Motor neuron survival is associated with reduced neuroinflammation and increased autophagy after brachial plexus avulsion injury in aldose reductase‑deficient mice

Journal of Neuroinflammation, 2022 · DOI: https://doi.org/10.1186/s12974-022-02632-6 · Published: November 16, 2022

Simple Explanation

Brachial plexus root avulsion (BPRA) leads to motor neuron death, upper limb dysfunction, neuroinflammation, and oxidative stress. This study investigates the role of aldose reductase (AR) in BPRA. The research demonstrates that AR upregulation correlates with disrupted autophagy, increased neuroinflammation, and motor neuron death after BPRA. AR knockout mice showed reduced neuroinflammation and increased autophagy, leading to improved motor neuron survival. The AR inhibitor epalrestat was found to be neuroprotective against BPRA injury by increasing autophagy, alleviating neuroinflammation, and rescuing motor neurons. This suggests AR as a potential therapeutic target for BPRA.

Study Duration

Not specified

Participants

Mice (wild-type and aldose reductase knockout)

Evidence Level

Not specified

Key Findings

1
AR upregulation in the spinal cord correlated with inactivated SIRT1–AMPK–mTOR pathway and disrupted autophagy following BPRA.
2
Absence of AR (AR knockout mice) prevented hyper-neuroinflammation, disrupted autophagy, and motor neuron death caused by BPRA injury.
3
AR inhibitor epalrestat is neuroprotective against BPRA injury by increasing autophagy level, alleviating neuroinflammation and rescuing MNs death in mice.

Research Summary

This study demonstrates that AR expression is markedly upregulated in the BPRA mice model. Genetic knockout or epalrestat pharmacological suppression of AR contributed to better MNs survival by attenuating BPRA-induced autophagy disruption and neuroinflammation. The results suggest that BPRA causes MNs autophagy dysregulation and MNs death. Heightened levels of P62 and reduced levels of LC3II found in BPRA mice model were associated with MNs death. The findings demonstrate that AR plays an important role in the divergence of microglial/macrophage functions after BPRA injury in mice and AR deficiency is neuroprotective in mice subjected to BPRA.

Practical Implications

Therapeutic Target

AR is identified as a potential therapeutic target for treating BPRA.

Pharmacological Intervention

AR inhibitors, such as epalrestat, could be a promising strategy for mitigating motor neuron death caused by BPRA.

Clinical Translation

Further biomedical studies and clinical trials are required to test the safety and efficacy of AR inhibitors in BPRA patients.

Study Limitations

1
The exact mechanism of autophagy, its regions and cell-type specificity remained unknown.
2
The actual relationship between AMPK and SIRT1 need us examine the LKB1 activity and NAD+ abundance in the future study.
3
Further studies with cell-specific AR knockout mice are necessary to understand the effect of AR on cell-type specificity autophagy function.

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