Contributions
Abstract: P1177
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Apart from relapse-remitting autoimmune activities and resulting transient functional deficits, multiple sclerosis (MS) is also characterized by impaired regeneration responses. Absent or diminished repair in the central nervous system (CNS) also relates to replacement of lost oligodendrocytes and myelin sheaths - the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation, recruitment and differentiation of resident oligodendroglial precursor cells (OPCs). However, the efficiency of successful remyelination reactions is limited and declines with disease duration and progression. Teriflunomide has recently been approved as a first-line treatment of relapsing remitting (RR-)MS in the US and the European Union. As active metabolite of leflunomide, an established disease-modifying antirheumatic drug, it is supposed to act mainly via inhibition of de novo pyrimidine synthesis exerting a cytostatic effect on proliferating B and T cells (Warnke et al., Clin Neurol Neurosurg 2013). With this study we aimed at uncovering the potential of teriflunomide to promote oligodendroglial activities in terms of myelin repair. Dose-dependency analysis revealed reduced OPC proliferation rates resulting from pyrimidine stress ultimately followed by cell cycle exit and when applied at higher doses leading to decreased survival rates. On the other hand, expression analysis of maturation markers/regulators such as CNPase, MBP and MOG, as well as of oligodendroglial differentiation competence markers p57kip2 and Mash1 (Göttle et al., J Neurosci 2015), along with stress associated genes p53, p63 and p73 revealed that short-term stimuli presented to young OPCs effectively promote their differentiation as opposed to long-term application. Moreover, myelination of CNS axons in vitro can efficiently be stimulated. Western blot analysis demonstrated that short and early teriflunomide pulses resulted in strong induction of p73 protein expression which is in agreement with a differentiation associated role for p73 in oligodendroglial cells (Billon et al., Development 2004).
Disclosure: Supported by Sanofi Genzyme GmbH, Germany
Abstract: P1177
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Apart from relapse-remitting autoimmune activities and resulting transient functional deficits, multiple sclerosis (MS) is also characterized by impaired regeneration responses. Absent or diminished repair in the central nervous system (CNS) also relates to replacement of lost oligodendrocytes and myelin sheaths - the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation, recruitment and differentiation of resident oligodendroglial precursor cells (OPCs). However, the efficiency of successful remyelination reactions is limited and declines with disease duration and progression. Teriflunomide has recently been approved as a first-line treatment of relapsing remitting (RR-)MS in the US and the European Union. As active metabolite of leflunomide, an established disease-modifying antirheumatic drug, it is supposed to act mainly via inhibition of de novo pyrimidine synthesis exerting a cytostatic effect on proliferating B and T cells (Warnke et al., Clin Neurol Neurosurg 2013). With this study we aimed at uncovering the potential of teriflunomide to promote oligodendroglial activities in terms of myelin repair. Dose-dependency analysis revealed reduced OPC proliferation rates resulting from pyrimidine stress ultimately followed by cell cycle exit and when applied at higher doses leading to decreased survival rates. On the other hand, expression analysis of maturation markers/regulators such as CNPase, MBP and MOG, as well as of oligodendroglial differentiation competence markers p57kip2 and Mash1 (Göttle et al., J Neurosci 2015), along with stress associated genes p53, p63 and p73 revealed that short-term stimuli presented to young OPCs effectively promote their differentiation as opposed to long-term application. Moreover, myelination of CNS axons in vitro can efficiently be stimulated. Western blot analysis demonstrated that short and early teriflunomide pulses resulted in strong induction of p73 protein expression which is in agreement with a differentiation associated role for p73 in oligodendroglial cells (Billon et al., Development 2004).
Disclosure: Supported by Sanofi Genzyme GmbH, Germany