IMID-284: a potent pyruvate kinase M2 inhibitor with dual anti-inflammatory and analgesic effects in intervertebral disc disease.

PURPOSE

Intervertebral disc degeneration (IVDD) is a major contributor to lower back pain and disability, driven by alterations in extracellular matrix (ECM) remodelling and inflammation following chondroptosis. While the relationship between IVDD and ECM biochemical changes is well-established, the specific role of pyruvate kinase M2 (PKM2) in this process remains unexplored. This study aimed to investigate the involvement of PKM2 in a Chondroitinase ABC (ChABC)-induced model of IVDD.

METHODS

We administered three different dosages of ChABC (0.0001U, 0.00025U, and 0.0005U) in the coccygeal disc. Subsequently, the model was validated through behavioural tests (tail flick and von Frey). Additionally, a comprehensive morphological evaluation of the disc was assessed using H&E, MT, and SO-FG staining. Also, various IHC markers like Collagen-I, II, Aggrecan, and SOX-9 expressions were analyzed.

RESULTS

Administration of a 0.00025U dose of ChABC at day 28 led to a significant upregulation of PKM2, TSK, IL-1β, and cellular hypertrophy, all hallmarks of IVDD. The onset of IVDD was associated with a decrease in collagen-II, Aggrecan, and markers of chondrogenesis, contributing to increased pain, inflammation, and tissue disorganization. Notably, selective inhibition of PKM2 using IMID-284 resulted in reduced pain and inflammation, alongside a protective effect on cartilage, suggesting that PKM2 plays a pivotal role in IVDD pathophysiology.

CONCLUSION

These findings indicate that PKM2 inhibition may represent a promising therapeutic strategy for mitigating the biochemical and structural changes underlying disc degeneration. Overall, the study provides new insights into how PKM2 inhibition could arrest the progression of IVDD, pain, and inflammation.