Validation of potential candidate biomarkers of drug-induced nephrotoxicity and allodynia in medication-overuse headache.
BACKGROUND
Medication-overuse headache (MOH) is a chronic disorder that results from the overuse of analgesics drugs, triptans or other acute headache compounds. Although the exact mechanisms underlying MOH remain still unknown, several studies suggest that it may be associated with development of "central sensitization", which may cause cutaneous allodynia (CA). Furthermore, the epidemiology of drug-induced disorders suggests that medication overuse could lead to nephrotoxicity. The aim of this work was to confirm and validate the results obtained from previous proteomics studies, in which we analyzed the urinary proteome of MOH patients in comparison with healthy non-abusers individuals.


METHODS
MOH patients were divided into groups on the basis of the drug abused: triptans, non-steroidal anti-inflammatory drugs (NSAIDs) and mixtures, (mainly containing indomethacin, paracetamol and, in some cases, caffeine). Healthy subjects, with a history of normal renal function, were used as controls. In this study, four proteins that were found differentially expressed in urine, and, on the basis of the literature review, resulted related to kidney diseases, were verified by Western Blot and Enzyme-linked Immunosorbent Assay (ELISA); Prostaglandin-H2 D-synthase (PTGDS), uromodulin (UROM), alpha-1-microglobulin (AMBP) and cystatin-C (CYSC).


RESULTS
Western blot analysis allowed to validate our previous proteomics data, confirming that all MOH patients groups show a significant over-excretion of urinary PTGDS, UROM, AMBP and CYSC (excluding triptans group for this latter), in comparison with controls. Moreover, the expression of PTGDS was further evaluated by ELISA. Also by this assay, a significant increase of PTGDS was observed in all MOH abusers, according to 2-DE and Western blot results.


CONCLUSIONS
In this study, we confirmed previous findings concerning urinary proteins alterations in MOH patients, identified and demonstrated the over-expression of PTGDS, UROM, AMBP, and CYSC, particularly in NSAIDs and mixtures abusers. Over-expression of these proteins have been related to renal dysfunction and probably, PTGDS, to the development of CA. The detection and confirmation of this proteins pattern represent a promising tool for a better understanding of potential nephrotoxicity induced by drugs overuse and may enhance awareness related to the MOH-associated risks, even in absence of clinical symptoms.
Department of Diagnostic Medicine, Clinic and Public Health, Proteomic Lab, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy, elisa.bellei@unimore.it.
Elisa
E
Bellei
Emanuela
E
Monari
Stefania
S
Bergamini
Aurora
A
Cuoghi
Aldo
A
Tomasi
Simona
S
Guerzoni
Michela
M
Ciccarese
Luigi Alberto
LA
Pini
D000082:Acetaminophen / Q000009:adverse effects; D000328:Adult; D000700:Analgesics / Q000009:adverse effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D015415:Biomarkers / Q000652:urine; D002908:Chronic Disease; D005260:Female; D051271:Headache Disorders, Secondary / Q000139:chemically induced* / Q000175:diagnosis / Q000652:urine*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000175:diagnosis / Q000652:urine*; D007213:Indomethacin / Q000009:adverse effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000652:urine*; D008297:Male; D008875:Middle Aged; D014363:Tryptamines / Q000009:adverse effects
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D014363:Tryptamines; D000082:Acetaminophen; D007213:Indomethacin