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.

In vitro and in vivo pharmacological models to assess demyelination and remyelination.

In making a selection of cellular tools and animal models for generating screening assays in the search for new drugs, one needs to take into consideration the practicality of their use in the drug discovery process. Conducting high-throughput primary screens using libraries of small molecules, close to 1 million members in size, requires the generation of large numbers of cells which are easily acquired, reliably enriched, and reproducibly responsive to standard positive controls. These cells need to be similar in form and function to their counterparts in human disease. In vitro assays that can be mechanized by using robots can therefore save time and costs. In selecting in vivo models, consideration must be given to the species and strain of animal chosen, the appropriateness of the model to human disease, the extent of animal husbandry required during the in-life pharmacological assessment, the technical aspects of generating the model and harvesting the tissues for analyses, the cost of research tools in terms of time and money (demyelinating and remyelinating agents, amount of compound to be generated), and the length of time required for drug testing in the model. A consideration of the translational aspects of the in vivo model compared to those used in the clinic is also important. These themes will be developed with examples for drug discovery in the field of CNS demyelination and repair, specifically as it pertains to multiple sclerosis.

Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation.

OBJECTIVE: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate. METHODS: We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived. RESULTS: We identified 132 genes differentially expressed by WMPCs; these included principal components of five receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-beta/zeta (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin. INTERPRETATION: The RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain.