title: Minocycline effects on the cerebrospinal fluid proteome of experimental autoimmune encephalomyelitis rats.
abstract: To identify response biomarkers for pharmaceutical treatment of multiple sclerosis, we induced experimental autoimmune encephalomyelitis (EAE) in rats and treated symptomatic animals with minocycline. Cerebrospinal fluid (CSF) samples were collected 14 days after EAE induction at the peak of neurological symptoms, and proteomics analysis was performed using nano-LC-Orbitrap mass spectrometry. Additionally, the minocycline concentration in CSF was determined using quantitative matrix-assisted laser desorption/ionization-triple-quadrupole tandem mass spectrometry (MALDI-MS/MS) in the selected reaction monitoring (SRM) mode. Fifty percent of the minocycline-treated EAE animals did not show neurological symptoms on day 14 ("responders"), while the other half displayed neurological symptoms ("nonresponders"), indicating that minocycline delayed disease onset and attenuated disease severity in some, but not all, animals. Neither CSF nor plasma minocycline concentrations correlated with the onset of symptoms or disease severity. Analysis of the proteomics data resulted in a list of 20 differentially abundant proteins between the untreated animals and the responder group of animals. Two of these proteins, complement C3 and carboxypeptidase B2, were validated by quantitative LC-MS/MS in the SRM mode. Differences in the CSF proteome between untreated EAE animals and minocycline-treated responders were similar to the differences between minocycline-treated responders and nonresponders (70% overlap). Six proteins that remained unchanged in the minocycline-treated animals but were elevated in untreated EAE animals may be related to the mechanism of action of minocycline.
authors: Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Marcel P
authors: MP
authors: Stoop
authors: Therese
authors: T
authors: Rosenling
authors: Amos
authors: A
authors: Attali
authors: Roland J W
authors: RJ
authors: Meesters
authors: Christoph
authors: C
authors: Stingl
authors: Lennard J
authors: LJ
authors: Dekker
authors: Hans
authors: H
authors: van Aken
authors: Ernst
authors: E
authors: Suidgeest
authors: Rogier Q
authors: RQ
authors: Hintzen
authors: Tinka
authors: T
authors: Tuinstra
authors: Alain
authors: A
authors: van Gool
authors: Theo M
authors: TM
authors: Luider
authors: Rainer
authors: R
authors: Bischoff
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D043424:Carboxypeptidase B / Q000134:cerebrospinal fluid; D002556:Cerebrospinal Fluid Proteins / Q000134:cerebrospinal fluid*; D003176:Complement C3 / Q000134:cerebrospinal fluid; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D005620:Freund's Adjuvant / Q000494:pharmacology; D008297:Male; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020543:Proteome / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D053719:Tandem Mass Spectrometry
chemical_list: D000276:Adjuvants, Immunologic; D002556:Cerebrospinal Fluid Proteins; D003176:Complement C3; D018696:Neuroprotective Agents; D020543:Proteome; D005620:Freund's Adjuvant; D043424:Carboxypeptidase B; D008911:Minocycline