First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides. (1st November 2019)

• Record Type: Journal Article
• Authors: Pietri, Mariel; Djillani, Alaeddine; Mazella, Jean; Borsotto, Marc; Heurteaux, Catherine
• Is Part Of: Neuropharmacology. Volume 158(2019)
• Publication Date: 2019-11-01
• Subjects: Post-stroke depression -- Mini-spadin -- Stroke -- TREK-1 channel -- Antidepressant; AA Arachidonic Acid -- AD Antidepressant -- BDNF Brain-Derived Neurotrophic Factor -- BrdU Bromodeoxyuridine -- CBF Cerebral Blood Flow -- CREB cAMP Response Element-Binding protein -- DRN Dorsal Raphe Nucleus -- FST Forced Swim test -- MAPK Mitogen-Activated Protein Kinase -- MCAO Middle Cerebral Artery Occlusion -- MDD Major Depressive Disorder -- MWM Morris Water Maze -- NSF Novelty Suppressed Feeding -- PI3K Phosphoinositide 3 Kinase -- PSD post-stroke depression -- PSD-95 Post-Synaptic Density protein of 95 kDa -- SSRI Selective Serotonin Reuptake Inhibitor -- TH Tyrosine Hydroxylase -- TREK-1 TWIK-related-potassium channel;type 1; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107715
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Post-stroke depression (PSD) is the most common mood disorder following stroke with high relevance for outcome and survival of patients. The TREK-1 channel represents a crucial target in the pathogenesis of stroke and depression. Spadin and its short analog mini-spadin were reported to display potent antidepressant properties. We investigated the therapeutic effects of mini-spadin in a mouse model of focal ischemia and PSD. To activate TREK-1 and induce neuroprotection a single low dose of mini-spadin (0.03 μg/kg) was intraperitoneally injected 30 min after the onset of ischemia, once a day during 7 days post-ischemia. Then, to inhibit TREK-1 and induce antidepressant effect, the peptide was injected at higher concentration (3 μg/kg) once a day for 4 days/week until the sacrifice of animals. Electrophysiological studies showed that mini-spadin had a biphasic action on TREK-1. At low doses, the channel activity was increased whereas at higher doses it was inhibited. Mini-spadin prevented the loss of body weight and the delayed dopaminergic degeneration in substantia nigra and improved the motor and cognitive ischemia-induced deficits. Moreover, mini-spadin prevented PSD analyzed in the Forced Swim (FST) and Novelty Suppressed Feeding (NSF) tests. Finally, enhanced neurogenesis and synaptogenesis contributed to the beneficial effects of mini-spadin against stroke and PSD. This work reveals the first evidence that the modulation of TREK-1 channels in the early and chronic phases of stroke as well as the stimulation of brain plasticity by mini-spadin could play a key role in its brain protective effects against stroke and its deleterious consequences such as PSD. Graphical abstract: Image 1 Highlights: TREK-1 activity was increased at low doses of mini-spadin and inhibited at higher doses. Low doses of mini-spadin improved the motor and cognitive ischemia-induced deficits. Mini-spadin prevented the loss of body weight and the dopaminergic degeneration. Mini-spadin enhanced neurogenesis and synaptogenesis. Mini-spadin displays beneficial effects against stroke and PSD.