Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration
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 injur...
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2020-05-01
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author | Arooj Mohsin Alvi Lina Tariq Al Kury Muhammad Umar Ijaz Fawad Ali Shah Muhammad Tariq Khan Ahmed Sadiq Sheikh Humaira Nadeem Arif-ullah Khan Alam Zeb Shupeng Li |
author_facet | Arooj Mohsin Alvi Lina Tariq Al Kury Muhammad Umar Ijaz Fawad Ali Shah Muhammad Tariq Khan Ahmed Sadiq Sheikh Humaira Nadeem Arif-ullah Khan Alam Zeb Shupeng Li |
author_sort | Arooj Mohsin Alvi |
collection | DOAJ |
description | 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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publishDate | 2020-05-01 |
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spelling | doaj.art-d447e9ceee0c4f4c83e460fe7d7741872023-11-20T01:47:23ZengMDPI AGBiomolecules2218-273X2020-05-0110681610.3390/biom10060816Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and NeurodegenerationArooj Mohsin Alvi0Lina Tariq Al Kury1Muhammad Umar Ijaz2Fawad Ali Shah3Muhammad Tariq Khan4Ahmed Sadiq Sheikh5Humaira Nadeem6Arif-ullah Khan7Alam Zeb8Shupeng Li9Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanCollege of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, UAEDepartment of Zoology, Wildlife, and Fisheries, University of Agriculture, Faisalabad 38000, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, PakistanState Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, ChinaIschemic 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.https://www.mdpi.com/2218-273X/10/6/816A3middle cerebral artery occlusionall-trans retinoic acidneurodegenerationantioxidant system |
spellingShingle | Arooj Mohsin Alvi Lina Tariq Al Kury Muhammad Umar Ijaz Fawad Ali Shah Muhammad Tariq Khan Ahmed Sadiq Sheikh Humaira Nadeem Arif-ullah Khan Alam Zeb Shupeng Li Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration Biomolecules A3 middle cerebral artery occlusion all-trans retinoic acid neurodegeneration antioxidant system |
title | Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration |
title_full | Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration |
title_fullStr | Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration |
title_full_unstemmed | Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration |
title_short | Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration |
title_sort | post treatment of synthetic polyphenolic 1 3 4 oxadiazole compound a3 attenuated ischemic stroke induced neuroinflammation and neurodegeneration |
topic | A3 middle cerebral artery occlusion all-trans retinoic acid neurodegeneration antioxidant system |
url | https://www.mdpi.com/2218-273X/10/6/816 |
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