Hippocampal neuropeptides as neurobiological targets in preclinical drug development for psychomotor epilepsy

Introduction
The epilepsies remain major neurological disorders and hit more than 1% of the world-wide population. Psychomotor epilepsy of temporal lobe origin is especially hard to control despite the introduction of almost 10 new generation anti-epileptic drugs (AEDs) in the last 10 years. Their anti-epileptic activity was mainly defined by acute seizure models such as the maximal electroshock and pentylenetetrazol (i.e. GABAA antagonist) seizure tests. As a result, their main mechanisms of actions are still blockade of voltage-dependent Na+ channels and reinforcement of GABAergic inhibition respectively (Löscher & Schmidt 2002). Unfortunately, the clinical evidence to date suggests that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage the refractory patient. Indeed, pharmacoresistance for all AEDs is observed in 25 to 40% of the patients suffering from psychomotor epilepsy (White 2003). Moreover, several adverse effects are known for most AEDs.
There is thus clearly a need for new AEDs with original mechanisms of action and fewer side effects. Epilepsy researchers have to identify innovative therapeutic approaches that reach beyond the symptomatic treatment of epilepsy to modify the progression and even prevent the development of epilepsy.
Refractory psychomotor epilepsy has an enormous impact on daily, social and psychosocial life of the patient and is clinically often accompanied by psychiatric dysfunctions such as anxiety and depression. Comorbid depression is significantly correlated with the poorest quality of life among epileptic patients (Cramer et al. 2003). More research in both our own and other laboratories is currently trying to unravel the common pathophysiological features of epilepsy and depression. Facilitation of central monoamine (serotonin 5-HT, noradrenalin NAD, dopamine DA) release is associated with both anticonvulsant and antidepressant effects (Jobe et al. 1999; Clinckers et al. 2004a-b). Limbic glutamate-monoamine interactions are linked to epilepsy and depression (Pralong et al. 2002). Another important comorbidity of refractory psychomotor epilepsy is cognitive decline. Neurobiological explanations again try to clarify their relation. Synaptic plasticity changes such as long-term potentiation (LTP) are regarded as key elements in learning and memory processes (Bliss & Collingridge 1993). Limbic epilepsy induces synaptic plasticity alterations and uses partly the hippocampal 'memory mechanisms'. Plasticity changes are also recognised factors in the evolution of epilepsy making the hippocampal network more susceptible for further seizures and refractoriness.

Aim of the present research proposal
The currently available AEDs symptomatically suppress epileptic seizures (i.e. anticonvulsant effect) without treating the cause or seizure recurrence. Innovative ways to follow in epilepsy research are:
1) To understand mechanisms of epileptogenesis (i.e. the origin of epilepsy) and search for drugs with anti-epileptogenic effects;
2) To get a better understanding of the processes in epilepsy progression in order to develop disease-modifying drugs;
3) To get insights into biological mechanisms of pharmacoresistance and test strategies for its reversal or prevention;
4) Not to overlook neurological comorbidities such as depression and cognitive decline.
Endogenous neuropeptides are complementary to the classic neurotransmitters and their functions range from transmitter to growth factor. They seem of particular importance when the CNS is challenged, such as during high frequency firing and pathological conditions, and thus also in epilepsy. These features together with the large number of neuropeptide receptors and expected lack of overt side effects of peptidergic ligands provide great opportunities for the discovery of new AED targets. In fact, recently a substance P (SubP)/NK1 blocker showed clinical efficacy for the treatment of depression and emesis (Hökfelt et al. 2003; Kramer et al. 2003).
In this project, we want to make a contribution to this interesting domain of research
- By investigating if certain subtype-selective peptidergic ligands (preferentially the synthetic ‘non-peptide structure’ ones) possess anticonvulsant and/or anti-epileptogenic properties.
- By testing if these subtype-selective peptidergic ligands are substrates for multidrugtransporters.
- By studying their interactions with the classical neurotransmitter systems, and their effects on the endogenous neuropeptide release itself.

Objectives
- To screen peptidergic ligands (both neuropeptide and non-peptide structure) in acute epilepsy models
- To test if interesting peptidergic receptor ligands are substrates for multidrugtransporters
- To investigate promising peptidergic ligands in chronic animal models of epileptogenesis.
- To study concomitantly the effects of the peptidergic ligands on in vivo neurotransmitter and neuropeptide release by microdialysis.