Contributions
Abstract: EP1674
Type: Poster Sessions
Abstract Category: Therapy - Tools for detecting therapeutic response
Introduction: In Multiple Sclerosis therapy an immunomodulatory effect was attributed to teriflunomide. It is known to block the de novosynthesis of pyrimidine in mitochondria by reversibly inhibiting the enzyme dihydroorotate-dehydrogenase (DHODH). In adult healthy mice high levels of DHODH activity were measured in the central nervous system (CNS). Besides, astrocytes and microglia - as CNS resident cell subsets - play a pivotal role during the inflammatory response once the disease has been initiated by lymphocytes and macrophages originating from the periphery in MS and EAE.
Objectives: We want to analyse whether these CNS components are affected by teriflunomide, especially the potential induction or inhibition of NOX enzymes activity in the tissue.
Methods: We recently developed a label-free analysis method (NADP(H)-FLIM) by which we can monitor cell function invivo to identify the cellular sources of oxidative stress in the CNS of mice. In this way, we analysed in the presented study effects of teriflunomide on NOX activation levels of CNS cells ex vivo in slice cultures of healthy mice (basal and after stimulation).
Results: In our ex vivo slice culture model, the contribution of astrocytes to oxidative stress within the tissue is equivalent to the contribution of the traditional phagocytes as microglia and macrophages after stimulation, thus reflecting the role of astrocytes as central contributors to oxidative stress in the acute and chronic phases of EAE. Interestingly we could not detect any increase or decrease of NOX enzyme activation after incubation of the tissue with teriflunomide in any analysed cell type in our ex vivo model.
Conclusion: We think that our results support the understanding of the direct effect of teriflunomide on astrocytes and microglia, especially regarding oxidative stress. It seems that teriflunomide is in our artificial model not directly anti-oxidative in the absence of overt inflammation. But regarding the drug safety we can also confirm that teriflunomide is not additionally inducing NOX activation in the cultured CNS tissue. A potential effect considering functional consequences of directly reducing neurodegeneration and promoting myelin preservation and repair in MS patients has to be evaluated in the future.
Disclosure: The study was supported by Sanofi-Genzyme to H.R. and R.N.; R.M., R.L. and C.U. have nothing to declare.
Abstract: EP1674
Type: Poster Sessions
Abstract Category: Therapy - Tools for detecting therapeutic response
Introduction: In Multiple Sclerosis therapy an immunomodulatory effect was attributed to teriflunomide. It is known to block the de novosynthesis of pyrimidine in mitochondria by reversibly inhibiting the enzyme dihydroorotate-dehydrogenase (DHODH). In adult healthy mice high levels of DHODH activity were measured in the central nervous system (CNS). Besides, astrocytes and microglia - as CNS resident cell subsets - play a pivotal role during the inflammatory response once the disease has been initiated by lymphocytes and macrophages originating from the periphery in MS and EAE.
Objectives: We want to analyse whether these CNS components are affected by teriflunomide, especially the potential induction or inhibition of NOX enzymes activity in the tissue.
Methods: We recently developed a label-free analysis method (NADP(H)-FLIM) by which we can monitor cell function invivo to identify the cellular sources of oxidative stress in the CNS of mice. In this way, we analysed in the presented study effects of teriflunomide on NOX activation levels of CNS cells ex vivo in slice cultures of healthy mice (basal and after stimulation).
Results: In our ex vivo slice culture model, the contribution of astrocytes to oxidative stress within the tissue is equivalent to the contribution of the traditional phagocytes as microglia and macrophages after stimulation, thus reflecting the role of astrocytes as central contributors to oxidative stress in the acute and chronic phases of EAE. Interestingly we could not detect any increase or decrease of NOX enzyme activation after incubation of the tissue with teriflunomide in any analysed cell type in our ex vivo model.
Conclusion: We think that our results support the understanding of the direct effect of teriflunomide on astrocytes and microglia, especially regarding oxidative stress. It seems that teriflunomide is in our artificial model not directly anti-oxidative in the absence of overt inflammation. But regarding the drug safety we can also confirm that teriflunomide is not additionally inducing NOX activation in the cultured CNS tissue. A potential effect considering functional consequences of directly reducing neurodegeneration and promoting myelin preservation and repair in MS patients has to be evaluated in the future.
Disclosure: The study was supported by Sanofi-Genzyme to H.R. and R.N.; R.M., R.L. and C.U. have nothing to declare.