Project: The pregnenolone-derivative MAP4343 as a new therapy for the treatment of depressive disorders: a preclinical project

The CO goal of DEPSTER is to complete the preclinical investigations required to validate the use of the molecule MAP4343 as an innovative compound for the treatment of depressive disorders. MAP4343 is a derivative of the neurosteroid pregnenolone able to modulate key regulators of neuronal morphology named cytoskeletal microtubules via a unique and original mechanism of action. To the best of our knowledge there are no similar drugs in development or onthe market. Initial data gathered by MAPREG show the potential antidepressant efficacy of MAP4343 and the success of DEPSTER could be a breakthrough in the depression market and a milestone for the future growth of the consortium Ps._x000D_A substantially reduced quality of life for 21 million people and a 118 billion Euro a year is the cost for depressive disorders in Europe (data from the European College of Neuropsychopharmacology). Individuals suffering from major depressive disorder (MDD) present a heterogeneous and complex pattern of symptoms including depressed mood, anhedonia, anergia, loss of interest, feelings of guilt, low self-esteem, disturbed sleep, weight loss, and poor concentration. Moreover, 60-70% of acutely depressed patients experience suicidal ideation and, tragically, 10-15% of depressed patients eventually commit suicide._x000D__x000D_The prevalent hypotheses of MDD postulate a dysregulation of the central nervous system monoamines (i.e. serotonin, noradrenaline and dopamine) and all currently available antidepressant drugs target the monoaminergic systems. Antidepressant drugs are blockbusters in the drug market having a global market of $21 billion in 2008. However, antidepressants have well known limitations, the most important being an approximately 2-4 week delay from the initiation of therapy to alleviation of symptoms and, in general, several treatment months before remission. Importantly, 20-40% of patients respond only partially or reCO refractory to treatment. These facts have led to recognition that enhanced monoaminergic neurotransmission per se is not sufficient for the clinical efficacy of antidepressant drugs and pharmaceutical companies are engaged in intense search for molecules with novel mechanism of actions that will be more efficacious, have faster onset of antidepressant effects and yet have a safe side effect profile._x000D_Recent magnetic resonance imaging (MRI) studies consistently show volume loss and structural abnormalities in specific brain regions, i.e. prefrontal cortex and hippocampus, of depressed individuals which correlate with the severity of the depression state. These brain abnormalities result from alterations in neuronal cells structure and decreased neurogenesis/cytogenesis which are a consequence of major changes at the cytoskeletal microtubular level. Therefore, pharmaceutical companies are looking for molecules able to reverse such neuronal structural alterations; however, these efforts have so far not been successful. The reason could be the lack of molecules with specific and direct effects on neuronal microtubular proteins. In contrast, the MAPREG molecule MAP4343 possesses such properties._x000D__x000D_Thus MAP4343 represents a potential antidepressant molecule which can be used as monotherapy or as add-on drug to conventional treatments. Such strategy aims to alleviate both structural and monoaminergic deficits thereby accelerating the onset and improving antidepressant therapy. The product is expected to cover a 15-20% of the market represented by depressed individuals that respond only partially or reCO refractory to antidepressant drugs, or experience major side effects._x000D__x000D_The DEPSTER consortium is formed by the R&D performing SME named MAPREG (Le Kremlin-Bicêtre; France) and two public institutions renowned as centres of excellence in psychopharmacology research, namely the Karolinska Institute (Stockholm, Sweden) and the German Primate Centre (Gottingen, Germany). DEPSTER will further explore the antidepressant efficacy of MAP4343 using well established animal models of depression to investigate the wide variety of pathogenetic features of the disease. Environmental and genetic rat models as well as their combination will be used. Moreover, the psychosocial stress will be applied to tree shrews (Tupaia belangeri; a species that has major genetic similarities to primates) to obtain data of translational relevance for future clinical studies. DEPSTER will be organized in four work packages (WPs) covering technical aspects to which each of the Ps will differentially contribute based on their expertise. The most advanced technological protocols in the field of neuropsychopharmacological research will be applied to study pharmacokinetics (WP1), behaviour (WP2), neuronal structure and neurogenesis/cytogenesis (WP3) and neurochemistry (WP4). _x000D__x000D_DEPSTER has many technological innovative aspects which will eventually lead to a novel antidepressant product of great interest for the market._x000D__x000D_

Acronym DEPSTER (Reference Number: 5291)
Duration 04/01/2010 - 04/07/2012
Project Topic Current antidepressant treatments are inadequate to rescue the brain structural alterations reported in depressed individuals. MAP4343 is an innovative neuronal plasticity modulator showing potential antidepressant efficacy. DEPSTER will validate the use MAP4343 as a novel therapy for depression.
Project Results
(after finalisation)
The results of DEPSTER clearly demonstrate that MAP4343 (pregnenolone-derivative) has behavioral properties indicative of both antidepressant and anxiolytic activity obtained from two animal species (rats and tree shrews). These behavioral effects correlated with changes in microtubular and synaptic proteins in brain regions and plasma supporting the unique antidepressant pharmacology of pregnenolone-derivatives such as MAP4343. Moreover, results on sleep patterns in stressed tree shrews indicate that MAP4343 and fluoxetine normalised sleep efficiency when compared to stressed animals receiving a vehicle solution only. Important to mention that fluoxetine disrupts physiological sleep, while MAP4343 did not. _x000D_In summary, the data obtained by DEPSTER support the progression of MAP4343 into clinical trials and to explore its antidepressant efficacy in a general group of patients with a broad profile of depressive symptoms (including sleep disorder) and possibly also containing aspects of anxiety.
Network Eurostars
Call Eurostars Cut-Off 3

Project partner

Number Name Role Country
3 Karolinska Institute Observer Sweden
3 MAPREG "The Cytoskeleton Company" Coordinator France
3 German Primate Center - Leibniz Institute for Primate Research Partner Germany