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Mdivi-1 alleviates brain damage and synaptic dysfunction after intracerebral hemorrhage in mice

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Abstract

As a selective inhibitor of mitochondrial fission protein dynamin-related protein-1 (Drp1), mitochondrial division inhibitor 1 (mdivi-1) can cross the blood–brain barrier (BBB) and exert neuroprotection. However, it remains unclear whether mdivi-1 can attenuate intracerebral hemorrhage (ICH)-induced secondary brain injury. This study was undertaken to characterize the roles of mdivi-1 in short-term and long-term behavioral outcomes, along with synaptic plasticity changes in mice after ICH. The results indicated mdivi-1 reversed Drp1 translocation and the morphologic changes of mitochondria, as well as ameliorated short-term neurobehavioral deficits, the BBB disruption and brain edema remarkably. In addition, mdivi-1 could rescue ICH-induced motor and memory dysfunctions. Mdivi-1 could also prevent ICH-induced reductions in synaptic proteins (synapsin I, PSD95) and phosphorylated cAMP-response element binding (p-CREB). In vitro, mdivi-1 inhibited hemin-induced hippocampal neuron death and improved neurite outgrowth. In conclusion, we found that mdivi-1 can alleviate short-term and long-term neurological deficits, synaptic dysfunction. These findings demonstrate that mdivi-1 may be beneficial in the treatment of secondary brain injury, synaptic dysfunction and neurological outcomes caused by ICH.

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Funding

This work was supported by the National Natural Science Foundation of China (81971163, 81400999), Suzhou Municipal Science and Technology Bureau (SYS2019027), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Correspondence to Chengliang Luo or Qianqian Li.

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The authors have no conflicts of interest regarding the publication of this article.

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This study has been approved by the Ethics Committee of Soochow University. All procedures performed in studies involving animals were in accordance with the ethical standards of all applicable laws, regulations, and standards in China and prevailing standards in the European Union.

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Communicated by Sreedharan Sajikumar.

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Zhang, Y., Rui, T., Luo, C. et al. Mdivi-1 alleviates brain damage and synaptic dysfunction after intracerebral hemorrhage in mice. Exp Brain Res 239, 1581–1593 (2021). https://doi.org/10.1007/s00221-021-06089-6

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Keywords

  • Mdivi-1
  • Dynamin-related protein-1 (Drp1)
  • Intracerebral hemorrhage (ICH)
  • Cognitive impairment
  • Synaptic dysfunction