Targeting MAPK Phosphorylation of Connexin43 Provides Neuroprotection in Stroke

Researchers from the University of British Columbia, Seattle and Belgium successfully used a new approach that significantly minimized brain damage caused by ischemic stroke in mouse models. The new approach works by blocking hemichannels—pathways allowing for the flow of chemical ions and small molecules—that are expressed by astrocytes, ie, cells playing a protective role for neurons in the brain.

The hypothesis is that when stroke occurs, these hemichannels open and leak toxic molecules into the space outside the astrocytes, causing inflammation and damage to neurons; therefore, blockade of these channels may minimize damage to the brain during stroke.

In this study, a genetic approach that mutated the channel proteins, called Connexin-43 (Cx43), was used to block the formation of hemichannels. This allows the astrocytes to protect the neurons, significantly reducing the size of the stroke injury in the brain. Pharmacological blockade of Cx43 hemichannels with a molecule called TAT-Gap19 in the same ischemic stroke model, also resulted in smaller stroke damage.

These two approaches demonstrate that Connexin hemichannel blockers could be used as a neuroprotective agent in stroke. Thus, a new treatment of ischemic stroke may soon be possible. 

Connexin hemichannel blockers also have a potential role in treating other neurodegenerative conditions such as traumatic brain injury and Alzheimer's disease.