Dottorato in FARMACOLOGIA E TOSSICOLOGIA

Titolo della tesi: IDENTIFICATION OF NEW MOLECULAR TARGETS FOR THE EXPERIMENTAL TREATMENT OF ABSENCE EPILEPSY

The epilepsies represent a heterogeneous group of disorders with different electrographic, etiologies, behavioural and seizure pattern which largely influence the quality of life of patients. Childhood absence epilepsy (CAE) accounts for 2% to 8% of patients with epilepsy and generally occurs at 4-12 years of age. CAE consists in a sudden start and termination of activity with loss of awareness for a number of seconds resulting in a blank stare, and sometimes accompanied by flickering of the eyelids and mouth movements. Recent studies showed that 30% of children with absence epilepsy fail to achieve seizure control and 60% are affected by severe neuropsychiatric comorbid conditions, in particular cognitive deficits and long-term psychosocial difficulties. Drugs currently used for the treatment of absence epilepsy include the T-type calcium channel blocker ethosuximide, and valproic acid, lamotrigine and clonazepam. All these drugs can be effective, but their use is limited by class-related adverse effects, such as sedation, dizziness, and cerebellar motor symptoms. For this reason, new anti-absence drugs are badly needed. The experiments described in this thesis aim to investigate new molecular targets for the experimental treatment of absence epilepsy. It has been suggested that the α2δ subunit of high voltage-activated VSCCs may be associated with T-type channels, whose activation contributes to the pathological oscillatory activity of the cortico-thalamo-cortical network. Considering that this subunit is also targeted by thrombospondins, which regulate synaptogenesis in the CNS, and it’s implicated in the process of epileptogenesis, the axis thrombospondins/2 may play a potential role in the pathophysiology of non-convulsive epilepsy that needs to be evaluated. Moreover, the role of the δ subunit contained in extrasynaptic GABAA receptors and thalamocortical tonic GABAA current in the development of absence seizures remains to be demonstrated; thus, an appropriate mouse model has been adopted. The melatoninergic system in absence seizures has been examined in WAG/Rij rats, also exploring whether melatonin could have an impact on the comorbid depression typical in these rats. Pharmacological studies have been carried out to establish whether positive allosteric modulators of mGlu5 receptors could be developed as putative anti-absence drugs, especially for patients who are refractory to conventional treatment.