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Balasubramide derivative 3C modulates microglia activation via CaMKKβ-dependent AMPK/PGC-1α pathway in
Yunjie Wang1, Wenchen Ruan1, Junru Mi2
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China.
Abstract:
Neuroinflammation plays a vital role in the pathological process of cerebral ischemic stroke, but currently there is no effective treatment. After ischemia, microglia-produced proinflammatory mediator expression contributes to the aggravation of neuroinflammation, while anti-inflammatory activation of microglia develops an anti-neuroinflammatory effect via secretion of anti-inflammatory factor. Promoting the anti-inflammatory activation of microglia might be an effective treatment of stroke. Previously, we discovered one derivative of the natural product (+)-balasubramide, compound 3C, that exhibits a remarkably anti-neuroinflammatory effect in vitro with unknown mechanisms. Thus in this study, we aimed to clarify its molecular mechanisms and determine whether compound 3C has a neuroprotective effect after ischemia via regulation on microglial inflammation. We found that compound 3C promoted the anti-inflammatory mediator expression and reduced the proinflammatory mediator expression in LPS-stimulated BV2 cells and mouse primary microglia cells, which were reversed by AMP-activated protein kinase (AMPK) inhibition or AMPK upstream calmodulin-dependent protein kinase kinase beta (CaMKKβ) inhibition. Compound 3C also prevented LPS-stimulated JNK activation and enhanced PGC-1α activation in microglia, which was attenuated by AMPK inhibition. Additionally, compound 3C ameliorated depressive behaviors in LPS-induced neuroinflammatory mice by promoting the anti-inflammatory activation of microglia. Furthermore, we found that compound 3C markedly reduced brain infarct volume, improved the neurological deficit in rats with ischemia and reduced the activated microglia/macrophage cells in the ischemic area, which concomitantly enhanced the anti-inflammatory mediator expression. A mechanistic study showed that the compound 3C-mediated activation of CaMKKβ, AMPK and PGC-1α is involved in the anti-neuroinflammatory and neuroprotective effects of 3C in the brain of LPS-treated mice and ischemic rats. Taken together, our results show that compound 3C could suppress neuroinflammation in vitro and in vivo by modulating microglial activation state through the CaMKKβ-dependent AMPK/PGC-1α signaling pathway, and maybe further be developed as a promising new drug candidate for the treatment of brain disorders such as stroke associated with brain inflammation.
Insights
Compound 3C, a novel therapeutic, effectively reduces neuroinflammation and brain damage in stroke models by promoting beneficial microglial activation via the CaMKKβ-AMPK/PGC-1α pathway.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Neuroinflammation exacerbates cerebral ischemic stroke, with microglia playing a dual role in promoting or resolving inflammation.
- Current treatments for neuroinflammation in stroke are limited, highlighting the need for novel therapeutic strategies.
- Microglial anti-inflammatory activation is a potential therapeutic target for stroke treatment.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the anti-neuroinflammatory effects of compound 3C, a derivative of (+)-balasubramide.
- To determine if compound 3C exerts neuroprotective effects in ischemic stroke by modulating microglial inflammation.
- To investigate the role of the CaMKKβ-AMPK/PGC-1α signaling pathway in compound 3C's actions.
Main Methods:
- In vitro studies using LPS-stimulated BV2 and primary microglia cells to assess mediator expression and signaling pathway activation.
- In vivo studies using LPS-induced neuroinflammatory mice to evaluate behavioral changes and microglial activation.
- In vivo studies using a rat model of cerebral ischemia to measure infarct volume, neurological deficits, and inflammatory markers.
Main Results:
- Compound 3C promoted anti-inflammatory and suppressed pro-inflammatory mediator expression in microglia, a process dependent on CaMKKβ and AMPK activation.
- Compound 3C inhibited JNK activation and enhanced PGC-1α activation in microglia, mediated by AMPK.
- Compound 3C ameliorated depressive behaviors in mice, reduced brain infarct volume and neurological deficits in rats, and decreased activated microglia/macrophages in ischemic brain tissue.
Conclusions:
- Compound 3C suppresses neuroinflammation and confers neuroprotection in stroke models by modulating microglial activation state.
- The anti-neuroinflammatory and neuroprotective effects of compound 3C are mediated through the CaMKKβ-dependent AMPK/PGC-1α signaling pathway.
- Compound 3C represents a promising drug candidate for treating neuroinflammatory brain disorders, including stroke.
