Grant round winners 2013
Reactive oxygen species (ROS), which include a number of free radicals, are thought to play important roles in ageing and cancer; and there is a growing use of anti-oxidants in both cancer therapies and the cosmetics industry. There is increasing evidence that ROS also play a crucial role in the death of neurons in a variety of conditions, including prolonged and repeated seizures; and they may contribute to the development of epilepsy following an injury to the brain such as stroke, trauma or infection. Clinical trials of potential anti-oxidants (eg vitamin E) in epilepsy have been disappointing, but this is likely to be due to insufficient understanding of the ways in which ROS are produced in the brain and the most effective ways of targeting them.
Professor Matthew Walker and colleagues, at University College London (UCL), now have early evidence that more targeted anti-oxidant treatments might succeed where others have failed. These act either by inhibiting the enzymes that produce ROS (approach A), or by increasing the ability of neurons to break ROS down into less harmful molecules (this is known as anti-oxidant defense – approach B). Epilepsy Research UK has awarded this group £133,755, over 30 months, to carry out a project entitled Preventing seizure induced cell death by NADPH oxidase inhibition and Nrf2 induction, in which they will explore these approaches further.
The team will use a variety of techniques (in animals and brain tissue) to compare the effectiveness of the approaches, both individually and in combination, to find out which is the most effective at preventing seizure-induced neuronal death and the longer-term consequences. Approach A will involve treatment with a compound that inhibits an enzyme known as NADPH oxidase (a major source of ROS), and approach B will involve treatment with a compound that enhances the activity of Nuclear factor eythroid 2-related factor 2 (Nrf2 – a key regulator of antioxidant defenses).The researchers will also explore how effective the therapies are (alone and in combination) in preventing seizures following a brain trauma, and in preserving memory.
This study will hopefully identify new antioxidant treatments that have the potential to prevent seizures and reduce their damaging impact upon the brain. The compounds used are already being tested in people with cancer, and so epilepsy clinical trials could be underway in 3-5 years. If they are successful it could have enormous implications for people with drug-resistant epilepsy.