Calpain-1, not Calpain-2, has relationship with HMGB1/TLR4/NF-ΚB signalling pathway variables in multiple sclerosis.

Background: Identification of the related signalling pathways is very crucial for demyelinating diseases.

Objectives: The aim of this study was to investigate the relation between Calpain-1 (CAPN1) and Calpain-2 (CAPN2) with the HMGB1/TLR4/NF-κB signaling pathway in patients with Multiple Sclerosis (pwMS) and Neuromyelitis Optica Spectrum Disorder (pwNMOSD).

Methods: We recruited 45 newly diagnosed patients during the relapse period, comprising 36 pwMS and 9 pwNMOSD. Twenty-eight patients with pseudotumor cerebri (pwPTC) were recruited as control. CAPN1, CAPN2, HMGB1, soluble TLR4 (sTLR4), NF-κB levels were compared between the groups by ELISA technique.

Results: pwMS had higher levels of CAPN1 than those with pwNMOSD and pwPTC. Similarly, pw MS had a considerably greater level of CAPN2 than pwPTC and pwNMOSD. Between the groups, there were no variations in HMGB1, sTLR4, NF-κB, and IL-37 levels. The CAPN1 and CAPN2 levels in the pwMS showed a favorable correlation. In pwMS, CAPN1 and HMGB1 also showed a positive correlation.

Conclusions: This study proposes a valuable and novel perspective on the pathophysiology of MS, placing CAPN1 as a potentially important contributor to neuroinflammatory signalling via HMGB1. Future research should aim to validate these findings using larger, balanced cohorts and include longitudinal CSF and serum analysis. Experimental in vitro or in vivo studies investigating CAPN1 inhibition and its impact on HMGB1-related signalling are necessary to explore therapeutic implications.