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Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration.

ABSTRACT: Oxidative stress-mediated neuroinflammatory events are the hallmark of neurodegenerative diseases. The current study aimed to synthesize a series of novel succinamide derivatives and to further investigate the neuroprotective potential of these compounds against scopolamine-induced neuronal injury by in silico, morphological, and biochemical approaches. The characterization of all the succinamide derivatives was carried out spectroscopically via proton NMR (1H-NMR), FTIR and elemental analysis. Further in vivo experiments showed that scopolamine induced neuronal injury, characterized by downregulated glutathione (GSH), glutathione S-transferase (GST), catalase, and upregulated lipid peroxidation (LPO). Moreover, scopolamine increased the expression of inflammatory mediators such as cyclooxygenase2 (COX2), nuclear factor kappa B (NF-kB), tumor necrosis factor (TNF-?), further associated with cognitive impairment. On the other hand, treatment with succinamide derivatives ameliorated the biochemical and immunohistochemical alterations induced by scopolamine, further supported by the results obtained from molecular docking and binding affinities.

SUBMITTER: Iqbal S

PROVIDER: S-EPMC7175202 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration.

Iqbal Sumbal S Shah Fawad Ali FA Shah Fawad Ali FA Naeem Komal K Nadeem Humaira H Sarwar Sadia S Ashraf Zaman Z Imran Muhammad M Khan Tariq T Anwar Tayyaba T Li Shupeng S

Biomolecules 20200313 3

Oxidative stress-mediated neuroinflammatory events are the hallmark of neurodegenerative diseases. The current study aimed to synthesize a series of novel succinamide derivatives and to further investigate the neuroprotective potential of these compounds against scopolamine-induced neuronal injury by in silico, morphological, and biochemical approaches. The characterization of all the succinamide derivatives was carried out spectroscopically via proton NMR (<sup>1</sup>H-NMR), FTIR and elemental ...[more]

PMID: 32183056

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Project description: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.

Project description:This review covers the preclinical and clinical literature supporting the role of melatonin in the management of brain injury-induced oxidative stress, neuroinflammation, and neurodegeneration, and reviews the past and current therapeutic strategies. Traumatic brain injury (TBI) is a neurodegenerative condition, unpredictably and potentially progressing into chronic neurodegeneration, with permanent cognitive, neurologic, and motor dysfunction, having no standard therapies. Due to its complex and multi-faceted nature, the TBI has highly heterogeneous pathophysiology, characterized by the highest mortality and disability worldwide. Mounting evidence suggests that the TBI induces oxidative and nitrosative stress, which is involved in the progression of chronic and acute neurodegenerative diseases. Defenses against such conditions are mostly dependent on the usage of antioxidant compounds, the majority of whom are ingested as nutraceuticals or as dietary supplements. A large amount of literature is available regarding the efficacy of antioxidant compounds to counteract the TBI-associated damage in animal and cellular models of the TBI and several clinical studies. Collectively, the studies have suggested that TBI induces oxidative stress, by suppressing the endogenous antioxidant system, such as nuclear factor erythroid 2-related factor-2 (Nrf-2) increasing the lipid peroxidation and elevation of oxidative damage. Moreover, elevated oxidative stress may induce neuroinflammation by activating the microglial cells, releasing and activating the inflammatory cytokines and inflammatory mediators, and energy dyshomeostasis. Thus, melatonin has shown regulatory effects against the TBI-induced autophagic dysfunction, regulation of mitogen-activated protein kinases, such as ERK, activation of the NLRP-3 inflammasome, and release of the inflammatory cytokines. The collective findings strongly suggest that melatonin may regulate TBI-induced neurodegeneration, although further studies should be conducted to better facilitate future therapeutic windows.

Dataset Information

Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration.

Publications

Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration.

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