Plasticité cérébrale et neuropathologies Nouvelles voies pour le médicament Synaptic plasticity and neuropathology : new approaches in drug discovery

Résumé

Il est désormais acquis que la plasticité neuronale est importante, même chez l’adulte, pour la formation de nouvelles connexions comme pour celle de nouveaux neurones (neurogenèse) ou de cellules gliales. Cependant, le vieillissement et les facteurs de stress peuvent altérer cette plasticité et favoriser le développement d’une atrophie cérébrale. Des anomalies de plasticité neuronale pourraient être l’un des facteurs contribuant au développement des maladies neuropsychiatriques, et ce aux différents stades de la vie. La compréhension de ces processus, l’étude de leur implication dans la pathologie neuropsychiatrique et la recherche d’agents pharmacologiques à visée thérapeutique susceptibles de moduler cette plasticité neuronale constitue un des thèmes centraux de la recherche en neurosciences au sein de l’Institut de Recherches Servier.

Summary

Neuronal plasticity is now known to be very important in the adult, both in the formation of new synaptic connections and of new neurones (neurogenesis) and of glial cells. However, old age and stress can inhibit this plasticity and lead to cerebral atrophy. The time course of changes in neuronal plasticity involves, in the first milliseconds to seconds, changes in synaptic strength (long term potentialisation, LTP, or long term depression, LTD), then, over minutes to hours, changes in the number of synaptic connections (linked to changes in neurotrophic factors), and over weeks to months, to changes in neuronal reconfiguration. These changes in brain systems are particularly targeted in psychiatric disorders to the areas which are sensitive to stress and play roles in memory and emotion (hippocampus, amygdala and prefrontal cortex). The discovery and development of drugs modifying neuronal plasticity and neurotrophins production has been a priority for Servier research for the last ten years ; Servier has a clinically effective antidepressant, tianeptine (Stablon^®), with a favourable side effect profile, but which does not inhibit the uptake of serotonin, or other monoamines. However, this drug can reverse the deleterious effects of stress on neuronal plasticity, thereby acting on the causes of psychiatric disorders. Furthermore, a new research area is being investigated - facilitation of AMPA receptors, favouring the production of neurotrophic factors.