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Updated: Feb 25, 2026
Isolation and Flow Cytometric Assessment of Neuroimmune Interactions in a Mini-Stroke Murine Model
Published on: June 20, 2025
A Dual AMPK/Nrf2 Activator Reduces Brain Inflammation After Stroke by Enhancing Microglia M2 Polarization
Yunjie Wang1, Yun Huang2, Yazhou Xu1
11 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University , Nanjing, P.R. China .
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.
Insights
A novel compound, HP-1c, shows promise for treating ischemic stroke by activating AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, reducing inflammation and oxidative stress.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Microglia-driven neuroinflammation is a key factor in ischemic stroke.
- Current treatments for ischemic stroke are limited.
- AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways are implicated in regulating microglial polarization and oxidative stress.
Purpose of the Study:
- To assess the dual therapeutic potential of a novel neuroprotectant, HP-1c, targeting both AMPK and Nrf2 activation for ischemic stroke treatment.
- To investigate HP-1c's effects on microglial polarization and oxidative stress in preclinical models of stroke.
Main Methods:
- Development of novel hybrid compounds (telmisartan and 2-(1-hydroxypentyl)-benzoate derivatives).
- In vitro and in vivo evaluation of HP-1c in rat and mouse models of transient and permanent focal cerebral ischemia.
- Assessment of microglial M1/M2 polarization, oxidative stress markers, and neurological deficits.
- Pharmacokinetic and toxicity studies of HP-1c in mice.
Main Results:
- HP-1c demonstrated superior anti-inflammatory and neuroprotective effects compared to existing agents in vitro.
- HP-1c significantly reduced brain infarct volume and improved neurological deficits in rat models of ischemic stroke, with a therapeutic window up to 24 hours.
- Beneficial effects were linked to M2 microglial polarization, reduced oxidative stress, and activation of the AMPK-Nrf2 pathway.
- HP-1c showed brain penetration, a favorable plasma half-life, and no observed toxicity in mice.
Conclusions:
- HP-1c, a novel compound with dual AMPK and Nrf2 activating properties, exhibits significant therapeutic potential for ischemic stroke.
- HP-1c's ability to modulate neuroinflammation and oxidative stress via the AMPK-Nrf2 pathway offers a promising new therapeutic strategy.
- Further studies are warranted to explore HP-1c as a novel treatment for ischemic stroke.
