Novel drug may transform epilepsy treatment

Monash University scientists have demonstrated that a novel drug can prevent the development of seizures in an animal model of Temporal Lobe Epilepsy (TLE), the most common type of epilepsy that develops after a brain injury.

The researchers from the Department of Neuroscience found that the compound Z944 prevented the development of TLE in 80% of animals, and also significantly improved depression and memory and learning problems associated with the disease.

First author in the study, published in Progress in NeurobiologyDr Pablo Casillas-Espinosa said the drug could be “transformative”.

TLE, the most common form of acquired epilepsy in adults, develops after a brain insult such as injury, stroke, infection or tumour. While drugs can be given to patients to suppress seizures, the disease is incurable.

Dr Casillas-Espinosa said the study, co-led by Professor Terry O’Brien, built on previous work into Z944 by the researchers, including one study that showed it stopped seizures in models of genetic epilepsy.

In the recent study, the scientists showed in a model of acquired brain injury that animals treated with Z944 developed less seizures than those administered a placebo and levetiracetam, one of the most widely prescribed new generation anti-epileptic drugs.

“Putting this in context of a patient, if a patient has a brain injury, stroke, brain infection or tumour you could give them the compound immediately afterwards, such as in the ambulance, and prevent the development of temporal lobe epilepsy,” Dr Casillas-Espinosa said. “It could prevent the problem rather than just treating it.

“We would need to further corroborate our findings, and proof from controlled clinical trials are required, but overall the findings are very exciting.”

The other finding in the study is that Z944 improved the co-morbidities associated with TLE.

“Epilepsy is not just the seizures that everybody is used to seeing but depression and cognitive impairment to memory and learning, which overall impact heavily on the quality of life of the patient,” Dr Casillas-Espinosa said. “These co-morbidities don’t respond well to commonly prescribed drugs or therapies the patients receive,” he said.

Dr Casillas-Espinosa said the study suggested that Z944, which is being trialled at the Alfred Hospital for genetic epilepsy, could translate easily to the clinic.

“It could be transformative for patients that could potentially go on to develop epilepsy after a brain insult. It’s extremely important because right now there’s nothing we can give to patients to avoid the development of epilepsy.

“Once it goes to clinical trial, and if successful, it will transform the field,” he said.

Professor Terry O’Brien, Head of the Department of Neuroscience, Monash University, and Program Director of Alfred Brain, Alfred Health, said that the 'Holy Grail' for therapy development in epilepsy was to find a medical treatment that was effective in preventing or reversing epilepsy development, rather than just suppressing seizures – as all currently available anti-epileptic drugs do. “The results from this paper suggest that Z944 could be such a treatment,” he said.

Z944 is a small molecule that modulates calcium channels, which are important in how neurons in the brain communicate. Calcium channels are like a passage in the membrane of neurons which open and close to allow calcium ions in and out of the neurons, which modulate and regulate electrical impulse transmission. Epilepsy can occur when neuronal transmission is not functioning properly, and studies have suggested that this is in part due to problems in calcium channels. Z944 modulates the function of these calcium channels, allowing the neurons to have a “normal” communication similar and thus preventing the development of seizures and epilepsy.

Casillas-Espinosa PM, Shultz SR, Braine EL, Jones NC, Snutch TP, Powell KL, O'Brien TJ. Disease-modifying effects of a novel T-type calcium channel antagonist, Z944, in a model of temporal lobe epilepsy. Prog Neurobiol. 2019 Aug 13:101677. doi: 10.1016/j.pneurobio.2019.101677. [Epub ahead of print]