Huang Jin, Tang Dang, Cao Yiqiang, Wang Yonggang, Long Jiang, Wei Lin, Song Hai
Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
Department of Ultrasound, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
Evid Based Complement Alternat Med. 2022 Apr 12;2022:3311250. doi: 10.1155/2022/3311250. eCollection 2022.
Phosphodiesterase 10A (PDE10A) is a dual-substrate phosphodiesterase that is highly expressed in the striatal complex. PDE10A is an important target for the treatment of ganglion dysfunction and neuroinflammation-related diseases, but its possible impact on traumatic brain injury (TBI) is still unclear. This study aims to investigate the protective effects of inhibiting PDE10A on neuroinflammation post-TBI injury and its possible molecular mechanism. The expression of PDE10A in rats and HT22 cells was determined by Western blotting. The neurological dysfunction of these rats was detected by Nissl staining, hematoxylin-eosin (HE) staining, and Morris water maze test. The activity of HT22 cells was measured by MTT. The findings of this study suggest that PDE10A is highly expressed in the brain tissue of TBI rats and HT22 cells induced by mechanical injury. Inhibition of PDE10A reduces the expression of interleukin-1 (IL-1) and interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-) in HT22 cells induced by mechanical injury to inhibit cell apoptosis. Simultaneously, inhibition of PDE10A in TBI rats reduces the time to find a visible platform in the same pool, while cAMP/PKA activator treatment alleviates all of the abovementioned phenomena. Additionally, it is further confirmed that inhibition of PDE10A activates the cAMP/PKA pathway and downregulates the expression of NRLP3. These findings demonstrate that inhibition of PDE10A exerts neuroprotection by inhibiting apoptosis and inflammation following TBI, at least partially by the cAMP/PKA/NLRP3 pathway.
磷酸二酯酶10A（PDE10A）是一种双底物磷酸二酯酶，在纹状体复合体中高度表达。PDE10A是治疗神经节功能障碍和神经炎症相关疾病的重要靶点，但其对创伤性脑损伤（TBI）的可能影响仍不清楚。本研究旨在探讨抑制PDE10A对TBI损伤后神经炎症的保护作用及其可能的分子机制。通过蛋白质免疫印迹法测定大鼠和HT22细胞中PDE10A的表达。通过尼氏染色、苏木精-伊红（HE）染色和莫里斯水迷宫试验检测这些大鼠的神经功能障碍。用MTT法检测HT22细胞的活性。本研究结果表明，PDE10A在TBI大鼠脑组织和机械损伤诱导的HT22细胞中高表达。抑制PDE10A可降低机械损伤诱导的HT22细胞中白细胞介素-1（IL-1）、白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-）的表达，以抑制细胞凋亡。同时，抑制TBI大鼠中的PDE10A可缩短在同一水池中找到可见平台的时间，而cAMP/PKA激活剂处理可缓解上述所有现象。此外，进一步证实抑制PDE10A可激活cAMP/PKA途径并下调NRLP3的表达。这些发现表明，抑制PDE10A通过抑制TBI后的细胞凋亡和炎症发挥神经保护作用，至少部分是通过cAMP/PKA/NLRP3途径实现的。
