Leflunomide treatment does not protect neural cells following Oxygen-Glucose Deprivation (OGD) in vitro

Curel, Claire J.M. and Nobeli, Irene and Thornton, C. (2024) Leflunomide treatment does not protect neural cells following Oxygen-Glucose Deprivation (OGD) in vitro. Cells 13 (7), p. 631. ISSN 2073-4409.

Abstract

Neonatal hypoxia-ischemia (HI) affects 2–3 per 1000 live births in developed countries and up to 26 per 1000 live births in developing countries. It is estimated that of the 750,000 infants experiencing a hypoxic-ischemic event during birth per year, more than 400,000 will be severely affected. As treatment options are limited, rapidly identifying new therapeutic avenues is critical, and repurposing drugs al- ready in clinical use offers a fast-track route to clinic. One emerging avenue for therapeutic intervention in neonatal HI is to target mitochondrial dysfunction, which occurs early in the development of brain injury. Mitochondrial dynamics are particularly affected, with mitochondrial fragmentation occurring at the expense of the pro-fusion protein Optic Atrophy (OPA)1. OPA1, together with mitofusins (MFN)1/2, are required for membrane fusion, and therefore, protecting their function may also safeguard mitochon- drial dynamics. Leflunomide, an FDA-approved immunosuppressant, was recently identified as an acti- vator of MFN2 with partial effects on OPA1 expression. We, therefore, treated C17.2 cells with Lefluno- mide before or after oxygen-glucose deprivation, an in vitro mimic of HI, to determine its efficacy as a neuroprotection and inhibitor of mitochondrial dysfunction. Leflunomide increased baseline OPA1 but not MFN2 expression in C17.2 cells. However, Leflunomide was unable to promote cell survival follow- ing OGD. Equally, there was no obvious effect on mitochondrial morphology or bioenergetics. These data align with studies suggesting that the tissue and mitochondrial protein profile of the target cell/tissue are critical for taking advantage of the therapeutic actions of Leflunomide.

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