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Open AccessArticle

Benzimidazole Containing Acetamide Derivatives Attenuate Neuroinflammation and Oxidative Stress in Ethanol-Induced Neurodegeneration

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Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan
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College of Natural and Health Sciences, Zayed University Abu Dhabi, Abu Dhabi 144534, UAE
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Department of Pharmacology, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad 747424, Pakistan
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Department of Pharmacy, Capital University of Science & Technology, Islamabad Expressway, Islamabad 747424, Pakistan
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State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
*
Authors to whom correspondence should be addressed.
Fawad Ali Shah is currently working as Post-Doctorate in Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, ON, Canada.
Biomolecules 2020, 10(1), 108; https://doi.org/10.3390/biom10010108
Received: 13 November 2019 / Revised: 25 December 2019 / Accepted: 4 January 2020 / Published: 8 January 2020
Oxidative stress-induced neuroinflammation is the prominent feature of neurodegenerative disorders, and is characterized by a gradual decline of structure and function of neurons. Many biochemical events emerge thanks to the result of this neurodegeneration, and ultimately provoke neuroinflammation, activation of microglia, and oxidative stress, leading to neuronal death. This cascade not only explains the complexity of events taking place across different stages, but also depicts the need for more effective therapeutic agents. The present study was designed to investigate the neuroprotective effects of newly synthesized benzimidazole containing acetamide derivatives, 3a (2-(4-methoxyanilino)-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide) and 3b (2-(Dodecylamino)-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide) against ethanol-induced neurodegeneration in the rat model. Both derivatives were characterized spectroscopically by proton NMR (1H-NMR) and carbon-13 NMR (13C-NMR) and evaluated for neuroprotective potential using different pharmacological approaches. In vivo experiments demonstrated that ethanol triggered neurodegeneration characterized by impaired antioxidant enzymes and elevated oxidative stress. Furthermore, ethanol administration induced neuroinflammation, as demonstrated by elevated expression of tumor necrotic factor (TNF-α), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX2), and ionized calcium-binding adapter molecule-1 (Iba-1), which was further validated by enzyme-linked immunosorbent assay (ELISA). Treatment with 3a and 3b ameliorated the ethanol-induced oxidative stress, neuroinflammation, and memory impairment. The affinity of synthesized derivatives towards various receptors involved in neurodegeneration was assessed through docking analysis. The versatile nature of benzimidazole nucleus and its affinity toward several receptors suggested that it could be a multistep targeting neuroprotectant. As repetitive clinical trials of neuroprotectants targeting a single step of the pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles of neuroinflammation. View Full-Text
Keywords: oxidative stress; neuroinflammation; docking; neuroprotective; cortex; hippocampus; ethanol oxidative stress; neuroinflammation; docking; neuroprotective; cortex; hippocampus; ethanol
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MDPI and ACS Style

Imran, M.; Al Kury, L.T.; Nadeem, H.; Shah, F.A.; Abbas, M.; Naz, S.; Khan, A.-U.; Li, S. Benzimidazole Containing Acetamide Derivatives Attenuate Neuroinflammation and Oxidative Stress in Ethanol-Induced Neurodegeneration. Biomolecules 2020, 10, 108.

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