Electroacupuncture suppresses neuronal ferroptosis to relieve chronic neuropathic pain

J Cell Mol Med, 2024 · DOI: 10.1111/jcmm.18240 · Published: January 1, 2024

Alternative Medicine Pain Management Genetics

Simple Explanation

This study investigates how electroacupuncture (EA) can help with chronic neuropathic pain (NP) by looking at a specific type of cell death called ferroptosis. NP is often hard to treat, and while EA is known to have pain-relieving effects, the exact ways it works are not fully understood. The researchers used rats with nerve injury to mimic NP and treated them with EA at specific acupoints. They found that EA reduced pain and nerve damage in the spinal cord. It also seemed to reverse the signs of ferroptosis, a process involving oxidative stress and iron build-up in cells. Further experiments showed that EA's protective effects might be linked to activating a pathway called Nrf2 signaling. When they blocked this pathway, EA's benefits were reduced, suggesting Nrf2 plays a role in how EA helps with NP.

Study Duration

Not specified

Participants

Male Sprague-Dawley rats

Evidence Level

Not specified

Key Findings

1
EA treatment effectively attenuated CCI-induced pain hypersensitivity and mitigated neuron damage and loss in the spinal cord of NP rats.
2
EA reversed the oxidative stress-mediated spinal ferroptosis phenotype by upregulating reduced expression of xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) and superoxide dismutase (SOD) levels, and downregulating increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), malondialdehyde levels and iron overload.
3
Inhibition of antioxidant pathway of Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect.

Research Summary

This study demonstrates the remarkable efficacy of EA intervention in ameliorating pain hypersensitivities induced by CCI and protecting neurons against injury and loss in NP rats. Moreover, EA effectively reverses GPX4-mediated neuronal ferroptosis in NP rats. Furthermore, we provided evidence that EA may promote the expression of Nrf2 and suppress Keap1 activity in the spinal cord, and blockade of the Nrf2 pathway partially inhibited the effectiveness of EA against ferroptosis. These findings provide the first in vivo evidence highlighting EA therapy's potential to protect against NP by suppressing neuronal ferroptosis in the spinal cord.

Practical Implications

Therapeutic Potential

EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting GPX4-mediated neuronal ferroptosis in the spinal cord, partly through the activation of Nrf2 signalling.

Underlying Mechanisms

The study provides insights into the molecular mechanisms by which EA exerts its analgesic effects in neuropathic pain conditions.

Novel Prospects

The findings unveil novel prospects for the prevention of this particular form of cell death in the context of NP.

Study Limitations

1
The mechanism of how EA treatment on ST36 and GV20 remotely inhibits neuronal ferroptosis activity remains unclear.
2
The role of EA in mediating pain relief via other central regions (e.g., brain) or peripheral nerves (e.g., dorsal root ganglion) remains inconclusive.
3
Future studies should employ ferroptosis inducers such as Erastin or RSL3 (GPX4 inhibitor) to elucidate the potential molecular mechanisms through which EA counteracts spinal ferroptosis.

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