Background and Aims: Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system generating symptoms such as neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) were oxidated compounds and their accumulation in plasma has been related to MS patient's clinical disability. However, the AOPPs involvement in the neuropathic pain- and anxiety-like symptoms it was not evaluated. We aimed to explore the central nervous system levels of AOPPs as a possible biomarker that can be used in MS neuropathic pain treatment or disease severity. 

Methods: We used female mice C57BL/6J to induce experimental autoimmune encephalomyelitis (EAE). The animals were evaluated for the clinical score, weight, strength of plantar pressure, rotarod test, and mechanical and cold allodynia before induction (baseline) and on days 7, 10, and 14. Also, on the 13 days post-induction evaluated nest building, open field and elevated plus maze tests. The animals were euthanized 14-day post-induction and the prefrontal cortex and spinal cord were removed to measure the levels of AOPPs and the activity of NADPH oxidase and myeloperoxidase (MPO) enzymes. We used a Principal Component Analysis (PCA) to estimate the potential multivariate correlation between PMS-EAE symptoms, AOPPs levels, and NADPH oxidase and MPO activity.

Results: The clinical score increased 14 days post-induction without changes in weight and mobility. The paw strength and the mechanical allodynia threshold decrease, and cold allodynia increases in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior without motor impairment. The PC1 (54.80%of the total variance) was positively associated with AOPP levels (all structures). clinical score, cold allodynia, NADPH activity (spinal cord and prefrontal cortex). and MPO activity (all structures). Statistical analyses showed that the PC1 score is increased in PMS-EAE mice compared to the control.

Conclusions: We showed the increase of AOPPs concentration and the NADPH oxidase and MPO activity in central nervous system structures at the nociceptive peak. We indicated that the AOPP levels influence the increase in clinical score and cold allodynia. In fact. the block of NADPH oxidase or MPO activity possibly influences the PMS-EAE clinical score and cold allodynia due to AOPPs reduction. Thus, we demonstrated the relationship between non-stimuli painful perception, anxiety-like, and hippocampal function in the PMS-EAE model.