Effects of Prophylactic and Therapeutic Teriflunomide in Transcranial Magnetic Stimulation–Induced Motor-Evoked Potentials in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis

Abstract

Teriflunomide is a once-daily oral immunomodulatory agent recently approved in the United States for the treatment of relapsing multiple sclerosis (RMS). This study investigated neurophysiological deficits in descending spinal cord motor tracts during experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis) and the functional effectiveness of prophylactic or therapeutic teriflunomide treatment in preventing the debilitating paralysis observed in this model. Relapsing-remitting EAE was induced in Dark Agouti rats using rat spinal cord homogenate. Animals were treated with oral teriflunomide (10 mg/kg daily) prophylactically, therapeutically, or with vehicle (control). Transcranial magnetic motor-evoked potentials were measured throughout the disease to provide quantitative assessment of the neurophysiological status of descending motor tracts. Axonal damage was quantified histologically by silver staining. Both prophylactic and therapeutic teriflunomide treatment significantly reduced maximum EAE disease scores (P , 0.0001 and P 5 0.0001, respectively) compared with vehicle-treated rats. Electrophysiological recordings demonstrated that both teriflunomide treatment regimens prevented a delay in wave-form latency and a decrease in wave-form amplitude compared with that observed in vehicle-treated animals. A significant reduction in axonal loss was observed with both teriflunomide treatment regimens compared with vehicle (P , 0.0001 and P 5 0.0014, respectively). The results of this study suggest that therapeutic teriflunomide can prevent the deficits observed in this animal model in descending spinal cord motor tracts. The mechanism behind reduced axonal loss and improved motor function may be primarily the reduced inflammation and consequent demyelination observed in these animals through the known effects of teriflunomide on impairing proliferation of stimulated T cells. These findings may have significant implications for patients with RMS.

Teriflunomide Attenuates Immunopathological Changes in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis

“…Other studies in animal models have shown that teriflunomide can also ameliorate or prevent the emergence of symptoms consistent with MS when animals are dosed at remission or prophylactically (24, 44). Studies in patients have also shown therapeutic benefits for patients with relapsing forms of MS, including subgroups with both higher and lower disease activity (45, 46).…”

Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action

“…Teriflunomide also acts by inhibiting protein tyrosine kinases, leading to decreased T cell proliferation, and by shifting the cytokine profile to prevent inflammation (ie, inhibiting synthesis of proinflammatory cytokines and promoting anti-inflammatory cytokines) 110. EAE animal models treated with teriflunomide showed a significant reduction in axonal damage by up to 96%, nonlatency or delay of motor-evoked potentials, and preservation of the anatomical integrity in both the ascending and descending tracts of the spinal cord, thus underscoring its direct effect on neuroprotection 111,112…”

“…Recent animal studies have shown that teriflunomide can significantly improve motor function and decrease the probability of debilitating paralysis, suggesting that it might become one of the early treatment drugs for MS 111. To this end, a Phase III clinical trial (TOPIC [Phase III Study with Teriflunomide Versus Placebo in Patients with First Clinical Symptom of Multiple Sclerosis]; ClinicalTrials.gov NCT00622700)113 is ongoing, with an expected study completion date of August 2015, that will inform the utility of teriflunomide in early clinical treatment.…”

Teriflunomide and Its Mechanism of Action in Multiple Sclerosis

“…Therapeutic dosing had similar effects [80]. Measurement of transcranial magnetic motor-evoked potentials showed that teriflunomide prevented a delay in waveform latency and a decrease in waveform amplitude [84]. …”