A Dual AMPK/Nrf2 Activator Reduces Brain Inflammation After Stroke by Enhancing Microglia M2 Polarization

Aims: Microglia-mediated neuroinflammation plays an important role in focal ischemic stroke, a disorder with no effective therapeutic agents. Since microglial polarization to the M2 phenotype and reduction of oxidative stress are mediated through AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) activation, we assessed the dual therapeutic effect of AMPK and Nrf2 activation by a novel neuroprotectant HP-1c in the treatment of ischemic stroke. Results: We developed a novel class of hybrids (HP-1a–HP-1f) of telmisartan and 2-(1-hydroxypentyl)-benzoate (HPBA) as a ring-opening derivative of NBP. The most promising hybrid, HP-1c, exhibited more potent anti-inflammatory and neuroprotective effects in vitro and reduced brain infarct volume and improved neurological deficits in a rat model of transient focal cerebral ischemia when compared with telmisartan alone, NBP alone, or a combination of telmisartan and NBP. HP-1c had a therapeutic window of up to 24 h, ameliorated ischemic cerebral injury in permanent focal cerebral ischemia, and improved motor function. The beneficial effects of HP-1c in ischemic stroke were associated with microglial polarization to the M2 phenotype and reduced oxidative stress. HP-1c also shifted the M1/M2 polarization in a mouse neuroinflammatory model. The anti-inflammatory and anti-oxidative effects of HP-1c were associated with AMPK-Nrf2 pathway activation for neuroprotection. We showed that HP-1c penetrates the brain, has a plasma half-life of around 3.93 h, and has no toxicity in mice. Innovation and Conclusion: Our study results suggest that HP-1c, with dual AMPK- and Nrf2-activating properties, may have potential in further studies as a novel therapy for ischemic stroke. Antioxid. Redox Signal. 28, 141–163.