Abstract
Intervertebral disc (IVD) degeneration (IDD) is a major cause of low back pain. The pathogenesis of IDD is associated with the disturbance of reactive oxygen species (ROS) equilibrium, inflammation, and matrix loss. Aspirin is a nonsteroidal anti-inflammatory drug that effectively inhibits inflammation and oxidative stress and has been widely used for the treatment of back pain. Therefore, we hypothesize that aspirin reverses the IDD process via antioxidative and anti-inflammatory effects on the AMPK signaling pathway. In vitro, aspirin diminished cellular oxygen free radicals (ROS, nitric oxide (NO)) and inflammatory cytokines (interleukin- (IL-) 1β and IL-6 and tumor necrosis factor alpha (TNF-α)) induced by lipopolysaccharides (LPS) in nucleus pulposus cells (NPCs). We found that aspirin preserved the extracellular matrix (ECM) content of collagen type II (COL2) and aggrecan while inhibiting the expression of matrix-degenerating enzymes, including matrix metalloproteinase 3 and 13 (MMP-3 and MMP-13) and A disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4, ADAMTS-5). Aspirin significantly promoted the ratios of p-AMPK to AMPK and p-ACC to ACC expression in NPCs. Furthermore, pretreatment with the AMPK inhibitor compound C abrogated the antioxidant effects of aspirin. In vivo, an IDD model was established in Sprague-Dawley rats via percutaneous disc puncture with the 20-gauge needle on levels 8-9 and 9-10 of the coccygeal vertebrae. Imaging assessment showed that after aspirin treatment, improvements in disc height index (DHI) ranged from 1.22-fold to 1.54-fold and nucleus pulposus signal strength improved from 1.26-fold to 1.33-fold. Histological analysis showed that aspirin treatment prevented the loss of COL2 and decreased MMP-3 and MMP-13, inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), IL-1β, and TNF-α expression in the IVD tissues. These results suggest that treatment with aspirin could reverse the IDD process via the AMPK signaling pathway, which provides new insights into the potential clinical applications of aspirin, particularly for IDD treatment.
Highlights
In the past few decades, the prevalence of degenerative disc diseases has increased, and low back pain is a major health problem [1, 2]
Some investigators have found that multiple pathological changes can Oxidative Medicine and Cellular Longevity enhance the levels of inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα)
aminoimidazole-4-carboxamide ribonucleotide (AICAR) plays a protective role against antioxidative stress by activating the AMPK signaling pathway. These findings indicate that aspirin attenuates LPS-induced oxidative stress and ameliorates nucleus pulposus cells (NPCs) dysfunction by activating the AMPK pathway
Summary
In the past few decades, the prevalence of degenerative disc diseases has increased, and low back pain is a major health problem [1, 2]. Some investigators have found that multiple pathological changes can Oxidative Medicine and Cellular Longevity enhance the levels of inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα). These cytokines can increase the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4, ADAMTS-5) and matrix metalloproteinase 3 and 13 (MMP-3, MMP-13) and promote aggrecan degradation [8, 9]. The IDD tissue contains many inflammatory cells which secrete TNF-α, IL-1β, and other cytokines found in the tissue at the injury site [10]. The expression of inflammatory cytokines is associated with degeneration but is considered as its cause
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