Gök Dağıdır Hale, Bukan Neslihan, Bahcelioglu Meltem, Çalıkuşu Ayşen, Alim Ece, Dizakar Saadet Özen, Topa Elif, Bolay Hayrunnisa
Department of Medical Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey.
Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Turkey.
FEBS Open Bio. 2025 Jan;15(1):69-80. doi: 10.1002/2211-5463.13889. Epub 2024 Oct 14.
Autism is a neurodevelopmental disorder with limited treatment alternatives and which incidence is increasing. Some research suggests that vagus nerve simulation might lead to the reduction of certain symptom. Therefore, we aimed to examine the effect of bilateral transcutaneous auricular vagus nerve stimulation (tVNS) on the inflammatory response in an adult valproic acid (VPA) induced mouse (C57BL6) model of autism for the first time. The autism model was induced by oral VPA administration (600 mg·kg) to C57BL/6 pregnant mice on E12.5 days. The study included three groups: the VPA Transcutaneous Auricular Stimulation Group (VPA + tVNS), the VPA Control Group (VPA + sham), and the Healthy Control Group (Control + sham). Each group included 16 mice (8 M/8 F). Our results show that serum IL-1β and IL-6 levels were significantly higher in male VPA-exposed mice than controls. However, IL-1β was significantly lower, and IL-6, TNF- α, and IL-22 were not different in female VPA-exposed mice compared to the control group. Brain NLRP3 levels were significantly higher in both sexes in the VPA autism model (P < 0.05). tVNS application increased brain NLRP3 levels in both sexes and reduced serum IL-1β levels in male mice. We conclude that cytokine dysregulation is associated with the VPA-induced adult autism model, and the inflammatory response is more pronounced in male mice. tVNS application altered the inflammatory response and increased brain NLPR3 levels in both sexes. Further studies are needed to understand the beneficial or detrimental role of the inflammatory response in autism and its sexual dimorphism.
自闭症是一种神经发育障碍，治疗选择有限且发病率不断上升。一些研究表明，迷走神经刺激可能会导致某些症状的减轻。因此，我们首次旨在研究双侧经皮耳迷走神经刺激（tVNS）对成年丙戊酸（VPA）诱导的自闭症小鼠（C57BL6）模型炎症反应的影响。自闭症模型是通过在E12.5天给C57BL/6怀孕小鼠口服VPA（600mg·kg）诱导的。该研究包括三组：VPA经皮耳刺激组（VPA + tVNS）、VPA对照组（VPA + 假刺激）和健康对照组（对照组 + 假刺激）。每组包括16只小鼠（8只雄性/8只雌性）。我们的结果表明，暴露于VPA的雄性小鼠血清IL-1β和IL-6水平显著高于对照组。然而，与对照组相比，暴露于VPA的雌性小鼠IL-1β显著降低，而IL-6、TNF-α和IL-22没有差异。在VPA自闭症模型中，两性的脑NLRP3水平均显著升高（P < 0.05）。应用tVNS增加了两性的脑NLRP3水平，并降低了雄性小鼠的血清IL-1β水平。我们得出结论，细胞因子失调与VPA诱导的成年自闭症模型有关，并且炎症反应在雄性小鼠中更明显。应用tVNS改变了炎症反应并增加了两性的脑NLPR3水平。需要进一步研究以了解炎症反应在自闭症及其性别差异中的有益或有害作用。
