Pannexins after stroke: knocking-out membrane channels to improve neurological function.

New therapeutic approaches are urgently needed to treat stroke patients. According to the World Health Organization this devastating disease affects 15 million people each year, among them about 10 million will die or live as functionally-disabled stroke survivors.

Despite these devastating numbers, only pharmacological and mechanical reperfusion therapies to restore the blood flow have proven to save lives and improve the neurological outcome of ischemic stroke patients. On the other side, hundreds of neuroprotective drugs targeting inflammation, oxidative stress, apoptosis and other cell-death triggers of the ischemic cascade, have failed to prove efficacy in clinical trials after obtaining encouraging supporting data from pre-clinical studies. Hence, enormous disappointment has struck researchers, neurologists and industry partners when translating basic science findings to the clinical practice.

This shocking reality has opened the eyes of many stroke researchers to look for new targets, and most importantly, to find new ways to validate potential therapeutic benefits in a bedside-to-bench strategy. In this regard, the main endpoint of stroke clinical trials designed to prove efficacy is to demonstrate improvement of neurological function in stroke survivors.

In recent publications from Bargiotas and colleagues, the authors show this new vision in the stroke research field: the authors focus their interest in pannexins, a family of proteins involved in basic cell-signaling functions, to demonstrate their role not only in brain injury but also in modifying functional outcome in a mouse model of stroke.

It is known that cell-to-cell communication occurs directly through gap-junctions between cells or by indirect paracrine signaling when cells release molecules such as ATP, ions or small metabolites into the extracellular space. With a structure similar to gap-junction forming connexins, recently discovered pannexins are membrane channels described to connect the cytosol with the extracellular space. Pannexin 1 (Px1) and pannexin 2 (Px2) are known to be expressed in the cerebral nervous system, in contrast to the other member of the family, pannexin 3. Interestingly, pannexins have been shown to be expressed in the brain both in neurons and astrocytes, while other authors have recently demonstrated their expression in vascular cells of the rat brain (Px1 expression in smooth muscle cells and Px2 in both endothelium and smooth muscle cells). Regarding function, channel activity has been demonstrated to be dependent on pannexins in neurons, whereas channel activity in astrocytes has been reported to be both independent and dependent on pannexins by different authors.,

Interestingly, Px1- and Px2-deficient mice, but not single knockouts, have recently shown to be protected in front of ischemia in an experimental model reproducing cortical infarcts, by reducing lesion volume and improving neurological outcome at short-term. Why do pannexins become involved in brain damage? Several authors speculate that K+ efflux, accumulation of reactive oxygen species and caspase expression after ischemia might activate and open these membrane channels leading to cell death, although the precise mechanisms still need to be fully characterized.

The knowledge on pannexin functions is incipient and continuously evolving. However Bargiotas and colleagues, have already explored the final consequences of knocking-out these proteins in the context of cerebral ischemia. Their results position pannexins as therapeutic targets to improve functional outcome in sensorimotor, anxiety and exploration functions after stroke. Certainly these are exciting results, but from a bedside-to-bench point of view it is still required to demonstrate if the reported neurological protection is sustained long-term, in old animals, in females or in other species and should be validated by independent researchers in other stroke models. Finally, it would be interesting to explore the pharmacological inhibition of pannexins to demonstrate functional benefits in pre-clinical models before we move to the clinical setting.