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A Single Administration of Riluzole Applied Acutely After Spinal Cord Injury Attenuates Pro-inflammatory Activity and Improves Long-Term Functional Recovery in Rats

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Abstract

After spinal cord injury (SCI), emergency treatment intervention can minimize tissue damage, which is closely related to the recovery of long-term function. Here, we examined whether the administration of a single dose of riluzole (6 mg/kg) immediately after SCI was a critical window for the drug to exert its regulatory effect and limit long-term neurological deficits. The animals were sacrificed 1 day after administration for investigation of neuronal survival and a potential neuroinflammatory response, and sacrificed in the 6th week for assessment of neurological function. Riluzole applied in a single dose immediately post-SCI decreased the mRNA level of interleukin-1β at 6 h, reduced the destruction of neurons, and reduced the activation of microglia/macrophage M1 expression at day 1 post-SCI. Additionally, riluzole-treated rats showed higher expressions of interleukin-33 and its receptor ST2 in microglia/macrophages of the spinal cord than vehicle-treated rats, suggesting that this signaling pathway might be involved in microglia/macrophage-mediated inflammation. At 6 weeks, riluzole-treated rats exhibited higher motor function scores than vehicle-treated controls. In addition, riluzole-treated rats exhibited higher expression of GAP43 protein and shorter N1 peak latency and larger N1-P1 amplitude in motor-evoked potentials, compared to vehicle-treated rats. Together, these data suggested that early application of riluzole after SCI could be crucial for long-term functional recovery, so it may represent a promising therapeutic candidate within the critical therapeutic window for acute SCI.

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Availability of Data and Material

The data that supported the findings of the present study are available from the corresponding authors upon reasonable request.

Abbreviations

SCI:

Spinal cord injury

CNS:

Central nervous system

M1:

M1 microglia/macrophage

M2:

M2 microglia/macrophage

HE:

Hematoxylin and eosin

BBB:

Basso, Beattie, Bresnahan

MEPs:

Motor-evoked potentials

IL:

Interleukin

TNF:

Tumor necrosis factor

TGF:

Transforming growth factor

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Funding

This work was supported by the National Natural Science Foundation of China (81901241).

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Author notes

  1. Qichao Wu, Wenkai Zhang and Shuo Yuan contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100043, China

    Qichao Wu, Shuo Yuan & Lei Zang

  2. Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China

    Wenkai Zhang, Yanjun Zhang & Xueming Chen

  3. Central Laboratory, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China

    Wenxiu Zhang, Yan Zhang & Xueming Chen

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  1. Qichao Wu
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  2. Wenkai Zhang
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  6. Yan Zhang
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Contributions

L.Z., X.C., and Q.W. designed the research. Q.W., Y.Z., W.Z., and S.Y. performed the research. Q.W. and W.Z. analyzed the data. Q.W., X.C., and Y.Z wrote the manuscript.

Corresponding authors

Correspondence to Xueming Chen or Lei Zang.

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Ethics Approval

All animal experiments were approved by the Institutional Animal Care and Use Committee of Capital Medical University. The animals were handled according to the guidelines set forth by the Chinese National Institutes of Health.

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Not applicable, because this study did not involve human participants.

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Not applicable, because this study did not involve human participants.

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Highlights

• Riluzole immediately applied in a single dose post-spinal cord injury (SCI), decreased the mRNA level of interleukin (IL)-1β at 6 h, and reduced the destruction of neurons at day 1 post-SCI.

• At 6 weeks, riluzole-treated rats exhibited better neurological function compared to vehicle-treated rats. This advantage may have been due to riluzole intervention during the acute phase of spinal cord injury.

• Anti-inflammatory effects may be another important mechanism of riluzole, in addition to its well-described function of reducing excitotoxicity by blocking glutamatergic neurotransmission.

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Wu, Q., Zhang, W., Yuan, S. et al. A Single Administration of Riluzole Applied Acutely After Spinal Cord Injury Attenuates Pro-inflammatory Activity and Improves Long-Term Functional Recovery in Rats. J Mol Neurosci 72, 730–740 (2022). https://doi.org/10.1007/s12031-021-01947-y

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