Introduction, objectives and overview of the research programme.

 

 

 

Epilepsy carries an enormous burden to the individual and to society. Epilepsy is the commonest serious neurological condition, and the most ubiquitous, affecting people of all ages and social classes. At least 60 million people worldwide (6 million people in Europe) have epilepsy. It has a tremendous impact not only to the individual but also to society – the estimated total cost of epilepsy in Europe in 2010 was €13.8 billion. Although commonly regarded as a disease, epilepsy is more appropriately considered a symptom of brain dysfunction whether the aetiology is genetic or acquired. Indeed, there are multifarious aetiologies of epilepsy ranging from specific brain insults such as head injury and prolonged seizures to more general dysfunction such as dementia, including Alzheimer’s Disease, and inflammatory diseases. The development of epilepsy (epileptogenesis) is associated with a multitude of changes in ion channels, receptors, synapses and network connectivity. It is likely that there is considerable redundancy in the epileptogenic process, so that targeting any one of these will not be effective - partly explaining why a variety of previously tried antiepileptogenic treatment strategies have failed. Indeed, there has been no clinical study that has demonstrated successful modification of the severity or frequency of epilepsy following such insults. ECMED is aimed at this treatment gap, and thus proposes a completely novel treatment and diagnostic approach. ECMED will also be relevant to epilepsy secondary to genetic conditions that disrupt or result from disruption of ECM.

 

Conventional approaches to studying epilepsy have concentrated on neurotransmitters, channels and receptors, and the modifications that can occur to these during the development of epilepsy (epileptogenesis). There is burgeoning evidence that ECM proteins play a fundamental role in neural development and regeneration, synaptic plasticity, neuronal excitability and network activity – key players in the pathogenesis of epilepsy. Evidence that supports this includes (a) the emerging role of ECM in brain diseases associated with epilepsy such as stroke, neurodegeneration, schizophrenia and autism; (b) the association between ECM protein mutations and epilepsy; and (c) the contribution of ECM to acquired epilepsy through changes in the synaptic plasticity machinery. ECMED aims (i) to understand the key mechanisms of epileptogenesis mediated by activity dependent remodelling of extracellular matrix, (ii) to detect and prevent changes in the ECM during early epileptogenesis, and (iii) to develop ECM-targeting treatment strategies for “opening a  window” for persistent structural normalisation of neural circuitries in late stages of epileptogenesis aswell as in established epilepsy.

 

Within these aims our objective are: (i) to understand remodelling of ECM during epileptogenesis, (ii) to identify ECM components or their degradation products that can serve as biomarkers for early diagnostics of epileptogenesis, (iii) to identify targets for prevention of epilepsy-related ECM alterations, (iv) to identify targets prompting restoration of neural connectivity during established epilepsy, and (v) to validate biomarkers and treatment targets in pre-clinical animal models.