Connexin43 Mimetic Peptides Reduce Swelling, Astrogliosis, and Neuronal Cell Death after Spinal Cord Injury

Connexin43 (Cx43) is up-regulated after spinal cord injury (SCI). The authors tested whether mimetic peptides, corresponding to short sequences of rat Cx43, would reduce the severity of damage in a rodent ex vivo model of SCI. Eleven peptides (peptides 1 to 11) corresponding to short amino acid sequences of the extracellular loops of rat Cx43 were tested. Two of these peptides, peptide4 (corresponding to Gap27) and peptide5, significantly reduced the degree of swelling after SCI in this model. Peptide5 produced the more significant reduction in swelling and was analyzed further. Treatment with peptide5 reduced both the level of Cx43 and the number of glial fibrillary acidic protein (GFAP)-positive astrocytes, and at the same time reduced the loss of NeuN-and SMI-32–positive neurons in a concentration-and time-dependent manner. In cell culture, low concentrations of peptide5 prevented hemichannel opening, but did not disrupt gap junctional communication. Higher concentrations prevented hemichannel opening, but also uncoupled existing gap junctions. This study supports the idea that regulation of Cx43 hemichannel opening using mimetic peptides may be a useful treatment for reducing the spread of damage after SCI.