Suppression of Schwann Cell Ferroptosis Mitigates Demyelination and Trigeminal Neuropathic Pain in the IoN-CCI Model.

Abstract

Demyelination is widely acknowledged as the underlying pathological mechanism of trigeminal neuralgia (TN), while ferroptosis has been implicated in neurodegenerative disorders associated with demyelination. However, the precise contribution of ferroptosis to TN-related demyelination has yet to be elucidated. To investigate the putative pathway implicated in neuropathic pain, we conducted RNA-seq analysis in the IoN-CCI rat model that is deemed to simulate the pathology of TN. Subsequently, we explored iron metabolism and the ferroptosis-related pathway in this TN model. Finally, we utilized Ferrostatin-1 and Liproxstatin-1 to suppress ferroptosis and assessed alterations in iron metabolism and myelin sheath integrity through immunohistochemistry and transmission electron microscopy. Our experiments showed that IoN-CCI induced ferroptosis, characterized by increased iron accumulation and decreased expression of GPX4, FPN, and SLC7A11. This resulted in mitochondrial shrinkage in Schwann cells and loosened wrapping of the myelin sheath, as well as activation of neuroinflammation and oxidative stress. Inhibition of ferroptosis reversed these effects and alleviated demyelination and neuropathic pain. In conclusion, our study has clarified the impact of ferroptosis-induced demyelination in TN, providing a potential strategy for treating TN and offering new insights into the study of peripheral nerve demyelination diseases.