Systemic Administration of Connexin43 Mimetic Peptide Improves Functional Recovery after Traumatic Spinal Cord Injury in Adult Rats

Blocking of Connexin43 hemichannels, the main gap junction protein located on astrocytes in the central nervous system, has been shown to reduce neural injury in a number of models. We demonstrated previously that local administration of a Connexin43 mimetic peptide, Peptide5, reduces secondary tissue damage after spinal cord injury (SCI). Here, we investigated whether acute systemic delivery of Peptide5 is also protective in a model of SCI. Rats were subjected to a mild spinal cord contusion using the Multicentre Animal Spinal Cord Injury Study impactor and were injected intraperitoneally with Peptide5 or a scrambled peptide immediately and at 2 h and 4 h post-injury. Rats were tested for locomotor recovery and pain hypersensitivity and euthanized at 8 h, 24 h, two weeks, or six weeks post-injury. Compared with control rats, Peptide5 treated rats showed significant improvement in hindlimb locomotor function between three and six weeks postinjury and reductions in at-level mechanical allodynia at weeks one and six post-injury. Immunohistochemistry showed that Peptide5 treatment led to a reduction in total Connexin43 and increased phosphorylated Connexin43 at 8 h compared with scrambled peptide. At two and six weeks, lesion size, the astrocytic and the activated macrophage, and/or microglial response were all decreased in the Peptide5 animals. In addition, neuronal cell numbers were higher in the Peptide5 animals compared with the scrambled peptide treated rats at two and six weeks. These results show for the first time that systemic administration of Peptide5 to block the pathological opening of Connexin43 hemichannels is a feasible treatment strategy in this setting, ameliorating the secondary SCI.