
Untreated Control NDEO 10mg/kg NDEO 10 mg/kg Lipanor® 13
1-time, path cour. path. mg/kg
■ Cholesterol BS ■ Triglyceride BS ■ Cholesterol L «Triglyceride L
Fig. 7. Lipid metabolism values changing in blood serum and liver after Nigella damascena essential
oil administration under acute tween lipid pathology. Note: NDEO - Nigella damascena essential oil; 1-time - one time administration; cour. - course administration; path. - pathology; BS - blood serum; L - liver; * - p>0.05 reliable relatively untreated
animals; # - p>0.05 reliable relatively control animals.
8 7 6 5 4 3 2 1 0
7.57
6.78#
5.72*#
Untreated Control NDEO 1time NDEO cour. path. Lipanor® 13
path. ml/kg
Cholestrol BS «Triglycerides BS «Cholesterol L «Triglycerides L
Fig. 8. Lipid metabolism values changing in blood serum (BS) and liver (L) after Nigella damascena essential oil administration at a dose of 10 mg/kg under subchronic vitamin D2 lipid pathology. Note: NDEO - Nigella damascena essential oil; ltime - one-time administration; cour. - course administration; path. - pathology; BS - blood serum; L - liver; * - p>0.001 difference reliability relatively untreated animals; # - p>0.001 difference reliability relatively control animals
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TT A y H TT KT Ii P E 3 y .n b T A T
Efremova M.P., Ivasheva A.V., Korokin M.V. Study of pharmacological activity of Nigella damascena fixed oil in experiment. Research Result: Pharmacology and Clinical Pharmacology. 2017;3(4):89-99.
3 2,5 2 1,5 1
0,5 0
2.833*
+135
1.213
100%
2.45*
+102
0.829
■32%
1.784#
+47%
Lipoprotein lipase
1,99
1.312#
+8.9%
1.09
+10
.1
+64%
Untreated NDEO NDEO Control 10mg/kg 10mg/kg
1time
cour
NDEO NDEO Lipanor® Lipanor®
10mg/kg 10mg/kg 13mg/kg 13mg/kg
ltime, course, 1time cour. path. path.
Fig. 9. The influence of Nigella damascena essential oil at a dose of 10 mg/kg on blood serum
lipoprotein lipase activity. Note: NDEO - Nigella damascena essential oil; 1time - one-time administration; cour. - course administration; path. - pathology; * - p>0.05 reliable relatively untreated animals; # - p>0.05 reliable relatively control animals
Conclusion
The experimental research resulted in conclusion that Nigella damascena essential oil has high activity while being safe for oral administration by mammal.
During the research adaptogene activity of Nigella damascena essential oil was determined by size of antihypoxic, actoprotective and stress protective effects whose intensity increases after course oil administration.
High stress protective effect of Nigella damascena essential oil was achieved at an experimental dose of 10 mg/kg.
Course administration of Nigella damascena essential oil normalized catecholamine level in blood, heart and brain under simulated stress. Changes of hormonemediatore balance have positive compensatory character. Nigella damascena essential oil practically non-toxic and has no irritant effect. It was determined experimentally that Nigella damascena essential oil at a dose of 10 mg/kg has positive impact on lipid profile by normalizing it under simulated CHF. Also, it was determined that after lipid metabolism values were changed under acute tween and
subchronical vitamin D2 lipid pathology Nigella damascena essential oil' therapeutic effect at a dose of 10 mg/kg stays equal to comparator drugs.
The active impact on blood serum lipoprotein lipase was determined, after onetime administration and course administration alike.
Conflicts of Interest
The authors have no conflict of interest to declare.
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Author contributors
Marina P. Efremova, Pharmacology department professor with Clinical pharmacology course at the Pyatigorsk Medical Pharmaceutical Institute of Volgograd Medical State University of the Ministry of Health Care of Russia, e-mail: [email protected]. Author of article.
Aelita V. Ivasheva, Doctor of biological sciences, professor, e-mail: [email protected]. Research supervisor of the experimental work, research advisor.
Mikhail V. Korokin, doctor of medical sciences, associate professor, Belgorod National Research University, e-mail: [email protected]. Science advisor, research advisor.
Received: October, 25, 2017
Accepted: November, 30, 2017
Available online: December, 30, 2017
