Peripheral nerve injury and oxidative stress can severely impair Schwann cell function by disrupting the expression of key myelin proteins, promoting intracellular lipid accumulation, and damaging mitochondrial integrity. These pathological changes are central to various neurodegenerative disorders and chemotherapy-induced peripheral neuropathy, yet effective therapeutic approaches remain limited. Clemastine, an FDA-approved antihistamine with known remyelination-enhancing effects in the central nervous system, has not been thoroughly explored for its protective role in peripheral myelinating cells under oxidative stress. In this study, we investigated the time-dependent protective effects of Clemastine in S16 Schwann cells exposed to hydrogen peroxide (H2O2) as a model of oxidative injury. Treatment with Clemastine significantly increased the expression of myelin-related proteins such as myelin protein zero (MPZ), alongside in increase in AMPK phosphorylation at Thr172. However, co-treatment with H2O2 ensued oxidative damage, leading to reduced pAMPK(T172) and MPZ expression, elevated ROS levels, and increased lipid accumulation. These results suggest that oxidative stress can attenuate Clemastine's effects in association with disrupted redox balance and energy metabolism. Subsequent treatment with Metformin (Met), a pharmacological activator of AMPK, was associated with partial recovery from H2O2-induced oxidative damage. Overall, our findings support the potential of a combinatorial approach using Clemastine and Met to promote myelin-related protein expression and lipid metabolic balance in Schwann cells under oxidative stress, rather than establishing a definitive synergistic or causal mechanism.
Yun et al. (Fri,) studied this question.