Cell pores’ discovery gives hope to millions of brain and spinal cord injury patients

Scientists have discovered a new treatment to dramatically reduce swelling after brain and spinal cord injuries, offering hope to 75 million victims worldwide each year.

The breakthrough in treating such injuries – referred to as central nervous system (CNS) edema - is thought to be hugely significant because current options are limited to putting patients in an induced coma or performing risky surgery.

The new treatment, developed by an international team of scientists working at Aston University and the University of Birmingham, (UK), Harvard Medical School (US), University of Calgary (Canada), Lund University (Sweden) and Copenhagen University (Denmark), features in the latest edition of the scientific journal Cell.

Joint first author of the paper, Andrea Halsey, received her PhD funding from Spinal Research through Dr Zubair Ahmed, the joint senior and corresponding author of this paper, of the University of Birmingham’s Institute of Inflammation and Ageing. 

The researchers used an already-licensed anti-psychotic medicine – trifluoperazine (TFP) – to alter the behaviour of tiny water channel ‘pores’ in cells known as aquaporins.

Testing the treatment on injured rats, they found those animals given a single dose of the drug at the trauma site recovered full movement and sensitivity in as little as two weeks, compared to an untreated group that continued to show motor and sensory impairment beyond six weeks after the injury.

The treatment works by counteracting the cells’ normal reaction to a loss of oxygen in the CNS – the brain and spinal cord - caused by trauma. Under such conditions, cells quickly become ‘saltier’ because of a build-up of ions, causing a rush of water through the aquaporins which makes the cells swell and exerts pressure on the skull and spine. This build-up of pressure damages fragile brain and spinal cord tissues, disrupting the flow of electrical signals from the brain to the body and vice versa.  

But the scientists discovered that TFP can stop this from happening. Focusing their efforts on important star-shaped brain and spinal cord cells called astrocytes, they found TFP prevents a protein called calmodulin from binding with the aquaporins. Normally, this binding effect sends the aquaporins shooting to the surface of the cell, letting in more water. By halting this action, the permeability of the cells is reduced.

Traditionally, TFP has been used to treat patients with schizophrenia and other mental health conditions. Its long-term use is associated with adverse side effects, but the researchers said their experiments suggested that just a single dose could have a significant long-lasting impact for CNS edema patients.

Since TFP is already licensed for use in humans by the US Federal Drug Administration (FDA) and UK National Institute for Health and Care Excellence (NICE) it could be rapidly deployed as a treatment for brain injuries. But the researchers stressed that further work would allow them to develop new, even better medicines based on their understanding of TFP’s properties.

Dr Zubair Ahmed of the University of Birmingham’s Institute of Inflammation and Ageing said:

“This is a significant advance from current therapies, which only treat the symptoms of brain and spinal injuries but do nothing to prevent the neurological deficits that usually occur as a result of swelling. The re-purposed drug offers a real solution to these patients and can be fast-tracked to the clinic.”

David Allen, FRCS RCPSG Director of Spinal Research's Board of Trustees, said:

"Post accident swelling is the enemy of spinal cord recovery. This might help in finding a cure for paralysis.”

You can read the full paper here: https://www.cell.com/cell/fulltext/S0092-8674(20)30330-5

Kitchen P^., Salman M.M^., Halsey A.M^., Clarke-Bland C., MacDonald J.A., Ishida H., Vogel H.J., Almutiri S., Logan A., Kreida S., Al-Jubair T., Missel J.W., Gourdon P., Tornroth-Horsefield S., Conner M.T., Ahmed Z*., Conner A.C*., Bill R.M*. (2020). Targeting aquaporin-4 subcellular localisation to treat central nervous system edema. Cell, doi: 10.1016/j.cell.2020.03.037.