Department of Geriatrics, Shanghai 4th People's Hospital, Tongji University, No.1279 Sanmen Road, Shanghai, 200081, China.
Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
J Mol Neurosci. 2024 Aug 19;74(3):78. doi: 10.1007/s12031-024-02254-y.
Constipation is a common symptom in patients with Parkinson's disease (PD) and is often associated with depression. Enteric glial cells (EGCs) are crucial for regulating intestinal inflammation and colon motility, and their activation can lead to the death of intestinal neurons. Glial cell line-derived neurotrophic factor (GDNF) has been recognized for its neuroprotective properties in various neurological disorders, including PD. This study explores the potential of GDNF in alleviating intestinal reactive gliosis and inflammation, thereby improving constipation and depressive behavior in a rat model of PD. A PD model was established via unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA). Five weeks post-injury, AAV5-GDNF (2 ~ 5 × 10) was intraperitoneally injected into experimental and control rats. Fecal moisture percentage (FMP) and colonic propulsion rate (CPPR) were used to evaluate colon motility. Colon-related inflammation and colonic epithelial morphology were assessed, and depressive behavior was analyzed one week before sampling. PD rats exhibited reduced colonic motility and GDNF expression, along with increased EGC reactivity and elevated levels of pro-inflammatory cytokines IL-1, IL-6, and TNF-α. Additionally, there was an up-regulation of CX43 and a decrease in PGP 9.5 expression. The intraperitoneal injection of AAV-GDNF significantly protected colonic neurons by inhibiting EGC activation and down-regulating CX43. This treatment also led to a notable reduction in depressive-like symptoms in PD rats with constipation. GDNF effectively reduces markers of reactive gliosis and inflammation, and promotes the survival of colonic neurons, and improves colonic motility in PD rats by regulating CX43 activity. Furthermore, GDNF treatment alleviates depressive behavior, suggesting that GDNF or its agonists could be promising therapeutic agents for managing gastrointestinal and neuropsychiatric symptoms associated with PD.
便秘是帕金森病（PD）患者的常见症状，常伴有抑郁。肠胶质细胞（EGCs）对于调节肠道炎症和结肠动力至关重要，其激活可导致肠神经元死亡。胶质细胞源性神经营养因子（GDNF）已被认为在包括 PD 在内的各种神经退行性疾病中有神经保护作用。本研究探讨了 GDNF 缓解 PD 大鼠模型中肠道反应性神经胶质增生和炎症，从而改善便秘和抑郁行为的潜力。通过单侧立体定向注射 6-羟多巴胺（6-OHDA）建立 PD 模型。损伤后 5 周，将 AAV5-GDNF（2~5×10）腹膜内注射到实验组和对照组大鼠中。使用粪便水分百分比（FMP）和结肠推进率（CPPR）评估结肠动力。评估结肠相关炎症和结肠上皮形态，并在取样前一周分析抑郁行为。PD 大鼠表现出结肠动力降低和 GDNF 表达减少，同时 EGC 反应性增加，促炎细胞因子 IL-1、IL-6 和 TNF-α水平升高。此外，CX43 上调，PGP 9.5 表达减少。AAV-GDNF 腹腔注射通过抑制 EGC 激活和下调 CX43，显著保护结肠神经元。这种治疗还导致 PD 伴便秘大鼠抑郁样症状明显减轻。GDNF 可有效降低反应性神经胶质增生和炎症标志物的表达，促进结肠神经元的存活，通过调节 CX43 活性改善 PD 大鼠的结肠动力。此外，GDNF 治疗可减轻抑郁行为，提示 GDNF 或其激动剂可能是治疗与 PD 相关的胃肠道和神经精神症状的有前途的治疗剂。
