Emergence of New Concept On Depression – ENCOD

The strengths of this project to ameliorate the properties of spadin come from the complementarity of technical approaches from the biochemical aspect to the behaviour of animals. Results will be validated both at the molecular and at the physiological levels. In aprticular, for a given peptide, bioavailability and antidepressant properties could be characterized by the complementarity of both laboratories involved in this project. Characterization of formulations which could lead to a chronic treatment will be also performed by both teams.

The main result is that spadin can act as a potent antidepressant without important side effects both in the brain and in the peripheral tissues. The other important achievement is that the peptide can be quantified in human blood leading to the possibility to correlate its level in the blood to a depressive state. Finally, we developed a new method of sub-cutaneous injection of spadin or of its derivatives which allows to release the peptide for two to three weeks.

The four tasks proposed in the project including dosing, formulation, bioavailability and side effects, are either achieved or close to validation. Firther works will be to prepare and characterize new spadin analogue formulations in order to be able to tests them for adverse effects (mutagenicity, toxicity, etc..), controls that are necessary before phase I clinical trials.

An article describing the absence of secondary effects of spadin has been published (Moha ou Maati et al, Neuropharmacol, 2012; 62(1):278-88). A patent describing the use of spadin for diagnosis has been submitted (Mazella et al, US Patent, #61/475,08.).

The aim of the project is the improvement of the treatment of psychiatric diseases, in particular the depression. Depression is a frequent disease than can reach to 20% of the population in the industrial countries. The origins of this pathology are various and numerous as well as the medical treatments, however, mechanisms of action of the drugs used are not clearly established. This project could lead to the development of a new type of anti-depressant from the results obtained about the action of the propeptide released from the maturation of the neurotensin receptor-3 on the activity of the potassium channel TREK-1. Indeed, an antagonist of this channel can be a potent anti-depressant. This propeptide is able to block TREK-1 activated by arachidonic acid, its antidepressant activity has been confirmed using different behavioral tests in mice.
The first objective of the project is to measure the expression of the propeptide in the blood of depressive patients in order to correlate its level to the depression behavior and then to use it as a pathological marker. The second goal of the project is to develop a method to deliver the peptide for a chronic treatment. This delivery system will allow to reduce the frequency of administration and then to improve therapeutic efficiencies. We will also try to identify the proteolytic sites of the propeptide to design new pseudo-peptidic analogues that are more bioavailable, these new molecules will be tested in behavioral experiments as already performed with the propeptide. Finally, both central and peripheral side effects of the propeptide will be evaluated to ensure its use as therapeutic tool.