Preclinical studies of methylthioadenosine for the treatment of multiple sclerosis.
BACKGROUND
Methylthioadenosine (MTA) is a natural metabolite with immunomodulatory properties. MTA improves the clinical course and pathology of the animal model of multiple sclerosis, even when therapy is started after disease onset.


OBJECTIVE
Our aim was to compare the efficacy of MTA in ameliorating experimental autoimmune encephalomyelitis (EAE) compared with first line approved therapies, to develop an oral formulation of MTA and to assess its pharmacokinetic profile.


METHODS
EAE was induced in C57BL/6 mice by immunization with MOG(35-55) peptide in Freund's Adjuvant. Animals were treated with MTA, interferon-beta or glatiramer acetate starting the day of immunization and the clinical score was collected blind. Pharmacokinetic studies were performed in Sprague Dawley rats by administering MTA by intraperitoneal injection and orally, and collecting blood at different intervals. MTA levels were measured by high-performance liquid chromatography.


RESULTS
We found that MTA ameliorated EAE in a dose-response manner. Moreover, the highest dose of MTA (60 mg/kg) was more efficacious than mouse interferon-beta or glatiramer acetate. We developed a salt of MTA for oral administration, with similar dose-response effect in the EAE model. Combination therapy assays between MTA and interferon-beta or glatiramer acetate were more effective than the individual therapies. Finally, oral MTA half-life was 20 min, with a C(max) of 80 mg/L and without signs of obvious toxicity (animal death, behavioural changes, liver enzymes).


CONCLUSIONS
In the EAE model MTA is more efficacious than first line therapies for multiple sclerosis, with a dose- response effect and higher efficacy when combined with interferon-beta or glatiramer acetate. Oral MTA was also effective in the animal model of multiple sclerosis.
Moreno
B
B
Department of Neuroscience, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, Spain.
Fernandez-Diez
B
B
Di Penta
A
A
Villoslada
P
P
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D000068717:Glatiramer Acetate; D006023:Glycoproteins; D006207:Half-Life; D007155:Immunologic Factors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007274:Injections, Intraperitoneal; D016899:Interferon-beta / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013872:Thionucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
D006023:Glycoproteins; D007155:Immunologic Factors; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010455:Peptides; D013872:Thionucleosides; C445081:myelin oligodendrocyte glycoprotein (35-55); D000068717:Glatiramer Acetate; D016899:Interferon-beta; D000241:Adenosine