Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kawasaki Medical School, Kurashiki, Japan.
J Neurochem. 2024 Sep;168(9):2690-2709. doi: 10.1111/jnc.16133. Epub 2024 May 21.
Recent studies have highlighted the potential involvement of reactive oxygen species (ROS) and microglia, a major source of ROS, in the pathophysiology of schizophrenia. In our study, we explored how the second-generation antipsychotic risperidone (RIS) affects ROS regulation and microglial activation in the hippocampus using a mouse ketamine (KET) model of schizophrenia. KET administration resulted in schizophrenia-like behaviors in male C57BL/6J mice, such as impaired prepulse inhibition (PPI) of the acoustic startle response and hyper-locomotion. These behaviors were mitigated by RIS. We found that the gene expression level of an enzyme responsible for ROS production (Nox2), which is primarily associated with activated microglia, was lower in KET/RIS-treated mice than in KET-treated mice. Conversely, the levels of antioxidant enzymes (Ho-1 and Gclc) were higher in KET/RIS-treated mice. The microglial density in the hippocampus was increased in KET-treated mice, which was counteracted by RIS. Hierarchical cluster analysis revealed three morphological subtypes of microglia. In control mice, most microglia were resting-ramified (type I, 89.7%). KET administration shifted the microglial composition to moderately ramified (type II, 44.4%) and hyper-ramified (type III, 25.0%). In KET/RIS-treated mice, type II decreased to 32.0%, while type III increased to 34.0%. An in vitro ROS assay showed that KET increased ROS production in dissociated hippocampal microglia, and this effect was mitigated by RIS. Furthermore, we discovered that a NOX2 inhibitor could counteract KET-induced behavioral deficits. These findings suggest that pharmacological inhibition of ROS production by RIS may play a crucial role in ameliorating schizophrenia-related symptoms. Moreover, modulating microglial activation to regulate ROS production has emerged as a novel avenue for developing innovative treatments for schizophrenia.
最近的研究强调了活性氧（ROS）和小胶质细胞（ROS 的主要来源）在精神分裂症病理生理学中的潜在作用。在我们的研究中，我们使用精神分裂症的小鼠氯胺酮（KET）模型探索了第二代抗精神病药利培酮（RIS）如何影响ROS 调节和小胶质细胞激活。KET 给药导致雄性 C57BL/6J 小鼠出现类似精神分裂症的行为，如听觉惊跳反应的前脉冲抑制（PPI）受损和过度活动。RIS 减轻了这些行为。我们发现，与激活的小胶质细胞主要相关的 ROS 产生酶（Nox2）的基因表达水平在 KET/RIS 治疗的小鼠中低于 KET 治疗的小鼠。相反，KET/RIS 治疗的小鼠中的抗氧化酶（Ho-1 和 Gclc）水平较高。KET 治疗的小鼠海马中小胶质细胞密度增加，RIS 可拮抗该作用。层次聚类分析显示小胶质细胞存在三种形态亚型。在对照小鼠中，大多数小胶质细胞为静止状-有棘突（I 型，89.7%）。KET 给药使小胶质细胞组成向中度有棘突（II 型，44.4%）和高度有棘突（III 型，25.0%）转变。在 KET/RIS 治疗的小鼠中，II 型下降到 32.0%，而 III 型增加到 34.0%。体外 ROS 测定表明 KET 增加了分离的海马小胶质细胞中的 ROS 产生，RIS 减轻了这种作用。此外，我们发现 NOX2 抑制剂可拮抗 KET 诱导的行为缺陷。这些发现表明，RIS 通过抑制 ROS 产生可能在改善精神分裂症相关症状方面发挥关键作用。此外，调节小胶质细胞激活以调节 ROS 产生已成为开发精神分裂症创新治疗方法的新途径。
