Department of Spine Surgery, Wuhan Fourth Hospital, Hanzheng Street, 473#, QiaoKou District, Wuhan, 430033, China.
Eur J Med Res. 2024 Aug 27;29(1):433. doi: 10.1186/s40001-024-02028-7.
Reduction of inflammatory damage and inhibition of nucleus pulposus (NP) apoptosis are considered to be the main effective therapy idea to reverse the intervertebral disc degeneration (IDD) and alleviate the chronic low back pain. The adenosine A2A receptor (A2AR), as a member of G protein-coupled receptor families, plays an important role in the anti-inflammation and relieving pain. So far, the impact of A2AR on IDD therapy is unclear. The aim of this study was to explore the role of Adenosine A receptor (AR) in the intervertebral disc degeneration (IDD) and clarify potential mechanism.
IL-1β and acupuncture was used to establish IDD model rats. AR agonist CGS-21680 and AR antagonist SCH442416 were used to investigate the therapeutical effects for IDD. Histological examination, western blotting analysis and RT-PCR were employed to evaluate the the association between AR and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway.
AR activity of the intervertebral disc tissues was up-regulated in feedback way, and cAMP, PKA and CREB expression were also increased. But in general, IL-1β-induced IDD promoted the significant up-regulation the expression of inflammatory factors. The nucleus pulposus (NP) inflammation was exacerbated in result of MMP3 and Col-II decline through activating NF-κB signaling pathway. AR agonist CGS-21680 exhibited a disc protective effect through significantly increasing AR activity, then further activated cAMP/PKA signaling pathway with attenuating the release of TNF-α and IL-6 via down-regulating NF-κB. In contrast, SCH442416 inhibited AR activation, consistent with lower expression levels of cAMP and PKA, further leading to the acceleration of IDD.
The activation of AR can prevent inflammatory responses and mitigates degradation of IDD thus suggest a potential novel therapeutic strategy of IDD.
减轻炎症损伤和抑制髓核细胞凋亡被认为是逆转椎间盘退变（IDD）和缓解慢性下腰痛的主要有效治疗思路。作为 G 蛋白偶联受体家族的一员，腺苷 A2A 受体（A2AR）在抗炎和缓解疼痛中发挥着重要作用。到目前为止，A2AR 对 IDD 治疗的影响尚不清楚。本研究旨在探讨 A 受体（AR）在椎间盘退变（IDD）中的作用，并阐明其潜在机制。
采用白细胞介素 1β（IL-1β）和针刺建立 IDD 模型大鼠。采用 AR 激动剂 CGS-21680 和 AR 拮抗剂 SCH442416 探讨其对 IDD 的治疗作用。采用组织学检查、Western blot 分析和 RT-PCR 评价 AR 与环磷酸腺苷（cAMP）/蛋白激酶 A（PKA）通路之间的关系。
椎间盘组织中 AR 活性呈反馈性上调，cAMP、PKA 和 CREB 表达也增加。但总体而言，IL-1β诱导的 IDD 促进了炎症因子的显著上调表达。核基质蛋白（MMP3）和Ⅱ型胶原（Col-II）的减少通过激活 NF-κB 信号通路，加剧了 NP 炎症。AR 激动剂 CGS-21680 通过显著增加 AR 活性，进而通过下调 NF-κB 进一步激活 cAMP/PKA 信号通路，减轻 TNF-α和 IL-6 的释放，表现出明显的椎间盘保护作用。相反，SCH442416 抑制 AR 激活，与 cAMP 和 PKA 的表达水平降低一致，进一步导致 IDD 加速。
AR 的激活可以防止炎症反应，减轻 IDD 的降解，从而为 IDD 提供了一种新的潜在治疗策略。
