Inhibition of astrocyte hemichannel improves recovery from spinal cord injury
Chao Zhang, … , Naomi L. Sayre, Jean X. Jiang
Chao Zhang, … , Naomi L. Sayre, Jean X. Jiang
Published March 8, 2021
Citation Information: JCI Insight. 2021;6(5):e134611. https://doi.org/10.1172/jci.insight.134611.
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Research Article Therapeutics

Inhibition of astrocyte hemichannel improves recovery from spinal cord injury

Abstract

Spinal cord injury (SCI) causes severe disability, and the current inability to restore function to the damaged spinal cord leads to lasting detrimental consequences to patients. One strategy to reduce SCI morbidity involves limiting the spread of secondary damage after injury. Previous studies have shown that connexin 43 (Cx43), a gap junction protein richly expressed in spinal cord astrocytes, is a potential mediator of secondary damage. Here, we developed a specific inhibitory antibody, mouse-human chimeric MHC1 antibody (MHC1), that inhibited Cx43 hemichannels, but not gap junctions, and reduced secondary damage in 2 incomplete SCI mouse models. MHC1 inhibited the activation of Cx43 hemichannels in both primary spinal astrocytes and astrocytes in situ. In both SCI mouse models, administration of MHC1 after SCI significantly improved hind limb locomotion function. Remarkably, a single administration of MHC1 30 minutes after injury improved the recovery up to 8 weeks post-SCI. Moreover, MHC1 treatment decreased gliosis and lesion sizes, increased white and gray matter sparing, and improved neuronal survival. Together, these results suggest that inhibition of Cx43 hemichannel function after traumatic SCI reduces secondary damage, limits perilesional gliosis, and improves functional recovery. By targeting hemichannels specifically with an antibody, this study provides a potentially new, innovative therapeutic approach in treating SCI.

Authors

Chao Zhang, Zhao Yan, Asif Maknojia, Manuel A. Riquelme, Sumin Gu, Grant Booher, David J. Wallace, Viktor Bartanusz, Akshay Goswami, Wei Xiong, Ningyan Zhang, Michael J. Mader, Zhiqiang An, Naomi L. Sayre, Jean X. Jiang

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Figure 8

Mice do not show improved recovery with Cx43 antibody 1 month after SCI.

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Mice do not show improved recovery with Cx43 antibody 1 month after SCI....
Thirty days after SCI, mice were injected with 25 mg/kg MHC1 via intracerebroventricular route. (A) Mice were subjected to broad impact (model 1). BMS test was performed 30 days after MHC1 administration. SCI+Saline (n = 14), SCI+MHC1 (n = 16). (B) Mice were subjected to a broad impact (model 1). The frozen sections of spinal cords 60 days after SCI were immunolabeled with anti-GFAP antibody, and GFAP-positive signals from perilesional area (area < 0.5 mm from injury border on sagittal sections) were quantified using NIH ImageJ software. Data are presented as mean ± SEM. SCI+Saline (n = 5), and SCI+MHC1 (n = 5). (C) Mice were subjected to focused impact (model 2), and BMS score was determined in mice treated with MHC1 or saline control. SCI+Saline (n = 9), SCI+MHC1 (n = 10). (D) Mice were subjected to focused impact (model 2). Four hours after ICV injection with saline or MHC1, spinal cords were isolated; the frozen sections of spinal cords around perilesional sites were immunolabeled with anti-human IgG secondary antibody and counterstained with DAPI. Scale bar, 500 μm (black), 10 μm (white, right panels). Two-way repeated measures ANOVA with time was used for BMS statistical analysis (A and C). Unpaired t test (1 tailed) was used in statistical analysis (B). *P < 0.05.