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Published on: January 22, 2017
The Sirtuin 5 Inhibitor MC3482 Ameliorates Microglia‑induced Neuroinflammation Following Ischaemic Stroke by
Qian Xia1, Yongbo Yu2, Gaofeng Zhan1
1Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
In our previous study, we concluded that sirtuin 5 (SIRT5) was highly expressed in microglia following ischaemic stroke, which induced excessive neuroinflammation and neuronal injury. Therefore, SIRT5-targeting interventions should reduce neuroinflammation and protect against ischaemic brain injury. Here, we showed that treatment with a specific SIRT5 inhibitor, MC3482, alleviated microglia-induced neuroinflammation and improved long-term neurological function in a mouse model of stroke. The mice were administrated with either vehicle or 2 mg/kg MC3482 daily for 7 days via lateral ventricular injection following the onset of middle cerebral artery occlusion. The outcome was assessed by a panel of tests, including a neurological outcome score, declarative memory, sensorimotor tests, anxiety-like behavior and a series of inflammatory factors. We observed a significant reduction of infarct size and inflammatory factors, and the improvement of long-term neurological function in the early stages during ischaemic stroke when the mice were treated with MC3482. Mechanistically, the administration of MC3482 suppressed the desuccinylation of annexin-A1, thereby promoting its membrane recruitment and extracellular secretion, which in turn alleviated neuroinflammation during ischaemic stroke. Based on our findings, MC3482 offers promise as an anti-ischaemic stroke treatment that targets directly the disease's underlying factors.
Insights
A novel SIRT5 inhibitor, MC3482, reduced neuroinflammation and brain damage in a mouse stroke model. This treatment improved neurological function by targeting annexin-A1, offering potential for new ischaemic stroke therapies.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Sirtuin 5 (SIRT5) is upregulated in microglia post-ischaemic stroke, contributing to neuroinflammation and neuronal damage.
- Targeting SIRT5 presents a potential therapeutic strategy to mitigate stroke-induced injury.
Purpose of the Study:
- To investigate the therapeutic potential of a specific SIRT5 inhibitor, MC3482, in a mouse model of ischaemic stroke.
- To elucidate the underlying mechanisms by which MC3482 exerts neuroprotective effects.
Main Methods:
- Mice with middle cerebral artery occlusion received daily lateral ventricular injections of MC3482 (2 mg/kg) or vehicle for 7 days.
- Neurological function was assessed using outcome scores, memory, sensorimotor, and anxiety-like behavior tests.
- Infarct size and inflammatory markers were quantified; molecular mechanisms involving annexin-A1 desuccinylation were explored.
Main Results:
- MC3482 treatment significantly reduced infarct size and suppressed key inflammatory factors.
- Improved long-term neurological function, including better memory and sensorimotor performance, was observed in MC3482-treated mice.
- MC3482 inhibited annexin-A1 desuccinylation, promoting its secretion and reducing neuroinflammation.
Conclusions:
- MC3482 effectively alleviates neuroinflammation and protects against ischaemic brain injury in a mouse stroke model.
- The therapeutic effect of MC3482 is mediated by the suppression of annexin-A1 desuccinylation.
- MC3482 demonstrates significant promise as a novel therapeutic agent for ischaemic stroke treatment.
