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

Biomolecules. 2020 May 26;10(6):816. doi: 10.3390/biom10060816.

Abstract

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.

Keywords: A3; all-trans retinoic acid; antioxidant system; middle cerebral artery occlusion; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Ischemic Stroke / drug therapy*
  • Ischemic Stroke / metabolism
  • Male
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Antioxidants
  • Neuroprotective Agents
  • Oxadiazoles
  • 1,3,4-oxadiazole