With NC3Rs funding, Dr Gavin Woodhall, from Aston University, has refined a rat epilepsy model minimising mortality and the intensive care the animals require.
Principal Investigator: Gavin Woodhall, Reader in Neuropharmacology
Organisation: Aston University
Award: £152,048, in 2007, over 36 months
Title: Refinement of a rat epilepsy model
Read more about Dr Woodhall's research.
Medication does not control seizures in 30% of people with epilepsy
Epilepsy is a chronic disorder characterized by seizures (or fits) due to abnormal or excessive neuronal activity in the brain. It affects between 1 to 2% of the world’s population, mainly young children and people over the age of 65. Seizures are also a major contributor to deaths following brain damage caused by stroke or head injury.
For most people with epilepsy (around 60%) there is no known cause (so-called ‘idiopathic’ epilepsy). Around 30% of sufferers have refractory epilepsy which does not respond to treatment.
Epilepsy induced experimentally in animals has high mortality rates
Temporal lobe epilepsy is the most common form of epilepsy and the most difficult to treat. It is modelled in rats by the injection of the convulsant pilocarpine after prior injection with lithium chloride. This induces status epilepticus – high intensity and continuous seizure activity lasting for more than 30 minutes.
Many rat models utilise prolonged status epilepticus of up to six hours, although two to four hours is typical. It is followed by the development of spontaneous recurrent seizures, usually occurring every one to three days. The procedure causes behavioural abnormalities, can lead to aspiration pneumonia as a result of the inhalation of saliva, requires intensive care of the animals for up to three days and is associated with high mortality (rates greater than 50% are reported in many publications). It is classified as causing substantial suffering under the Animals (Scientific Procedures) Act 1986.
A refined rat model of epilepsy with lower mortality rates
With NC3Rs funding, Dr Gavin Woodhall, Aston University, has refined the lithium-pilocarpine rat epilepsy model by exploiting the pharmacological control of seizure activity.
In the new model, status epilepticus is induced using low doses of pilocarpine. Once status epilepticus is observed, seizures are ameliorated to a lower intensity level using the alpha-2 agonist xylazine.
After approximately one hour, the seizures are then terminated by administration of a multicomponent drug cocktail which blocks glutamatergic and enhances GABAergic neurotransmission. The time spent in status epilepticus and the intensity of the seizures is reduced and this has a number of animal welfare advantages compared to the standard rat model.
The mortality rate of the rats in Dr Woodhall’s experiments has decreased from approximately 25% to less than 2%. The rats recover within six to eight hours, hand feeding and other care measures are not necessary and normal behaviour is restored within 24 hours. Recurrent seizures occur every one to seven days. These refinements should enable the severity limit of this procedure to be downgraded under the Animals (Scientific Procedures) Act 1986.
Better representation of human epilepsy
The refined rat model has a number of features which improve its clinical relevance. In humans, status epilepticus is rare and temporal lobe epilepsy most commonly involves brief focal seizures and limited brain damage. The standard lithium-pilocarpine model in rats, by contrast, involves global seizures and results in widespread brain damage and cell death.
The new model better mimics the development of the human disease in that there is little cell death, and there is a slow and variable time course to the development of recurrent seizures. Of particular interest is the fact that, the seizure locus moves with time, which in paediatric epilepsy is known as ‘migration of the irritative zone’. This has not previously been observed in rats and suggests that what is being modelled has some similarities with epilepsy in the juvenile brain.
Sharing best practice
This work has been presented at the Society for Neuroscience meeting in 2009 and the British Neuroscience Association biennial meeting in 2011. The refined procedure has also been adopted by other UK researchers.
This case study was published in a review of our research portfolio in September 2011.