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.