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Depression is a disease that is particularly frequent, affecting up to 20% of the population in Western countries. The origins of this pathology involve multiple genes as well as environmental and developmental factors leading to a disorder that remains difficult to treat. Several therapies for depression have been developed and these mainly target monoamine neurotransmitters. However, these treatments are not only associated with numerous adverse effects, but they are also ineffective for more than one-third of patients. Therefore, the need to develop new concepts to treat depression is crucial. Recently, studies using knockout mouse models have provided evidence for a crucial role of two members of the two-pore domain potassium channel (K2P ) family, tandem P-domain weak inward rectifying K(+) (TWIK)-related K(+) channel 1 (TREK-1) and TWIK-related acid-sensitive K(+) channel 3 (TASK-3) in the pathophysiology of depression. It is believed that TREK-1 and TASK-3 antagonists could lead to the development of new antidepressants. Herein, we describe the discovery of spadin, a natural peptide released from the maturation of the neurotensin receptor-3 (also known as sortilin), which specifically blocks the activity of the TREK-1 channel and displays particular antidepressant properties, with a rapid onset of action and the absence of adverse effects. The development of such molecules may open a new era in the field of psychiatry.

International audience; ÐMany models of induced ischemic and epileptic tolerance have now been described in the brain. Although detailed mechanisms underlying such protections still remain largely unknown, induction of heat shock proteins is amongst the endogenous responses believed to play an important role in cellular defense mechanisms. This study reveals that the development of epileptic tolerance also coincides with the induction of the 70,000 mol. wt heat shock protein expression within the time window of protection. Adenosine agonists or ATP-sensitive potassium channel openers have also been shown to exert strong neuroprotective effects when injected shortly prior to a severe ischemic or epileptic insult. The present work shows that adenosine receptor activation and ATP-sensitive potassium channel opening induce 70,000 mol. wt heat shock protein expression in the rat hippocampus and are able to mimic neuroprotection driven by preconditioning. R-phenylisopropyladenosine, a purine agonist, or (2)cromakalim, an ATP-sensitive potassium channel opener, was administered three days prior to a lethal ischemic or epileptic episode to mimic preconditioning. Neurodegeneration was assessed using Cresyl Violet staining and cellular DNA fragmentation visualized by the terminal deoxynucleotidyl transferase-mediated 2 H-deoxyuridine 5 H-triphosphate±biotin nick end labeling method. 70,000 mol. wt heat shock protein expression was analysed by western blotting and immunohistochemistry. The results show a long-lasting neuroprotection induced by activation of adenosine receptors or ATP-sensitive K 1 channels as early as three days prior to induction of a severe ischemic or epileptic challenge. This protective effect is associated with enhanced 70,000 mol. wt heat shock protein expression also occurring three days following administration of R-phenylisopropyladenosine or (2)cromakalim. These ®ndings support the idea that preconditioning doses of R-phenylisopropyladenosine and (2)cromakalim act as mild cellular stresses inducing neuroprotection in a manner similar to a mild kainate treatment prior to a lethal ischemic or severe epileptic insult three days later. They also suggest that a delayed 70,000 mol. wt heat shock protein expression induced by excitatory neuronal stresses such as short ischemia, mild kainic acid treatment or activation of adenosine receptors and ATPsensitive potassium channels is predictive of neuronal survival against a subsequent lethal injury.

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