2. Academic Validation
  3. An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke

An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke

  • Sci Transl Med. 2021 Jun 9;13(597):eabb6716. doi: 10.1126/scitranslmed.abb6716.
Zongping Fang 1,  Di Wu 2,  Jiao Deng 1,  Qianzi Yang 1,  Xijing Zhang 1,  Jian Chen 2,  Shiquan Wang 1,  Sijun Hu 3,  Wugang Hou 1,  Siming Ning 3,  Yi Ding 4,  Zhongmin Fan 1,  Zhenhua Jiang 1,  Junjun Kang 5,  Yingying Liu 5,  Jinlin Miao 6,  Xunming Ji 7,  Hailong Dong 8,  Lize Xiong 9 1
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine and Department of Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 2 Department of neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing 10053, China.
  • 3 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 4 Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 5 Department of Neurobiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 6 National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 7 Department of neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing 10053, China. mzkxlz@126.com lizexiong@tongji.edu.cn hldong6@hotmail.com jixm@ccmu.edu.cn.
  • 8 Department of Anesthesiology and Perioperative Medicine and Department of Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. mzkxlz@126.com lizexiong@tongji.edu.cn hldong6@hotmail.com jixm@ccmu.edu.cn.
  • 9 Translational Research Institute of Brain and Brain-Like Intelligence and Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200434, China. mzkxlz@126.com lizexiong@tongji.edu.cn hldong6@hotmail.com jixm@ccmu.edu.cn.
PMID: 34108252 DOI: 10.1126/scitranslmed.abb6716
Abstract

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)-cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal Apoptosis and Necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients.

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