Université Côte D'Azur, CNRS, IPMC, UMR7275, 660 Route des Lucioles, Sophia Antipolis, 06560, Valbonne, France.
Université Côte D'Azur, CNRS, IPMC, UMR7275, 660 Route des Lucioles, Sophia Antipolis, 06560, Valbonne, France.
Neuropharmacology. 2019 Nov 1;158:107715. doi: 10.1016/j.neuropharm.2019.107715. Epub 2019 Jul 17.
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.
中风后抑郁（PSD）是中风后最常见的情绪障碍，与患者的预后和生存密切相关。TREK-1 通道是中风和抑郁发病机制中的一个关键靶点。Spadin 及其短的类似物 mini-spadin 被报道具有很强的抗抑郁作用。我们研究了 mini-spadin 在局灶性缺血和 PSD 小鼠模型中的治疗效果。为了激活 TREK-1 并诱导神经保护，在缺血发作后 30 分钟，单次给予低剂量的 mini-spadin（0.03μg/kg）腹腔内注射，在缺血后 7 天内每天一次。然后，为了抑制 TREK-1 并诱导抗抑郁作用，该肽以更高的浓度（3μg/kg）每天一次注射，每周 4 天，直到动物被处死。电生理研究表明，mini-spadin 对 TREK-1 具有双相作用。在低剂量下，通道活性增加，而在高剂量下则被抑制。Mini-spadin 防止了体重减轻和黑质多巴胺能神经元的延迟变性，并改善了运动和认知缺血引起的损伤。此外，mini-spadin 还可预防强迫游泳（FST）和新异食物抑制摄食（NSF）试验中的 PSD。最后，增强的神经发生和突触发生有助于 mini-spadin 对抗中风和 PSD 的有益作用。这项工作首次证明，TREK-1 通道在中风的早期和慢性阶段的调节以及 mini-spadin 对大脑可塑性的刺激，可能在其对抗中风及其有害后果（如 PSD）的脑保护作用中发挥关键作用。
