Ricerc@Sapienza

To date, the main therapeutic strategy for drug resistant mesial temporal lobe epilepsy (TLE) is temporal lobe resection. Here we propose to decrease the cortical hyperexcitability typical of this pathology by potentiating selected subpopulations of nicotinic acetylcholine receptors (nAChRs) expressed in GABAergic interneurons, by means of selective positive allosteric modulators (PAMs), and thus increasing the inhibitory GABAergic neurotransmission. Heteromeric nAChRs expressed in cortical interneurons represent a suitable pharmacological target because they are able to modulate GABA release, and their function appear to be unaffected by epilepsy. Furthermore, our preliminary results show that desformylflustrabromine (dfBr), a PAM selective for alpha4beta2 nAChRs, in the presence of nicotinic activation is able to significantly and selectively increase the inhibitory neurotransmission in the human TLE cortex
By complementary experiments on human tissues and on animal models, we aim: a) to identify a PAM-based pharmacological protocol able to increase GABAergic transmission in the TLE cortex; b) to obtain the control of seizures in animal models; c) to build significant correlations between the clinical status of epileptic patients, their cortical neurotransmission, and the response of their brain tissues to PAM treatment. With this project, we expect to obtain a detailed picture of the cortical effects of PAMs selective for heteromeric nAChRs, both in animal models of epilepsy and in human temporal tissues, with a particular focus on the modulation of inhibitory and excitatory synaptic transmission. Furthermore, the new pharmacological PAM-based protocol, along with all the molecular, cellular, histological, functional, behavioural and clinical data obtained in this study, might pave the way towards clinical trials in human patients.