title: Spadin as a new antidepressant: absence of TREK-1-related side effects.
abstract: Despite several decades of research, current antidepressant (AD) treatments remain of a limited efficacy justifying the need to find new drugs. These drugs have to be more efficacious, more rapid and display lesser side effects. Using rodent models, we recently identified spadin as a new antidepressant molecule that acts more quickly than classical ADs, working within 4 days to get same effects obtained with other ADs after 21 days. Spadin blocks TREK-1 K(2P) potassium channels that are considered as new targets for ADs. Deletion of the TREK-1 channel is known to increase sensitivity to pain, seizures and ischemia. Thus blocking these channels could result in deleterious side effects. In this study we showed that spadin did not interfere with other TREK-1 controlled functions such as pain, epilepsy and ischemia. We also demonstrated that spadin was unable to inhibit currents generated by TREK-2, TRAAK, TASK and TRESK four other K2P channels. More importantly, spadin did not induce cardiac dysfunctions, did not block I(Kr) and I(Ks) and did not modify the systolic pressure or cardiac pulses. After a three week treatment spadin remained an efficacious AD and did not modify the infarct size in brain following focal ischemia. Finally, we showed that kainate induced seizures and glycemia were not modified by spadin treatments. These data, together with those previously published reinforce the idea that spadin represents a good candidate for a new generation of ADs. This article is part of a Special Issue entitled 'Anxiety and Depression'.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS, UMR6097), Université de Nice Sophia Antipolis, 660 Route des Lucioles, 06560 Valbonne, France.
authors.forename: H
authors.initials: H
authors.lastname: Moha Ou Maati
authors.forename: J
authors.initials: J
authors.lastname: Veyssiere
authors.forename: F
authors.initials: F
authors.lastname: Labbal
authors.forename: T
authors.initials: T
authors.lastname: Coppola
authors.forename: C
authors.initials: C
authors.lastname: Gandin
authors.forename: C
authors.initials: C
authors.lastname: Widmann
authors.forename: J
authors.initials: J
authors.lastname: Mazella
authors.forename: C
authors.initials: C
authors.lastname: Heurteaux
authors.forename: M
authors.initials: M
authors.lastname: Borsotto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D001786:Blood Glucose / Q000187:drug effects; D020520:Brain Infarction; D016827:CD8 Antigens / Q000235:genetics; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D003292:Convulsants / Q000633:toxicity; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004558:Electric Stimulation; D049452:Green Fluorescent Proteins / Q000235:genetics; D019417:Hindlimb Suspension; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007608:Kainic Acid / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000235:genetics / Q000503:physiopathology; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000633:toxicity; D010455:Peptides / Q000627:therapeutic use*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013550:Swimming / Q000523:psychology; D014162:Transfection
chemical_list: D000928:Antidepressive Agents; D001786:Blood Glucose; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D003292:Convulsants; D010455:Peptides; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C485184:enhanced green fluorescent protein; C103742:potassium channel protein TREK-1; C551795:spadin peptide; D049452:Green Fluorescent Proteins; D007608:Kainic Acid; D010433:Pentylenetetrazole