Palonosetron attenuates 1,2-dimethyl hydrazine induced preneoplastic colon damage through downregulating acetylcholinesterase expression and up-regulating synaptic acetylcholine concentration

摘要

The present study was undertaken to evaluate the effect of palonosetron (PAL) against 1,2-dimethylhydrazine (DMH)-induced colon cancer. Wistar albino rats were randomly divided into four groups (n = 8). Group 1 served as normal control (1 mM EDTA + saline, 2 ml per kg per day, s.c.); group 2 toxic control; group 2, 3 and 4 received DMH (20 mg per kg per week, s.c.), for 6 weeks; groups 3 and 4 also received PAL (0.25 and 0.50 mg per kg per day, p.o) for 6 weeks. DMH treated rats showed altered heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), distorted antioxidant markers (TBAR's, SOD, catalase, GSH) and increased levels inflammatory markers (COX). The colonic surface architecture, studied using scanning electron microscopy (SEM), revealed aberrant crypts (500x) and preneoplastic nodules (2000x). PAL treatment helped to minimize the ACF count, and restored oxidative and inflammatory markers favorably. To further validate our results, we directed our study to define the effect of PAL on acetylcholine (Ach) neurotransmission using a simple model organism, C. elegans. Increased cholinergic transmission by PAL (8 mu M) was evident in the worms when studied through an aldicarb assay. However, PAL (2 mu M, 4 mu M and 8 mu M) treatment negatively modulated nAchR, when evaluated using the levamisole assay. The increased synaptic Ach levels can be attributed to the decreased levels of acetylcholinesterase (AchE), which could be attributed to the decreased genomic levels of ace-1 and ace-2. The above findings were also supported by the fact, that we observed decreased AchE activity in PAL treated rats. In addition the downregulation in the expression of unc-38 (one of the necessary components of nAchR) sufficiently links with the decreased nAchR activity. Our findings emphasize the potential role of PAL in the suppression of colon carcinogenesis.