2. Academic Validation
  3. Targeting TNF-α: The therapeutic potential of certolizumab pegol in the early period of cerebral ischemia reperfusion injury in mice

Targeting TNF-α: The therapeutic potential of certolizumab pegol in the early period of cerebral ischemia reperfusion injury in mice

  • Int Immunopharmacol. 2024 Aug 20:137:112498. doi: 10.1016/j.intimp.2024.112498.
Dexiao Wang 1,  Jie Zhao 1,  Jingyu Zhang 1,  Changling Lv 2,  Shuangyan Bao 1,  Pengfei Gao 1,  Miao He 2,  Lijuan Li 3,  Hairong Zhao 4,  Chenggui Zhang 5
Affiliations

Affiliations

  • 1 Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
  • 2 Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China.
  • 3 Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; School of Public Health, Dali University, Dali, PR China. Electronic address: lelejuan@126.com.
  • 4 Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China. Electronic address: hr_zhaoxmu@126.com.
  • 5 Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China. Electronic address: chenggui_zcg@hotmail.com.
PMID: 38908079 DOI: 10.1016/j.intimp.2024.112498
Abstract

The neuroinflammatory response triggered by cerebral ischemia-reperfusion injury (CIRI) is characterized by the upsurge of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, which promote leukocyte infiltration and subsequent accumulation in the ischemic zone. This accumulation further intensifies inflammation and aggravates ischemic damage. Certolizumab pegol (CZP), a monoclonal antibody targeting TNF-α, is widely used in treating various inflammatory diseases. This study explored the therapeutic potential of CZP in a mouse model of CIRI, induced by middle cerebral artery occlusion (MCAO), focusing on its influence on the microglial inflammatory response. In vitro analyses revealed that CZP markedly inhibits TNF-α-stimulated inflammation in primary microglia with an EC50 of 1.743 ng/mL. In vivo, MCAO mice treated with CZP (10 μg/mouse, i.p.) for 3 days showed reduced infarct volume, partially improved neurological function, and diminished blood-brain barrierdisruption. Additionally, CZP treatment curtailed microglial activation and the release of pro-inflammatory mediators in the early stages of stroke. It also favorably modulated microglial M1/M2 polarization, rebalanced Th17/Treg cells dynamics, and inhibited Caspase-8-mediated GSDMD cleavage, preventing microglial Pyroptosis. Collectively, this study described that the treatment with CZP reversed damaging process caused by CIRI, offering a promising therapeutic strategy for the treatment of ischemic stroke.

Keywords

Caspase 8; Cerebral ischemia-reperfusion injury; Certolizumab pegol; Leukocyte infiltration; Microglial pyroptosis; TNF-α.

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