Hypoglycemic Activity of the Total Ecdysteroid Extract from Ajuga turkestanica

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HYPOGLYCEMIC ACTIVITY OF THE TOTAL ECDYSTEROID EXTRACT FROM Ajuga turkestanica T. A. Kutepova,1 V. N. Syrov,1 Z. A. Khushbaktova,1 and Z. Saatov1 Translated from Khimiko-Farmatsevticheskii…

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HYPOGLYCEMIC ACTIVITY OF THE TOTAL ECDYSTEROID EXTRACT FROM Ajuga turkestanica T. A. Kutepova,1 V. N. Syrov,1 Z. A. Khushbaktova,1 and Z. Saatov1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 11, pp. 24 – 25, November, 2001. Original article submitted October 30, 2000. In recent years, there has been an extensive search for new effective hypoglycemic agents among natural sub- stances [1 – 3]. In this respect, a promising source is offered by phytoecdysteroids. Some compounds of this class pro- duce, in addition to the anabolic effect, a certain hypoglyce- mic action [4, 5]. In connection with this, the purpose of our study was to obtain the total ecdysteroid extract from Ajuga turkestanica (which is economically more profitable in com- parison to the isolation of individual ecdysteroids) and to as- sess the hypoglycemic activity of this extract on the model of alloxan-induced hyperglycemia and diabetes. EXPERIMENTAL PART The sum of ecdysteroids (including 22-acetylcyasterone, cyasterone, ecdysterone, and turkesterone) was obtained from Ajuga turkestanica (Rgl.) Brig. (Labiatae family) col- lected in canyons near Derbent (Surkhan Region, Uzbekistan). The extraction procedure was conducted as de- scribed in [6 – 10]. The hypoglycemic activity was studied on a group of white mongrel male rats weighing 160 – 180 g. The hyperglycemia model was induced by alloxan (150 mg:kg, s.c.) injected in the form of freshly prepared 5% aqueous so- lution. The phytoecdysteroid preparation was introduced once per day in a dose of 5 mg:kg (the most effective dose determined in preliminary experiments) over a period of seven days, beginning on the third day after alloxan injec- tion. In some experiments, on the third day after alloxan in- jection, the test animals (deprived of food overnight) were divided into groups with approximately equal blood glucose index. One group served as control and the other groups were treated with ecdysteroids, after which all animals were ad- mitted to the standard vivarium diet and (3 h later) character- ized with respect to the blood glucose level. In the chronic diabetes test, the effect of phytoecdysteroids was determined 30 days after alloxan injection. The reference drug was maninil administered in a daily dose of 5 mg:kg. Each preparation was studied in eight inde- pendent tests. the blood for analyses was taken from tail vein; the blood glucose was determined by the orthotoluidine technique [11]. The experimental data were statistically pro- cessed in terms of the Student t-criterion. RESULTS AND DISCUSSION On the third day after alloxan injection, all surviving rats (50%) were characterized by increased blood glucose level (the secondary hyperglycemia peak according to [12]). With respect to the degree of hyperglycemia, the test animals could be divided into three groups in which the glucose con- tent in the blood serum fell within 150 mg% (group I), 150 – 250 mg% (II), and 250 – 400 mg%. The alloxan-in- duced hyperglycemia exhibited a stable character and was re- tained on the seventh day of observation (see the data for 608 0091-150X/01/3511-0608$25.00 © 2001 Plenum Publishing Corporation Pharmaceutical Chemistry Journal Vol. 35, No. 11, 2001 1 Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, Uzbekistan. TABLE 1. Effects of the Sum of Ecdysteroids and Maninil on the Blood Glucose Level in Rats with Alloxan-Induced Hyperglycemia Experiment Glucose level, mg% P (relative to initial level) initial (3rd day after alloxan injection) final (7th day of phytoecdysteroid treatment) Control I 153 � 6.41 159 � 4.8 Phytoecdysteroids 159 � 6.8 93.8 � 5.6* < 0.001 Maninil 152 � 6.9 76.8 � 3.4*,** < 0.001 Control II 242 � 8.6 251 � 16.7 Phytoecdysteroids 236 � 9.2 145 � 6.4* < 0.001 Maninil 245 � 12.0 163 � 9.3* < 0.001 Control III 381 � 12.8 357 � 9.5 Phytoecdysteroids 379 � 19.8 272 � 8.9* < 0.001 Maninil 358 � 21.7 318 � 18.2** < 0.25 Notes. 