Sun Piyun, Zhao Tianshu, Zhou Jinlong, Qi Huiping, Qian Guibin
Altern Ther Health Med. 2023 Oct;29(7):340-347.
Neuroinflammation after spinal cord injury (SCI) can lead to long-term damage in neural tissue, which can cause the destruction and dysfunction of the neurological system. Roflupram (ROF), a selective phosphodiesterase 4 inhibitor, may play a protective role against neuropathological diseases, but the specific role of ROF in SCI treatment is unknown.
The study intended to investigate the anti-inflammatory mechanism and therapeutic effects of ROF to determine if it can attenuate lipopolysaccharide (LPS)-induced microglia that induces neuroinflammation and decrease neural-tissue damage following an SCI.
The research team performed an animal study.
The study took place at the Fourth Affiliated Hospital of Harbin Medical University in Harbin, China.
The animals were female C57BL/6 mice, aged 8 weeks and weighing approximately 20 g.
For the in-vitro study, the research team divided BV2 microglial cells into three groups: (1) the control group, which received no LPS stimuli and no ROF treatment, (2) the LPS group, which received LPS stimuli but no ROF treatment, and (3) LPS+ROF group, which received both LPS stimuli and ROF treatment. For the in-vivo study, the research team randomly divided the mice into three groups: (1) the sham group, for which the team didn't induce SCI and which received no ROF treatment (2) the SCI group, for which the team induced SCI but which received no ROF treatment, and (3) the SCI+ROF group, for which the team induced SCI and which received the ROF treatment.
The research team evaluated: (1) the cell viability of the BV2 microglia cells after five doses of ROF and the RNA levels of inflammatory-activation-related factors, the inflammatory pathway; (2) in-vitro inhibition of inflammation in LPS-activated microglia; (3) the anti-neuroinflammatory role of ROF after SCI induction in vitro; and (4) the role of ROF in neural-structure protection and locomotor-function recovery in vitro.
In the in-vitro study, the ROF attenuated microglial inflammation through the inhibition of the NLRP3 inflammasome in vitro, reduced neuroinflammation, and protected against neuronal loss. In the in-vivo study with mice, the ROF: (1) improved the functional recovery of locomotor skills after induction of SCI; (2) acted in an anti-inflammatory role in SCI, restraining microglial inflammation by inhibition of the "nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3" (NLRP3) inflammasome and reduction of caspase-1-dependent, interleukin-1 beta (IL)-1β; and (3) reduced neuronal death and protected against tissue loss, improving functional recovery after an SCI.
The current study demonstrated that ROF can reduce the levels of inflammation in the tissue after spinal cord injury by modulating the AMPK/NLRP3 signaling pathway, thereby promoting the recovery of motor function in mice. ROF is a promising drug for prevention of neural-tissue damage following neural injury.
脊髓损伤（SCI）后的神经炎症可导致神经组织的长期损伤，进而引起神经系统的破坏和功能障碍。罗氟司特（ROF）是一种选择性磷酸二酯酶4抑制剂，可能对神经病理性疾病起到保护作用，但ROF在SCI治疗中的具体作用尚不清楚。
本研究旨在探讨ROF的抗炎机制和治疗效果，以确定其是否能减轻脂多糖（LPS）诱导的小胶质细胞活化所引发的神经炎症，并减少SCI后的神经组织损伤。
研究团队进行了一项动物研究。
研究在中国哈尔滨的哈尔滨医科大学附属第四医院进行。
实验动物为8周龄、体重约20 g的雌性C57BL/6小鼠。
在体外研究中，研究团队将BV2小胶质细胞分为三组：（1）对照组，未接受LPS刺激和ROF治疗；（2）LPS组，接受LPS刺激但未接受ROF治疗；（3）LPS + ROF组，接受LPS刺激和ROF治疗。在体内研究中，研究团队将小鼠随机分为三组：（1）假手术组，未诱导SCI且未接受ROF治疗；（2）SCI组，诱导SCI但未接受ROF治疗；（3）SCI + ROF组，诱导SCI并接受ROF治疗。
研究团队评估了：（1）五剂ROF后BV2小胶质细胞的细胞活力以及炎症激活相关因子的RNA水平、炎症信号通路；（2）对LPS激活的小胶质细胞的体外炎症抑制作用；（3）SCI诱导后ROF在体外的抗神经炎症作用；（4）ROF在体外对神经结构保护和运动功能恢复的作用。
在体外研究中，ROF通过体外抑制NLRP3炎性小体减轻小胶质细胞炎症，减少神经炎症，并防止神经元丢失。在小鼠体内研究中，ROF：（1）改善了SCI诱导后运动技能的功能恢复；（2）在SCI中发挥抗炎作用，通过抑制“核苷酸结合结构域、富含亮氨酸重复序列家族、含pyrin结构域3”（NLRP3）炎性小体和减少半胱天冬酶-1依赖性白细胞介素-1β（IL）-1β来抑制小胶质细胞炎症；（3）减少神经元死亡并防止组织丢失，改善SCI后的功能恢复。
当前研究表明，ROF可通过调节AMPK/NLRP3信号通路降低脊髓损伤后组织中的炎症水平，从而促进小鼠运动功能的恢复。ROF是一种有潜力预防神经损伤后神经组织损伤的药物。
