Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy
- Wenzhou Medical University, China
- Beijing Institute of Technology, China
- Stanford University, United States
- Second Affiliated Hospital, Wenzhou Medical University, China
- Third Affiliated Hospital of Sun Yat-sen University, China
- National Eye Institute (NIH), United States
Abstract
Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: 1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. 2) Even with possible access for “local refrigeration”, cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4°C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.
Data availability
Computer program download site:https://github.com/LujieZhang/Preoperative-planning.The processed gene expression data in this paper have been deposited into the NCBI GEO database: GSE182164. RNA-seq data download site: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE182164.
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Author details
Funding
National Key Research and Development Program of China Stem Cell and Translational Research (2021YFA1101200)
- Wencan Wu
National Key Research and Development Program of China (2016YFC1101200)
- Wencan Wu
National Natural Science Foundation of China (81770926)
- Wencan Wu
National Natural Science Foundation of China (81800842)
- Yikui Zhang
Key R&D Program of Zhejiang Province (2018C03G2090634)
- Wencan Wu
Key R&D Program of Zhejiang Province (2021C03065)
- Wencan Wu
Key R&D Program of Wenzhou Eye Hospital (YNZD1201902)
- Wencan Wu
National Key Research and Development Program of China (2019YFC0119300)
- Jian Yang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experiments were conducted following the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research guidelines.All protocols were approved by the Institutional Animal Care and Use Committee in the Wenzhou Medical University (Wenzhou, China, ID number: wydw2020-0789) and the Joinn Laboratory (Suzhou, China, ID number: P19-S445-PD).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy
eLife 11:e75070.
https://doi.org/10.7554/eLife.75070
