[WATCH] Maltese scientists claim stroke drug breakthrough

Prof. Mario Valentino explains what the researchers found

Research undertaken by scientists at the University of Malta and University of Plymouth has led to the identification of a drug which can potentially protect the brain from damage induced by stroke.

Stroke is a devastating neurological disorder which leaves victims with limited functional outcome and is the main cause of disability worldwide.

The collaborative study found that when the drug QNZ-46 was administered systemically to mice before an induced stroke, it protected the entire brain, opening the possibility of a new treatment for individuals at high risk of having a stroke.

Previous studies which attempted to find such a drug have so far been unsuccessful, in part because of their adverse side effects and lack of specificity. Stroke affects all cellular elements of the brain and impacts areas traditionally classified as both gray matter and white matter.

“We identified QNZ-46 as a possible drug. Much to our surprise we found that when this was administered before a stroke, it protected all areas of the brain”

Professor Mario Valentino, the scientist leading the Malta team together with Dr Jasmine Vella, Dr Christian Zammit and Eng. Robert Zammit, told MaltaToday their research had uncovered that the source of damage is due to the unregulated and overabundant release of the glutamate, a neurotransmitter which floods the brain minutes after a stroke.

This leads to the over-excitation of neurons and support cells, leading to their death.

Historically, it was always assumed that the support cells were contributing to this neurotransmitter overload, as a result of their reduced pumping activity from the energy failure that sets in with the stroke.

“Our discovery of glutamate as the cause of damage was a great finding for us,” Valentino said. “We managed to precisely localise the release of glutamate from nerve fibres at source, along with the activation of their bindings sites localised in the protective myelin sheaths, which led to the injury in the white matter.

“Once we identified the mechanism causing the injury, we went through several databases to see if we could find a potential drug to block these receptors and limit the damage.”

Valentino highlighted: “We identified QNZ-46 as a possible drug. Much to our surprise we found that when this was administered before a stroke, this not only protected the brain’s white matter fibres and myelin, but also all areas of the brain.”

Rodent study

Using sophisticated imaging techniques, the scientists were able to confirm the potential protection afforded by the drug after a stroke.

“In the majority of stroke research in our lab we use a multitude of lasers in combination with genetically engineered mice, which express neurons that are fluorescent to light stimulation,” Valentino said.

“This allows us to visualise the nervous system in real time and observe what happens during brain injury and recovery, when testing for drugs.

“We induce a stroke by a surgical procedure, which involves the insertion of a filament into a very tiny blood vessel in the brain to mimic the occurrence of a stroke in humans.

“Our studies are augmented through the additional use of various color-tagged antibodies that specifically recognise different types of cells in the brain. This helps us identify those cell types which are affected as a consequence of a stroke and those that can recover with drug treatment.”

Tiny: a mouse brain

The next steps

The next stage after this particular study is to examine any possible adverse side effects the drug might have.

“Right now, in the short term, there seem to be no negative side effects, but pending the outcome of toxicological studies, we hope that the drug might one day be exploited further to find its way into clinical trials and to benefit patients,” Valentino said.

The drug would be very suitable to people who are at high risk of having a stroke. This would include people who do not manage their high blood pressure, and sedentary and obese people.

Valentino said that functional health problems arising from damage to white matter fibres and their associated myelin sheaths could also be safeguarded under this drug treatment.

“Therefore, it comes without saying that this may be potentially very effective in the treatment of multiple sclerosis, where myelin damage is the primary cause of the devastating disorder,” he said.

Another possibility is to test the drug on pre-term and term infants who have suffered an ischemic episode during development and that are known to have a high probability of developing cerebral palsy, the most common neurodevelopmental disorder in children.”

In terms of a time frame for when the drug could possibly be made available, Valentino could not speculate. “It all depends on the toxicological, behavioural and functional tests over an extended period of time. Up to this point they seem to be very promising.”

The full study, entitled Vesicular glutamate release from central axons contributes to myelin damage was spearheaded and funded by the University of Plymouth and the Biotechnology and Biological Sciences Research Council. Locally, this was generously supported by E.J. Busuttil Ltd through their EVOS ®FL Auto Imaging System and the Alfred Mizzi Foundation through RIDT, and is available for reading in Nature Communications.