Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Av. Moraes Rego s/n, Recife CEP, PE, 50670-420, Brazil.
Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil.
J Neuroimmune Pharmacol. 2024 Jul 23;19(1):36. doi: 10.1007/s11481-024-10142-w.
Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.
新的研究表明，代谢紊乱，如糖尿病和肥胖症，作为精神疾病的风险因素起着重要作用。这种联系为创造新型抗抑郁药物提供了一个潜在的途径，即重新利用最初开发用于治疗糖尿病的药物。早期的研究表明，GLP-1（胰高血糖素样肽-1）类似物在各种神经疾病模型中表现出神经保护特性，包括阿尔茨海默病、帕金森病和中风等疾病。此外，GLP-1 类似物已被证明能够增强神经发生，这一过程对于记忆形成以及信息处理的认知和情感方面都具有重要意义。然而，司美格鲁肽是否作为抗抑郁药和抗焦虑药有效仍不确定。为了解决这个问题，我们的研究集中在一种与 2 型糖尿病相关的抑郁小鼠模型上，该模型由高脂肪饮食（HFD）诱导。在该模型中，我们每周腹膜内注射司美格鲁肽（0.05mg/kg），以评估其作为抗抑郁和抗焦虑治疗选择的潜力。糖尿病小鼠的血糖、血脂谱和胰岛素抵抗更高。此外，喂食 HFD 的小鼠表现出更高的血清白细胞介素（IL）-1β和脂多糖（LPS）水平，与情绪和认知受损有关。行为反应分析表明，司美格鲁肽的给药有效减轻了抑郁和焦虑样行为，同时增强了认知功能。此外，司美格鲁肽治疗还保护了突触可塑性，并逆转了 HFD 喂养引起的海马神经炎症，改善了胰岛素通路的激活，显示了司美格鲁肽的保护作用。我们还发现，司美格鲁肽治疗减少了海马齿状回区的星形胶质细胞和小胶质细胞增生。此外，司美格鲁肽预防了 2 型糖尿病引起的 pro-opiomelanocortin（POMC）和 G 蛋白偶联受体 43（GPR43）的损伤，同时增加了海马中的 NeuN+和胰高血糖素样肽-1 受体（GLP-1R+）神经元。我们的数据还表明，司美格鲁肽增加了海马中的 5-羟色胺（5-HT）和 5-羟色胺转运体（5-HTT）和谷氨酸能受体。最后，司美格鲁肽改变了肠道微生物群的组成（增加了拟杆菌、嗜酸双歧杆菌和布劳特氏菌），减少了肠漏，改善了肠-脑轴。总之，司美格鲁肽有可能成为治疗抑郁和焦虑的治疗工具。
