Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil.
Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/ Aggeu Magalhães Institute (IAM), Recife, PE, Brazil.
J Neuroimmune Pharmacol. 2024 Aug 19;19(1):45. doi: 10.1007/s11481-024-10148-4.
Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.
多发性硬化症 (MS) 是一种严重影响中枢神经系统 (CNS) 的致残性疾病。除了神经症状外，它还具有神经精神共病，如焦虑和抑郁。磷酸二酯酶-5 抑制剂 (PDE5Is) 如西地那非和他达拉非已被证明具有抗抑郁样作用，但支持这种作用的机制尚未完全阐明。为了解决这个问题，我们使用了多发性硬化症的 EAE 模型、行为测试、免疫荧光、免疫组织化学、western blot 和 16S rRNA 测序。在这里，我们表明 EAE 小鼠的抑郁样行为是由于神经炎症、突触可塑性降低、谷氨酸能神经传递功能障碍、糖皮质激素受体 (GR) 抵抗、血脑屏障 (BBB) 通透性增加、免疫细胞浸润中枢神经系统以及炎症、肠道通透性增加和远端结肠的免疫细胞浸润。此外，16S rRNA 测序显示，EAE 小鼠的行为功能障碍与肠道微生物群的变化有关，例如厚壁菌门和 saccharibacteria 的丰度增加，变形菌门、拟杆菌属和脱硫弧菌的丰度减少。此外，我们检测到肠杆菌科和脱硫弧菌科的丰度增加，而约翰逊乳杆菌的丰度降低。令人惊讶的是，我们表明他达拉非可能通过针对所有上述疾病方面发挥抗抑郁样作用。总之，我们的工作表明，EAE 中的焦虑和抑郁样行为与大量神经免疫和肠道微生物群介导的机制有关，而他达拉非发挥抗抑郁样作用可能是通过针对这些机制。利用他达拉非的这些作用机制的知识对于为患有抑郁症的患者进行未来的临床试验铺平道路非常重要。
