Inhibition of Ferroptosis-like Cell Death Attenuates Neuropathic Pain Reactions Induced by Peripheral Nerve Injury in Rats

Background: Relationships between iron-dependent ferroptosis and nerve system diseases have been recently revealed. However, the role of ferroptosis in neuropathic pain (NeP) remains to be elucidated. Thus, we aimed to investigate whether ferroptosis in spinal cord contributes to NeP induced by a chronic constriction injury (CCI) of the sciatic nerve.

Methods: Forty Sprague-Dawley rats received CCI or sham surgery, and were randomly assigned to the following four groups: sham group; CCI + LIP group; CCI + Veh group; and CCI group. Liproxstatin-1 or corn oil were separately injected intraperitoneally for three consecutive days after surgery in the CCI + LIP or CCI + Veh group. The mechanical and thermal hypersensitivities were tested after surgery. Biochemical and morphological changes related to ferroptosis in the spinal cord were also assessed. These included iron content, glutathione peroxidase 4 (GPX4) and anti-acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, lipid peroxidation assays, as well as mitochondrial morphology.

Results: CCI-induced NeP was followed by iron accumulation, increased lipid peroxidation and dysregulation of ACSL4 and GPX4. Moreover transmission electron microscopy confirmed the presence of aberrant morphological changes on mitochondrial, such as mitochondria shrinkage and membrane rupture. Furthermore, the administration of liproxstatin-1 on CCI rats attenuated hypersensitivities, lowered the iron level, decreased spinal lipid peroxidation, restored the dysregulations in GPX4 and ACSL4 levels, and protected against CCI induced morphological changes in mitochondria.

Conclusions: Our findings indicated the involvement of ferroptosis in CCI induced NeP, and point to ferroptosis inhibitors such as liproxstatin-1 as potential therapies for hypersensitivity induced by peripheral nerve injury.

Significance: The spinal ferroptosis-like cell death was involved in the development of neuropathic pain resulted from peripheral nerve injury, and inhibition of ferroptosis by liproxstatin-1 could alleviate mechanical and thermal hypersensitivities. This knowledge suggested that ferroptosis could represent a potential therapeutic target for neuropathic pain.