Whitaker J, Coward L, Kirk M, Goodwin J, Jackson P and Cao L, Departments of
Neurology, Pharmacology, and Chemistry, University of Alabama at Birmingham,
and the Birmingham Veterans Medical Center, Birmingham, Alabama, USA

Background: Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the human central nervous system in which axonal damage also occurs and likely underlies the ultimate progressive course of MS. There is little or no documented benefit from the current treatment of primary or secondary progressive MS. Studies of urinary myelin basic protein like material (MBPLM), so designated because it is immunoreactive as a cryptic epitope in peptide 83-89 of the human MBP molecule of 170 amino acids, by radioimmunoassay (RIA) have shown that it is present in normal adults, remains normal in relapsing-remitting but is increased in the primary and secondary progressive (SP) MS. Its level is correlated with black hole volume on T1-weighted cranial MRI in more advanced SP MS. Investigations have been completed in identifying p-cresol sulfate (p-CS) as the dominant component of urine MBPLM and has permitted analytic methods to measure it directly in urine and serum. Materials and Methods: MBPLM was purified from urine by a series of fractionation procedures, monitored by the RIA for urine MBPLM, and characterized by electrospray ionization mass spectrometry (ESMS) and nuclear magnetic resonance (NMR) spectroscopy. Specimens of urines and sera were analyzed by ESMS and multiple reaction monitoring (MRM). Results: Both ESMS and NMR spectroscopy indicate that a major component of urine MBPLM is p-CS. Synthesized p-CS reacts less but in parallel with MBP peptide 83-89 in the same RIA for MBPLM. Another small molecule(s), yet to be identified, co-purifies with p-CS and increases its immunoreactivity. Urine p-CS measured by MRM and urine MBPLM detected by RIA are highly correlated (r=0.780). p-CS is found in serum at lower levels but correlates well (r=0.822) with urine p-CS adjusted for creatinine content. Conclusion: The appearance, source, and fate of p-CS in urine and other body fluids may reflect normal or pathological mechanisms relevant to the axonal damage and progressive worsening that is disabling in MS. Its detection by standard analytic techniques and its presence in serum enhance the feasibility of further investigations of the relationship and role of p-CS to MS and using it as a means to recognize and select effective treatments for reverse MS.