Journal of Molecular Pharmaceutics & Organic Process Research
Open Access

Abstract

Background: Several herbicides, especially paraquat, are persistent organic pollutants which cause damage to humans and animals through reactive oxygen and nitrogen species. Coumarins are fused benzene and pyrone ring systems with a wide spectrum of bioactivities. The objective of the current investigation was to assess the preventive effect of Coumarin-2-Aminothiazole (C2A) in a rat model of paraquat-induced toxicity. Methodology: Acute oral toxicity was conducted according to the OECD guidelines 425 (limit test). In-vitro anti-oxidant activity was evaluated by DPPH assay. Male rats were divided into 6 groups (n=5). Paraquat (10 mg/ kg BW i.p) was administered to all groups except normal control 2 h prior to the stranded drug and treatment administration. Normal and disease control rats received normal saline whereas treatment groups received 10,20 and 30 mg/kg C2A for 21 days. Levodopa/carbidopa (7 mg/kg) was used as standard therapy. Behavioural tests (elevated plus maze, light/dark box, morris water maze) were performed at 7-day interval during whole study period. The rats were euthanized at day 21. Analysis included Enzyme Linked Immuno Sorbent Assay (ELISA) for measuring levels of inflammatory markers (IL-1b, IL-6 and TNF�±). Assays for oxidative stress Super-Oxide Dismutase activity (SOD), Catalase (CAT), reduced Glutathione (GSH), Malondialdehyde (MDA) and Nitric Oxide (NO) were also accessed. Neurotransmitters, Dopamine (DA) and Nor-Adrenaline (NA) levels were measured. Computer-aided molecular modeling was used to examine the conformational relationship between the C2A and Toll Like Receptor 4 (TLR4). Results: C2A revealed no toxicity up to the dose of 2000 mg/kg. C2A exhibited potent anti-oxidant activity with an IC 50 of (82.6 �¼g/mL) as compared to standard ascorbic acid (37.50 �¼g/mL). C2A treated groups significantly increased (p<0.05) time spent in open arms and light chamber compared to the disease control group whereas decreased in escape latency (p<0.05) was observed. The findings suggested a decline in inflammatory markers upon treatment with C2A. TNF-ï�¡, IL-1ï�¢ and IL-6 concentrations were restored (p<0.001) in C2A treated rats. Similar findings were observed for oxidative stress markers. Activities of SOD, CAT and concentration of GSH, MDA and NO were restored (p<0.001) in brain homogenate and serum samples of treated rats. Dopamine and noradrenaline levels were also improved upon treatment with C2A (p<0.001). The docking score of TLR is -5.6 Kcal/mol, C2A demonstrated positive interactions with the relevant proteins' critical amino acid residues. Conclusion Treatment with C2A prevented the paraquat-induced toxicity in the brain due to its antioxidant and anti-inflammatory properties. The main mechanism involved in ameliorating paraquat toxicity in the brain is through reduction of oxidative stress and Neuroinflammation. Keywords: Neurotoxicity, Coumarin 2 aminothiazole, Inflammatory markers, Oxidative stress, Neurotransmitter.

Biography

Ali Sharif is from Department of Pharmacology, Institute of Pharmacy, Lahore College for Women University Lahore, Pakistan.