1 Average blood glucose level before alloxan injection was 85 – 95 mg%. Here and in Tables 2 and 3, differences are reliable for a confidence level of p < 0.05: * relative to control; ** between compared drugs. control groups in Table 1). In the animals treated with phytoecdysteroids, the glycemic index was reduced. In group I, the blood glucose level on the seventh day of treatment de- creased by 41.1% to reach a level almost characteristic of in- tact animals. In group II, the hypoglycemic effect was less pronounced: a 38.6% decrease relative to the initial level. A minimum decrease in the glucose level was observed in group III; nevertheless, even in this group the decrease (28.2%) was statistically reliable (Table 1). An additional evidence for the significant hypoglycemic effect of the total ecdysteroid extract was provided by the ex- periment on rats with alloxan-induce hyperglycemia, in which the treatment began after a food load. Table 2 presents the results of this test for animals with the initial blood glu- cose level within 200 – 250 mg%. In the control group, the blood glucose after feeding exhibited a reliable 29.3% in- crease. In contrast, the level of glucose in rats treated with ecdysteroids did not increase after the food load; moreover, the blood glucose at the end of this experiment was 23.1% lower than the initial level ( p < 0.05) and 43.3% lower as compared to the corresponding untreated control. In the test animals with stably expressed chronic alloxan-induced dia- betes, the hypoglycemic action of phytoecdysteroids was 23.4% (Table 3). A comparison of the hypoglycemic effect of the sum of ecdysteroids and the reference drug maninil (widely used in the treatment of diabetes [13]) showed that, in animals with a relatively low excess of glucose in the blood, the action of phytoecdysteroids was less pronounced as compared to that of maninil. As the initial blood glucose level increased, the drug effects exhibited leveling, whereas against a stable chronic diabetes background, the hypoglycemic effect of the sum of ecdysteroids was more pronounced than that of maninil. These results are probably explained by a more diversi- fied mechanism of action of the sum of ecdysteroids. On the one hand, the effect of the phytopreparation (like that of steranabols) can be related to a mediated activation of the glycogen synthesis function of the liver and to an increase in the resistance of peripheral tissues with respect to insulin. These mechanisms were repeatedly revealed by investiga- tions of the effects of individual phytoecdysteroids and nerobol on the metabolism of hydrocarbons in the animal [5, 14, 15]. On the other hand, there is evidence that the sum of phytoecdysteroids can stimulate the synthesis of endogen insulin by increasing the growth of cells in the insulin-pro- ducing apparatus of the pancreas [16]. On the contrary, the hypoglycemic effect of maninil is mostly related to stimula- tion of the pancreatic �-cells and is not manifested under conditions of their dysfunction or loss [13, 17]. Thus, the results of our experiments showed that the sum of phytoecdysteroids extracted from Ajuga turkestanica can be considered as a promising hypoglycemic preparation. REFERENCES 1. M. I. Aizikov, Author’s Abstract of Candidate’s (Med.) Thesis [in Russian], Karaganda (1975). 2. V. I. Hukeri, G. A. Kalyani, and H. K. Kalrani, Fitoterapia, 59(1), 68 – 70 (1988). 3. M. A. Tashmukhamedova, O. A. Mukhina, V. N. Syrov, et al., Probl. Endokrinol., 38(1), 48 – 50 (1992). 4. T. Yoshida, T. Otaka, M. Uchiyama, and S. Ogawa, Biochem. Pharmacol., 20(12), 3263 – 3268 (1971). 5. V. N. Syrov, Z. A. Khushbaktova, and M. A. Tashmukhame- dova, Dokl. Akad. Nauk Resp. Uzbekistan, No. 4, 46 – 49 (1997). 6. B. Z. Usmanov, Ya. V. Rashkes, and N. K. Abubakirov, Khim. Prir. Soedin., No. 2, 215 – 219 (1978). 7. H. Hikino, Y. Hikino, K. Nomoto, and T. Takemoto, Tetrahe- dron, 24(13), 4895 – 4906 (1968). 8. B. Z. Usmanov, M. B. Gorovits, and N. K. Abubakirov, Khim. Prir. Soedin., No. 4, 535 – 536 (1971). 9. 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Hypoglycemic Activity of the Total Ecdysteroid Extract from Ajuga turkestanica 609 TABLE 2. Effects of the Sum of Ecdysteroids and Maninil on the Blood Glucose Level after Food Load in Rats with Alloxan-Induced Hyperglycemia Experiment Glucose level, mg% P (relative to initial level) initial (3rd day after alloxan injection) final (3 h after feeding) Control 232 � 14.8 300 � 16.0 < 0.01 Phytoecdysteroids 221 � 13.5 170 � 14.9* < 0.05 Maninil 236 � 16.2 223 � 17.2*,** > 0.5 TABLE 3. Effects of the Sum of Ecdysteroids and Maninil on the Blood Glucose Level in Rats with Chronic Alloxan-Induced Diabe- tes Experiment Glucose level, mg% P (relative to initial level) initial (3rd day after alloxan injection) final (7th day of phytoecdysteroid treatment) Control 235 � 17.8 245 � 24.4 > 0.5 Phytoecdysteroids 227 � 15.1 174 � 12.0* < 0.02 Maninil 232 � 11.4 226 � 10.1** > 0.5