ENGLISH PRESENTATION

Inserm UMR-S 1144

Therapeutic Optimization in Neuropharmacology

The principal objectives of our project can be summarized as follows:

• To identify molecular signatures predicting treatment failure or relapse in patients with addiction, bipolar disorders and cognitive dysfunction. In accordance with the recruitment of patients, we will focus our study on those treated for severe mood, opiate or cocaine use disorders, and those exhibiting persistent cognitive dysfunction Lithium, a major mood-regulator for which 60% of patients are considered "poor responders", will be an area of particular focus. 
• To characterize the mechanisms of toxicity of psychotropic drugs, including new psychoactive substances (“party drugs”), alone or in combination, and to identify factors of individual vulnerability.
• To characterize the structure and molecular changes induced in the blood-brain barrier (BBB) by chronic exposure to psychotropic drug or pathological conditions. New regulatory mechanisms for the exchange or transport of substances across the BBB could be discovered, explaining response variability and leading to therapeutic or diagnostic applications.
• To favor the development of new therapeutic strategies for the treatment of stroke and other cerebrovascular diseases by promoting basic science discoveries and to combine them with clinical investigations.

The Unit (Prof. Xavier Declèves, Director, PharmD, PhD and Dr Cynthia Marie-Claire, Co-Director, Research Director CNRS) is organized into four teams to encourage their multidisciplinary nature and interactions within and between them.

Team 1 : "Biomarkers of therapeutic response and relapse in neuropsychiatric diseases" (headed by Prof. Frank Bellivier, MD, PhD, psychiatrist, and Dr. Cynthia Marie-Claire, PhD, Senior Researcher from the Centre National de la Recherche Scientifique (CNRS) develops research programs on biomarkers (central or peripheral, using molecular or imaging investigations) that could predict the psychotropic drugs response and relapse prediction in addictive (opiates, cocaine), mood, and neurodegenerative disorders. Patients are recruited through the specialized centers for drug addiction, mood disorders and neurocognition at Fernand Widal Hospital (Paris University Hospitals).

Team 2 : "Mechanisms of toxicity and therapeutic optimization of psychotropic drugs", (headed by Prof. Bruno Mégarbane, MD, PhD, clinical toxicologist and Prof. Nadia Benturquia, Senior Researcher from Université Paris Cité, neuropharmacologist aims to identify the predictive factors of response variability to psychoactive drugs (including illegal drugs, and central analgesics), in situations of poisoning (aiming to better understand mechanisms of toxicity) and prescription (aiming to optimize strategies of patient treatment). Identification of factors of response variability is conditioned by transversal investigations including pharmacogenetics, pharmacokinetics (PK) and pharmacodynamics (PD) of psychotropic drugs as well as mechanisms of drug-drug interactions which may explain this variability in patients with highly prevalent polypharmacy.

Team 3 : "Pathophysiology and therapeutic targets of the blood-brain barrier", headed by Prof. Xavier Declèves, PharmD, PhD, Pharmacokinetician, and Prof Salvatore Cisternino, PharmD, PhD, Pharmacokineticianconducts fundamental research into the BBB. Its objective is to study and identify the mechanisms involved in the regulation of molecular exchanges across the BBB, under pathological conditions or in models of exposure to psychoactive substances (drugs of abuse or therapeutic drugs used in the context of addiction or bipolar disorder). In the long term, this project aspires to improve, on the one hand, the treatment of psychiatric disorders and addiction, and on the other, our understanding of the mechanisms brought into play in these pathological situations. This new knowledge will allow us to define biomarkers of interest to the clinic, and to designate new therapeutic targets.

Team 4 : " Innovative diagnosis and treatment of cerebral stroke ", headed by Dr. Benoit Ho-Tin-Hoé, PhD, Senior Researcher from the INSERM Institute and Prof. Mickaël Mazighi, MD, PhD. conducts its research in tight collaboration with clinical neurology groups from Lariboisière and Rothschild Foundation Hospitals. Their research focuses on how actors of the thromboinflammatory cascade like platelet, leukocytes, and endothelial cells contribute to the pathophysiology of cerebrovascular diseases.

Its objective is to promote basic science discoveries and to combine them with clinical investigations, in order to favor the development of new therapeutic strategies for the treatment of stroke and other cerebrovascular diseases.