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

Biomolecules

Lina Tariq Al Kury¹  Muhammad Umar Ijaz²  Arooj Mohsin Alvi³  Arif-ullah Khan³  Ahmed Sadiq Sheikh³  Fawad Ali Shah³  Humaira Nadeem³  Muhammad Tariq Khan³  Alam Zeb³  Shupeng Li⁴ 

[1] College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, UAE;Department of Zoology, Wildlife, and Fisheries, University of Agriculture, Faisalabad 38000, Pakistan;Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan;State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China;

关键词: A3;    middle cerebral artery occlusion;    all-trans retinoic acid;    neurodegeneration;    antioxidant system;   

DOI  :  10.3390/biom10060816

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown