First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides.

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.