&lt;p&gt;Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: a computational and pharmacological approach&lt;/p&gt;

Kury, Lina T. Al; Zeb, Alam; Abidin, Zain Ul; Irshad, Nadeem; Malik, Imran Riaz; Alvi, Arooj Mohsin; Ahmad, Sareer; Faheem, Muhammad; Khan, Arif Ullah; Shah, Fawad Ali; Li, Shupeng

doi:10.2147/dddt.s207310

Cited by 40 publications

(37 citation statements)

References 57 publications

(43 reference statements)

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“…The final GSH values were expressed in µmoles/mg of proteins. Likely, for the determination of GST activity, the previously reported protocol was followed [ 32 ]. 5 mM GSH and 1 mM CDNB in 0.1 M phosphate buffer solution were freshly prepared.…”

Section: Methodsmentioning

confidence: 99%

Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration

et al. 2020

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Ischemic stroke is categorized by either permanent or transient blood flow obstruction, impeding the distribution of oxygen and essential nutrients to the brain. In this study, we examined the neuroprotective effects of compound A3, a synthetic polyphenolic drug product, against ischemic brain injury by employing an animal model of permanent middle cerebral artery occlusion (p-MCAO). Ischemic stroke induced significant elevation in the levels of reactive oxygen species and, ultimately, provoked inflammatory cascade. Here, we demonstrated that A3 upregulated the endogenous antioxidant enzymes, such as glutathione s-transferase (GST), glutathione (GSH), and reversed the ischemic-stroke-induced nitric oxide (NO) and lipid peroxidation (LPO) elevation in the peri-infarct cortical and striatal tissue, through the activation of endogenous antioxidant nuclear factor E2-related factor or nuclear factor erythroid 2 (Nrf2). In addition, A3 attenuated neuroinflammatory markers such as ionized calcium-binding adapter molecule-1 (Iba-1), cyclooxygenase-2 (COX-2), tumor necrotic factor-α (TNF-α), toll-like receptors (TLR4), and nuclear factor-κB (NF-κB) by down-regulating p-JNK as evidenced by immunohistochemical results. Moreover, treatment with A3 reduced the infarction area and neurobehavioral deficits. We employed ATRA to antagonize Nrf2, which abrogated the neuroprotective effects of A3 to further assess the possible involvement of the Nrf2 pathway, as demonstrated by increased infarction and hyperexpression of inflammatory markers. Together, our findings suggested that A3 could activate Nrf2, which in turn regulates the downstream antioxidants, eventually mitigating MCAO-induced neuroinflammation and neurodegeneration.

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Section: Methodsmentioning

confidence: 99%

Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration

et al. 2020

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“…Brain tissues were fixed in 4% paraformaldehyde and embedded in paraffin, and 4 μm coronary sections were cut using a rotary microtome (29). Tissue sections on coated slides were de-paraffinized, with three different absolute xylenes and were rehydrated with ethyl alcohol [from 100% (absolute) to 70%].…”

Section: Methodsmentioning

confidence: 99%

Pathological Comparisons of the Hippocampal Changes in the Transient and Permanent Middle Cerebral Artery Occlusion Rat Models

Shah

Kury

et al. 2019

Front. Neurol.

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Ischemic strokes are categorized by permanent or transient obstruction of blood flow, which impedes delivery of oxygen and essential nutrients to brain. In the last decade, the therapeutic window for tPA has increased from 3 to 5–6 h, and a new technique, involving the mechanical removal of the clot (endovascular thrombectomy) to allow reperfusion of the injured area, is being used more often. This last therapeutic approach can be done until 24 h after stroke onset. Due to this fact, more acute ischemic stroke patients are now being recanalized, and so tMCAO is probably the “best” model to address these patients that have a potential good outcome in terms of survival and functional recovery. However, permanent occlusion patients are also important, not only to increase survival rate but also to improve functional outcomes, although these are more difficult to achieve. So, both models are important, and which target different stroke patients in the clinical scenario. Hippocampus has a vital role in memory and cognition, is prone to ischemic induced neurodegeneration. This study was designed to delineate the molecular, pathological, and neurological changes in rat models of t-MCAO, permanent MCAO (pMCAO), and pMCAO with diabetic conditions in hippocampal tissue. Our results showed that these three models showed distinct discrepancies at numerous pathological process, including key signaling molecules involved in neuronal apoptosis, glutamate induced excitotoxicity, neuroinflammation, oxidative stress, and neurotrophic changes. Our result suggests that the two commonly used MCAO models exhibited tremendous differences in terms of neuronal cell loss, glutamate excitotoxic related signaling, synaptic transmission markers, neuron inflammatory and oxidative stress molecules. These differences may reflect the variations in different models, which may provide valuable information for mechanistic and therapeutic inconsistences as experienced in both preclinical models and clinical trials.

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“…Concisely, the same concentrations of GST and 1-chloro-2,4-dinitrobenzene were mixed and diluted with a 0.1 M solution of PBS (pH 6.5). After serial dilution from tissue homogenate, the absorbance was measured at 340 nm [6].…”

Section: Gsh and Gsh S-transferase (Gst) Assaymentioning

confidence: 99%

“…The homeostatic equilibrium maintained naturally between reactive oxygen species (ROS) and endogenous antioxidants plays a vital role in continuing healthy tissue life. Elevated ROS production predisposes human health to several disorders such as neurodegenerative and inflammatory disorders [5][6][7]. Activation of microglia is another important hallmark in central nervous system (CNS) inflammation, which plays a principal role in immune response in the brain [8].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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<p>Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: a computational and pharmacological approach</p>

Cited by 40 publications

References 57 publications

Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration

Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration

Pathological Comparisons of the Hippocampal Changes in the Transient and Permanent Middle Cerebral Artery Occlusion Rat Models

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

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