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Teriflunomide preserves neuronal activity and protects mitochondria in brain slices exposed to oxidative stress

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Item Type:Article
Title:Teriflunomide preserves neuronal activity and protects mitochondria in brain slices exposed to oxidative stress
Creators Name:Malla, B. and Liotta, A. and Bros, H. and Ulshöfer, R. and Paul, F. and Hauser, A.E. and Niesner, R. and Infante-Duarte, C.
Abstract:Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.
Keywords:Mitochondria, Neurodegeneration, Teriflunomide (TFN), Oxidative Stress, Dihydroorotate Dehydrogenase (DHODH), Multiple Sclerosis, Mitochondrial Morphology, Mitochondrial Motility, Acute Hippocampal Slices, Two-Photon Microscopy, Animals, Mice
Source:International Journal of Molecular Sciences
Page Range:1538
Date:28 January 2022
Official Publication:https://doi.org/10.3390/ijms23031538
PubMed:View item in PubMed

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