Galantamine attenuates N,N-dimethyl hydrazine induced neoplastic colon damage by inhibiting acetylcholinesterase and bimodal regulation of nicotinic cholinergic neurotransmission

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Abstract

The present study reveals the effect of galantamine (GAL) against 1, 2-dimethylhydrazine (DMH) induced colon cancer. Wistar albino rats were arbitrarily divided into four groups (n = 8). Group 1 served as normal control (normal saline, 3 ml/kg/day, p.o.); group 2, 3 and 4 received DMH (20 mg/kg/week, s.c.), for 6 weeks; groups 3 and 4 also received GAL (2 and 4 mg/kg/day, p.o) for 6 weeks. DMH treated rats showed decreased heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), increased thiobarbituric acid reactive substances (TBARs) along with the decrease in the enzymatic activity of superoxide dismutase (SOD) and catalase. Increased levels of inflammatory marker cyclooxygenase (COX) and lipoxygenase (LOX) was also evident in DMH treated animals. The colonic surface architecture was studied using scanning electron microscopy revealed aberrant crypts(X500) and neoplastic nodules (X2000). GAL treatment helped to minimize the ACF count, restored oxidative stress and inflammatory markers favorably. To further validate our results, our study was directed to define the effect of GAL on acetylcholine neurotransmission using a simple model organism, Caenorhabditis elegans (C. elegans). Increased synaptic cholinergic transmission by GAL (32 μM) was evident in the worms when studied through aldicarb assay. However, GAL (32 μM) treatment negatively modulated α7 nicotinic acetylcholine receptor (α7nAch receptor), when evaluated using the levamisole assay. GAL (32 μM) treatment down regulated the genomic expression of ace-1, ace-2 along with unc-29, unc-38, and unc-50 (essential components of α7 nAch receptor). GAL by inhibiting AchE and regulating Alpha7nACh activity can improve cholinergic neurotransmission.

Graphical abstract

Schematic representation of the GAL mediated regression of colon cancer

Graphical abstract

GAL treatment in Albino wistar rats resulted in mitigation of colon cancer as indicated through photomicrographs of scanning electron micrographs; The molecular events underlying neuronal transmission were studied through a different model organism, C. elegans, where in it was revealed that GAL treatment increased synaptic ach resulting from downplaying of genes coding for AchE.

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