Drug discovery in a model of temporal lobe epilepsy
Key Words
Epilepsy, anti-epileptic drugs
Benefits
Epilepsy is a chronic neurological disorder that affects 0.5-1% of the population and for which there is no cure. Approximately 30% of all epilepsy patients receive little or no benefit from existing anti-epileptic drugs.
We have spent a number of years investigating the effects of new drug compounds upon epileptiform (‘epilepsy-like’) activity in acute brain slices and acute whole animal models of seizure.
This work has identified a number of drugs that exert potent anti-epileptiform and anti-seizure effects which must now be studied in models of the disease itself, epilepsy, in order to a) meet clinical and regulatory requirements to justify human clinical trials and b) better understand the mechanisms underlying the effects of these drugs.
Benefits
The evidence produced by this project will determine whether new compounds hold sufficient promise for testing in human clinical trials. Drugs successful in human clinical trials will have a significant beneficial effect upon the >30% of people living with poorly controlled epilepsy. Understanding how these drugs work will help us understand what makes treatment-resistant epilepsy different from other epilepsies which in turn aids the development of new treatments.
Animals used
Rats 1000 over 5 years
Adverse effects
Depending on the efficacy of the test compounds being studied and once rendered epileptic, animals will experience spontaneous seizures. Whilst behaviourally dramatic, consciousness is lost during seizures and amnesia (in humans) is very common.
Adverse events include death from seizure and, very rarely in this model, biting of the tongue during seizure. Some animals will be implanted with screws or a cannula in the skull in order to monitor brain activity. They will experience some pain during recovery from the screw implantation process that can be controlled with analgesia.
Replacement
Epilepsy is a disorder of the whole body (brain and periphery) and, as such, is too complex for current in vitro approaches to properly model it. Moreover, regulatory (EMA) requirements demand testing in whole animal models.
Reduction Experiment sizes will be determined by statistical power calculations. We will use established quantitative scoring systems to assess seizures induced. A professional statistician will be consulted when required.
Refinement
The majority of existing, initial in vivo anticonvulsant testing to date has been conducted in rats, providing a large body of evidence with which to compare our results and reduce the need to replicate some investigations for which results are already available.
Mouse models of seizure are less discriminatory and predictive than rat models since mice exhibit different seizure circuits in the brain compared to rats and humans. The model is the gold standard animal model of spontaneous recurrent seizure (epilepsy). Anaesthetised models are unsuitable since involvement of the periphery is eliminated and so renders the model less predictive.