Inhibition of astrocyte hemichannel improves recovery from spinal cord injury.

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

doi:10.1172/jci.insight.134611

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.

Highlights

Spinal cord injury (SCI) results in approximately 13,000 admissions to hospitals in the United States and between 250,000 and 500,000 injuries worldwide each year [1]
We tested the specificity of MHC1 to connexin 43 (Cx43) using HeLa-Cx43 cells, which are stably transfected with Cx43
This study indicates the potential involvement of Cx43 hemichannels, which have been reported to mediate the release of ATP from astrocytes, leading to microglial recruitment and neuronal cell death [35,36,37,38]

Summary

Introduction

Spinal cord injury (SCI) results in approximately 13,000 admissions to hospitals in the United States and between 250,000 and 500,000 injuries worldwide each year [1]. After the initial primary injury, secondary damage occurs, when edema, loss of blood flow, metabolic crisis, and spreading depolarizations cause the area of spinal cord damage to increase [2]. These processes elicit increased levels of extracellular molecules and ions, which include glutamate, lactate, K+, nitric oxide, arachidonate, reactive oxygen species, and ammonia. Secondary injury results in glial scar formation and neuronal cell death [3] These can be detrimental to axon regeneration and contribute to other complications that arise from SCI, such as neuropathic pain and spasticity [9]. Because strategies that regenerate axons are limited, therapeutically preventing secondary damage after SCI represents a significant strategy in improving patient outcomes

Methods

Results

Conclusion