Dihydroartemisinin Attenuated Intervertebral Disc Degeneration via Inhibiting PI3K/AKT and NF-κB Signaling Pathways

Abstract

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). However, effective therapeutic drugs for IDD remain to be further explored. Inflammatory cytokines play a pivotal role in the onset and progression of IDD. Dihydroartemisinin (DHA) has been well reported to have powerful anti-inflammatory effects, but whether DHA could ameliorate the development of IDD remained unclear. In this study, the effects of DHA on extracellular matrix (ECM) metabolism and cellular senescence were firstly investigated in nucleus pulposus cells (NPCs) under tumor necrosis factor alpha (TNFα)-induced inflammation. Meanwhile, AKT agonist sc-79 was used to determine whether DHA exerted its actions through regulating PI3K/AKT and NF-κB signaling pathways. Next, the therapeutic effects of DHA were tested in a puncture-induced rat IDD model. Finally, we detected the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens. We demonstrated that DHA ameliorated the imbalance between anabolism and catabolism of extracellular matrix and alleviated NPCs senescence induced by TNFα in vitro. Further, we illustrated that DHA mitigated the IDD progression in a puncture-induced rat model. Mechanistically, DHA inhibited the activation of PI3K/AKT and NF-κB signaling pathways induced by TNFα, which was undermined by AKT agonist sc-79. Molecular docking predicted that DHA bound to the PI3K directly. Intriguingly, we also verified the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens, suggesting that DHA may qualify itself as a promising drug for mitigating IDD.

Spatiotemporal Characterization of Human Early Intervertebral Disc Formation at Single‐Cell Resolution

“…The rat IDD model was established as described previously. [ 108 ] Briefly, the rats were anesthetized, and tail skin was sterilized. In addition, needles (21‐gauge) were adopted to puncture the IVDs to a depth of ≈5 mm, rotated 360°, and kept in the IVD for 1 min.…”

Dynamics of N6‐methyladenosine modification during aging and their potential roles in the degeneration of intervertebral disc

“…The top 20 GO and KEGG terms are listed in Figure S3C,D. Remarkably, the enriched KEGG pathways were related to the progression of aging and IDD, such as PI3K-Akt signaling pathway, 34 MAPK signaling pathway, 35 and NF-κB signaling pathway. 4,34 Besides, there were 625genes increased and 307 genes decreased in 20 M vs. 10 M (Table S6 and Figure S4A,B).…”

From hyperglycemia to intervertebral disc damage: exploring diabetic-induced disc degeneration

“…Physiotherapy also plays a vital role in relieving the symptoms of IDD. On the drug therapy aspect, opioids, steroids, and non-steroidal anti-inflammatory drugs play an important role in controlling pain and improving function and quality of life ( 28 – 30 ). While medications prove effective in managing pain and inflammation, prolonged use carries potential side effects, with opioids posing a risk of dependence.…”