Abstract
Medicinal plants represent an interesting reservoir of natural substances for the discovery of new therapeutic molecules. The interest of this work is to explore the therapeutic potential of medicinal plants, which are known for their neuromodulation effects, by studying their ability to target the activity of T-type calcium channels which play a major role in neuronal hyperexcitability and the pathophysiology of epilepsy and other neurological diseases.The first objective of my thesis was to study the effect of Mediterranean plant extracts; Lavandula stoechas, Rosmarinus officinalis and Peganum harmala and their active ingredients; linalool, rosmarinic acid and harmaline, respectively, on T-type calcium currents using the patch clamp technique in whole-cell configuration. Electrophysiological recordings from HEK-293 cells expressing T-type channels show that lavender, rosemary and Harmal significantly reduce T-type currents over the potential range tested. The natural products shifted steady-state inactivation towards more negative membrane potentials and some plants (Peganum harmala) significantly accelerate the inactivation kinetics of T-type channels. The second objective was to study the anticonvulsant / antiepileptic activity of these plants as well as TTA-A2, a selective T-type channel blocker, in an epilepsy model in zebrafish. Our results validate the PTZ and 4-AP as inducers of convulsions in zebrafish and both models could be used to screen for anticonvulsant and/or antiepileptic molecules. Our results show that rosemary, lavender and TTA-A2 inhibit seizures-like activity in these two models. Overall, this project suggests that T-type channels are involved in the neuroprotective and anticonvulsant properties of the studied medicinal plants and validates the role of medicinal plants as a valuable source of therapeutic products.