Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis.
Teriflunomide is an orally available anti-inflammatory drug that prevents T and B cell proliferation and function by inhibition of dihydroorotate dehydrogenase. It is currently being developed for the treatment of multiple sclerosis (MS). We report here for the first time the anti-inflammatory effects of teriflunomide in the Dark Agouti rat model of experimental autoimmune encephalomyelitis (EAE). Neurological evaluation demonstrated that prophylactic dosing of teriflunomide at 3 and 10 mg/kg delayed disease onset and reduced maximal and cumulative scores. Therapeutic administration of teriflunomide at doses of 3 or 10 mg/kg at disease onset significantly reduced maximal and cumulative disease scores as compared to vehicle treated rats. Dosing teriflunomide at disease remission, at 3 and 10 mg/kg, reduced the cumulative scores for the remaining course of the disease. Teriflunomide at 10 mg/kg significantly reduced inflammation, demyelination, and axonal loss when dosed prophylactically or therapeutically. In electrophysiological somatosensory evoked potential studies, therapeutic administration of teriflunomide, at the onset of disease, prevented both a decrease in waveform amplitude and an increase in the latency to waveform initiation in EAE animals compared to vehicle. Therapeutic dosing with teriflunomide at disease remission prevented a decrease in evoked potential amplitude, prevented an increase in latency, and enhanced recovery time within the CNS.
Merrill
Jean E
JE
Sanofi-Aventis, Bridgewater, NJ 08807, USA. jean.merrill@sanofi-aventis.com
Hanak
Susan
S
Pu
Su-Fen
SF
Liang
Jinjun
J
Dang
Chelsea
C
Iglesias-Bregna
Deborah
D
Harvey
Brian
B
Zhu
Bin
B
McMonagle-Strucko
Kathleen
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D001522:Behavior, Animal; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003437:Crotonates / Q000008:administration & dosage / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects*; D006885:Hydroxybutyrates; D008297:Male; D009570:Nitriles; D051381:Rats; D014052:Toluidines / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002491:Central Nervous System Agents; D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide