A Comparative Study of the Effects of Aversectin C, Abamectin and Ivermectin on Apoptosis of Rat Thymocytes Induced by Radiation and Dexamethasone

Abstract

The effects of avermectins on radiation-and dexamethasone-induced apoptosis of rat thymocytes have been studied. In particular, the properties of abamectin (avermectin B 1 ), ivermectin (22,23-dihydroavermectin B 1 , H 2 B 1 ) and aversectin C were examined. Aversectin C is a mixture of eight naturally occurring avermectins of the following composition: B 1 (42%), B 2 (22%), A 1 (13%) and A 2 (23%). This mixture is currently widely used as active ingredient in veterinary antiparasitic formulations produced by Pharmbiomed Co. Apoptosis was estimated by membrane damage, nuclear pycnosis (or chromatin condensation), DNA fragmentation and percentage of cells with subdiploid DNA. It was shown that aversectin C inhibits thymocyte apoptosis induced by both agents. The IC 50 dose was in the range of 0.1-0.3 µg/ml for aversectin C, whereas abamectin and ivermectin produced no effect up to 1 µg/ml. It is suggested that avermectins of the A series are responsible for the high anti-apoptotic activity exhibited by aversectin C. Thus, aversectin C is not only an effective antiparasitic drug but is also capable of exhibiting some other useful activities, e.g. a cytoprotective effect exerted on the mammalian immune cells. Avermectins, antiparasitic drugs, apoptosis, thymocytes, dexamethasone, gamma raysThe avermectins are a family of closely related 16-membered macrocyclic lactones produced by the fungus Streptomyces avermitilis. Nearly all the avermectins exhibit a broad spectrum of activity against nematode and arthropode parasites, with the B 1a compound being the most potent (Campbell 1989). Accordingly, it was used as active ingredient in commercial antiparasitic formulations. Until recently, there were basically two types of such avermectin-based active ingredients, i.e. ivermectin (consisting mainly of avermectin H 2 B 1a ) and abamectin (predominantly containing avermectin B 1a ). However, several years ago the Pharmbiomed Co. started manufacturing the veterinary and plant protection formulations based on a new active ingredient -aversectin C which is an intrinsic mixture of eight naturally occurring avermectins. Preliminary experiments demonstrated that aversectin C (presumably due to the presence of avermectins of both the A-and B-series) possesses some new useful features compared to ivermectin and abamectin, e.g. with the same high efficacy, the spectrum of activity is broader, level of residues is lower and, hence, the shorter withdrawal periods could be recommended (Simetsky et al. 1994;Berezkina et al. 1996). Furthermore, degradation of aversectin C in soil and water was found to be more effective compared to abamectin and ivermectin ( M o sin et al. 1998) and, hence, ecologically aversectin C is safer.

New Ventures in the Genotoxic and Cytotoxic Effects of Macrocyclic Lactones, Abamectin and Ivermectin

“…These findings are in accordance with our recent observations indicating that Ivermectin is unable to induce an increase in the frequency of sister chromatid exchanges in CHO-K1 cells within the 1-10 g/ml concentration-range [Molinari et al, 2009]. Negative results have also been observed for the induction of apoptosis in rat thymocytes in vitro [Korystov et al, 1999]. It should be mentioned that Molinari and coworkers [2009] have recently reported the induction of a significant delay in cell-cycle progression and a concomitant reduction of the proliferative rate index in CHO-K1 cells treated with 25 g/ml of Ivermectin.…”

“…The ability of Ivermectin to produce forward mutation at the thymidine kinase locus ( Tk +/-to Tk -/-) of mouse lymphoma Fischer L5178Y cells was studied, and negative results have also been reported for this end-point [Merck and Co., 1980a]. Effects of Ivermectin on unscheduled DNA synthesis were studied in IMR-90 20-60 g/ml 5-20 g/ml Negative Negative Merck and Co., 1980a In vitro unscheduled DNA synthesis IMR-90 human fibroblasts IMR-90 human fibroblasts + S9 300-1,000 g/ml 10-100 g/ml Negative Negative Merck and Co., 1980b In vitro comet assay CHO-K1 cells 5-50 g/ml Positive Molinari et al, 2009 In vitro sister chromatid exchanges Peripheral human lymphocytes ≥0.30 g/ml Positive Aleksić and Barjaktarović, 1993 In vitro sister chromatid exchanges Peripheral human lymphocytes Not specified Negative Aleksić et al, 1996 In vitro sister chromatid exchanges CHO-K1 cells 1-250 g/ml Negative Molinari et al, 2009 In vitro apoptosis induction Rat thymocytes 1 g/ml Negative Korystov et al, 1999 In vitro mitotic index CHO-K1 cells 1-250 g/ml Positive Molinari et al, 2009 In vitro cell-cycle progression CHO-K1 cells 1-250 g/ml Positive Molinari et al, 2009 In vitro neutral red assay CHO-K1 cells 0.25-250 g/ml Positive Molinari et al, 2009 In normal human embryonic lung fibroblasts in the presence and absence of rat liver microsomal activation systems. Regardless of the concentration employed, the drug did not produce any significant increase in background thymidine incorporation [Merck and Co., 1980b].…”

DNA damage kinetics and apoptosis in ivermectin‐treated chinese hamster ovary cells

“…These finding are in accordance with our recent observations indicating that IVM is unable to induce sister chromatid exchanges in Chinese hamster ovary (CHO‐K1) cells (Molinari et al ., ). Negative results have also been observed for the induction of apoptosis in rat thymocytes in vitro (Korystov et al ., ). On the other hand, we recently reported the induction of cytotoxicity, e.g.…”

Studies revealing bioremediation potential of the strain Burkholderia sp. GB-01 for abamectin contaminated soils

“…Abamectin inhibits the gamma-aminobutyric acid (GABA) induced neurotransmission, and causes paralysis in parasites (Campbell et al 1983;Turner and Schaeffer 1989;Shoop et al 1995). It is also a chloride channel inhibitor, which makes it likely to affect the membrane stability (Korystov et al 1999). The mode of action of avermectins is not, however, specific to parasitic arthropods and nematodes, and consequently may affect other organisms in the environment (McKellar 1997).…”