Epilepsy is a common and diverse set of chronic neurological disorders characterized by seizures. Some definitions of epilepsy require that seizures be recurrent and unprovoked, but others require only a single seizure combined with brain alterations which increase the chance of future seizures. In many cases a cause cannot be identified; however, factors that are associated include brain trauma, strokes, brain cancer, and drug and alcohol misuse among others.
Epileptic seizures result from abnormal, excessive or hypersynchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, and nearly 80% of epilepsy occurs in developing countries. Epilepsy becomes more common as people age. Onset of new cases occurs most frequently in infants and the elderly. As a consequence of brain surgery, epileptic seizures may occur in recovering patients.
Epilepsy is usually controlled, but not cured, with medication. However, more than 30% of people with epilepsy do not have seizure control even with the best available medications. Surgery may be considered in difficult cases.
Accordingly, there is a need to develop new drugs that will be suitable for preventing or treating epilepsy and especially chronic epilepsy. In this way, it has been suggested that characterization of new therapeutic compounds in epilepsy may be highly desirable.
Kainate (KA), an analogue of glutamate, is a potent neurotoxin that has long been known to induce behavioral and electrophysiological acute seizures reminiscent of those found in patients with temporal lobe epilepsy (TLE). However, whether kainate receptors (KARs) activated by the endogenous agonist glutamate play any role in the chronic phase of TLE was yet unknown until Jul. 24, 2014 (the inventors has published the data of the present invention; Peret et al. 2014), although this could represent a promising therapeutic approach. In animal models of TLE and in human patients, neuronal tissue undergoes major reorganization. Sprouting of hippocampal mossy fibers is one of the best documented examples of seizure-triggered reactive plasticity in human patients and animal models of TLE [Represa et al., 1989a; Represa et al., 1989b, Sutula et al., 1989; Mello et al., 1993; Isokawa et al., 1993; Franck et al., 1995; Okazaki et al., 1995; Gabriel et al., 2004;]. This sprouting leads to the formation of powerful recurrent excitatory circuits between dentate granule cells (DGCs), which accounts for, in part, the enhanced ability of the hippocampus to generate epileptiform activity in the hippocampus of human patients and animal models of TLE [Tauck and Nadler, 1985; Mello et al., 1993; Patrylo and Dudek, 1998; Lynch and Sutula, 2000; Buckmaster et al., 2002; Scharfman et al., 2003; Gabriel et al., 2004]. In addition to axonal rewiring, mossy fiber sprouting triggers the recruitment of kainate receptors (KARs) at the aberrant recurrent excitatory synapses in DGCs. Indeed, inputs impinging on DGCs operate mostly via aberrant KARs and drive synaptic events with abnormal long lasting kinetics not present in naïve conditions [Epsztein et al., 2005; Epsztein et al., 2010; Artinian et al., 2011]. In keeping with this, an increased density of kainate binding sites was previously reported in the DG of epileptic patients [Represa et al., 1989b].
State of art, already shows the implication of GluK1 and GluK2 receptors and the potential use of antagonists of these KARs in acute seizures (induced by convulsive chemical agents) in naïve animals [see for example Jane et al., 2009]. However, experiments disclosed in this state of art only relate to cases of acute seizures; these set of experiments have not addressed chronic epilepsy and notably the morpho-functional re-organisation of neuronal networks not present in naïve animals and the sprouting of hippocampal mossy fibers. This re-organisation is only present when chronic epilepsy is installed (i.e. weeks after the initial status epilepticus induced by one injection of convulsive chemical agent like kainate or pilocarpine) and thus not just after one application of the convulsive agents in naïve tissue. More, until Jul. 24, 2014 (the inventors has published the data of the present invention; Peret et al. 2014), the state of the art did not unveil the role of kainate receptors in chronic epileptic conditions.