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 6

Blocking Cx43 hemichannel function by MHC1 antibody decreases spinal cord gliosis, protects neuron survival and reduces SCI lesion under the model 2 impact.

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Blocking Cx43 hemichannel function by MHC1 antibody decreases spinal cor...
Spinal cords of SCI treated with saline control or MHC1 antibody were isolated 56 days after the model 2 impact. (A) The frozen sections were immunolabeled with anti-GFAP antibody and counterstained with DAPI. Left panels show representative images of GFAP immunofluorescence. Right panel show the quantification of GFAP-positive signals from perilesional area (area < 0.5 mm from injury border on sagittal sections) by NIH ImageJ software. Images were taken from perilesional area. White line labels the injury site border, and the area under the white lines is the lesion site. Scale bar: 0.5 mm. (B) The frozen sections were immunolabeled with anti-MAP2 antibody and counterstained with DAPI. Upper panels show representative images of MAP2 immunofluorescence, and lower panel shows the quantification of MAP2-positive signals from perilesional area (area < 0.5 mm from injury border on sagittal sections) by NIH ImageJ software. All images were taken from perilesional area. White line labels the injury site border, and the area under the white lines is the lesion site. Scale bar: 0.5 mm. (C) The white lines define SCI lesion areas (upper panel), and the sizes of lesion areas were quantified by NIH ImageJ software (lower panel). Scale bar: 50 μm. Data are presented as mean ± SEM. Unpaired t test (1 tailed) was used in statistical analysis. (A–C). For GFAP and MAP2 staining, SCI+Saline (n = 6), SCI+MHC1 (n = 6). For lesion area, SCI+Saline (n = 5), SCI+MHC1 (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001.