Toxicity Evaluation of the Naphthalen-2-yl 3,5-Dinitrobenzoate: A Drug Candidate for Alzheimer Disease.

Fareeha Anwar,Lee Yean Kee,Sarfraz Ahmad,Muhammad Usman Mirza,Uzma Saleem,Bashir Ahmad,Matheus Froeyen,Atta-Ur Rehman,Iskandar Abdullah

doi:10.3389/fphar.2021.607026

Abstract

The presented study was designed to probe the toxicity potential of newly identified compound naphthalen-2-yl 3,5-dinitrobenzoate (SF1). Acute, subacute toxicity and teratogenicity studies were performed as per Organization of economic cooperation and development (OECD) 425, 407, and 414 test guidelines, respectively. An oral dose of 2000 mg/kg to rats for acute toxicity. Furthermore, 5, 10, 20, and 40 mg/kg doses were administered once daily for 28 days in subacute toxicity study. Teratogenicity study was performed with 40 mg/kg due to its excellent anti-Alzheimer results at this dose. SF1 induced a significant rise in Alkaline Phosphatases (ALP), bilirubin, white blood cells (WBC), and lymphocyte levels with a decrease in platelet count. Furthermore, the reduction in urea, uric acid, and aspartate transaminase (AST) levels and an increase in total protein levels were measured in subacute toxicity. SF1 increased spermatogenesis at 5 and 10 mg/kg doses. Teratogenicity study depicted no resorptions, early abortions, cleft palate, spina bifida and any skeletal abnormalities in the fetuses. Oxidative stress markers (Superoxide dismutase (SOD), Catalase (CAT), and glutathione (GSH) were increased in all the experiments, whereas the effect on melanoaldehyde Malondialdehyde (MDA) levels was variable. Histopathology further corroborated these results with no change in the architectures of selected organs. Consequently, a 2000 mg/kg dose of SF1 tends to induce minor liver dysfunction along with immunomodulation, and it is well below its LD 50. Moreover, it can be safely used in pregnancy owing to its no detectable teratogenicity.

Highlights

Toxicity profiling is cardinal in the screening and development of new drugs before clinical trials (Arome and Chinedu, 2013)
Subacute oral toxicity and teratogenicity experimental protocols were approved from Ethical Committee of Riphah Institute of Pharmaceutical Sciences (Research Ethical Committee REC), Lahore campus, with the voucher number of REC/RIPS-LHR/035 for further considerations under the rules and regulations of National Institute of Health (NIH, United States) guide for the care and use of laboratory animals
The results indicate that LD50 of SF1 is at a dose considerably higher than 2000 mg/kg

Summary

Introduction

Toxicity profiling is cardinal in the screening and development of new drugs before clinical trials (Arome and Chinedu, 2013). International regulatory bodies for the toxicity studies (OECD, GSH, EPA, EEC, etc.) determine the potential hazards and risks of the substances on the human beings by comparing the dose-related toxic effects that occur in the animal models (Lewis et al, 2002). Toxicity studies using animal models provide several advantages including controlled duration of exposure, the easy examination of all tissues and estimation of various biochemical and pathological markers (Arome and Chinedu, 2013; Dandekar and et al, 2010). The benefits of the toxicity profiling lie in the identification of possible hazards, but it characterizes potentially toxic effects that can be produced by the test compounds on different doses and on different treatment time durations. The importance of toxicity studies emerged in the 1960s when thousands of children were born with severe congenital disabilities due to the use of anticancer drug thalidomide; commonly known as thalidomide catastrophe (Klaassen, 1996)

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