Potential Drug Mechanism For Drug-Resistant Epilepsy Identified

While most epileptic seizures do not cause any lasting effect on the brain, seizures which are repeated or last up to or over an hour are potentially fatal. There are drugs designed to stop seizures from occurring, but there are some people who have drug-resistant epilepsy and therefore can’t be helped by these drugs.

A multicontinental collaboration of researcher groups have discovered a possible treatment for drug-resistant epilepsy through targeting a protein implicated in our cells protective response to oxidative stress – a common initiator of cell damage or death.

The drug, RT408 (omaveloxolone), activates a cellular defence pathway (Nrf2) which upregulates the expression of antioxidative proteins from over 200 different genes. This drug is currently being trialled for Friedreich’s ataxia, a disease where reduced expression of frataxin protein and mitochondrial dysfunction leads to increased oxidative stress, leading to progressive neurodegeneration.

Omaveloxolone Effects

The research group found that omaveloxolone reduced the amount of damage which occurs from seizures, and can even help prevent the seizure from occurring in the first place. This exhibits a neuroprotective and disease modifying effect from omaveloxolone administration.

In their cell based model, the researchers found that omaveloxolone reduced reactive oxygen species production, as well as decreasing cell death. These results warranted investigation of the drug in an animal model of drug-resistant epilepsy.

This rat model used was designed to mimic hippocampal sclerosis – severe neuron loss and immune cell disruption in the hippocampus region of the brain – which is a major cause of drug-resistant epilepsy.

When investigating the effects of omaveloxolone in a rat model of drug-resistant epilepsy, they found reduced brain cell death and a drastically reduced onset of seizures in the weeks and months following the initial surgically induced seizure.

Seizure Blocking Drugs

Epilepsy is a common and diverse neurological condition which manifests in a range of different seizures occurring from abnormal electrical activity in the brain.

When these seizures occur more than once in an hour or last for a long period of time they can be extremely dangerous, and are termed as status epileptic. This is because of the mass production of reactive oxygen species, which can damage the brain and even prove fatal if the seizure is allowed to continue.

There are drugs to stop seizures from occurring but these are not always effective, with 30% of people that have epilepsy having drug-resistant epilepsy.

Nrf2 Activation Target

Omaveloxolone activates nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently upregulates a plethora of antioxidative genes. Through this mechanism a single drug – like omaveloxolone – can upregulate multiple antioxidative pathways, in contrast to drugs which target the reactive oxygen species directly.

The Nrf2 activation target also has the potential to provide a longer lasting effect than reactive oxygen species targeting drugs, as these direct targeting compounds are short lived as a consequence of the oxidative scavenging process.

This discovery could aid the treatment of epilepsy and drug-resistant epilepsy, providing a protective solution to repeated seizures. Drugs which target Nrf2 are being increasingly researched for multiple diseases, owing to the involvement of reactive oxygen species in pathogenesis.

Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, Dinkova-Kostova AT, Kovac S, Abramov AY, Walker MC.
KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy
Brain. 2018 Mar 12. doi: 10.1093/brain/awy071

Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: Claudius Griesinger. CC BY

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