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

• Published in: Journal of neuroinflammation Vol. 19; no. 1; p. 271
• Main Authors: Zhong, Ke, Huang, Yu, Zilundu, Prince Last Mudenda, Wang, Yaqiong, Zhou, Yingying, Yu, Guangyin, Fu, Rao, Chung, Sookja Kim, Tang, Yamei, Cheng, Xiao, Zhou, Lihua
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.11.2022; BioMed Central; BMC
• Subjects: Aldehyde reductase; Aldehyde Reductase - genetics; Aldehyde Reductase - metabolism; Aldose reductase; Animals; Antibodies; Autophagy; Autophagy (Cytology); Brachial plexus; Brachial Plexus - injuries; Brachial Plexus - metabolism; Brachial plexus root avulsion; Brain injury; Cell death; Complications and side effects; Development and progression; Diabetes mellitus; Enzymes; Health aspects; Inflammation; Ischemia; Laboratory animals; Lipid metabolism; Lipid peroxidation; Metabolism; Mice; Motoneurons death; Motor neurons; Motor Neurons - metabolism; Nerves; Neuroinflammation; Neuroinflammatory Diseases; Neurological research; Neurons; Neuroprotection; Oxidative stress; Peripheral neuropathy; Rats; Rats, Sprague-Dawley; Retinopathy; Rodents; SIRT1 protein; Spinal cord; Spinal cord injuries; Surgery; TOR protein; Transplants & implants; China; United Kingdom > UK; United States > US; Neuroinflammation; Aldose reductase; Autophagy; Brachial plexus root avulsion; Motoneurons death
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02632-6

Brachial plexus root avulsion (BPRA) is frequently caused by high-energy trauma including traffic accident and birth trauma, which will induces massive motoneurons (MNs) death as well as loss of motor and sensory function in the upper limb. The death of MNs is attributed to energy deficiency, neuroinflammation and oxidative stress at the injured ventral horn of spinal cord triggered by BPRA injury. It has been reported which aldose reductase (AR), an endogenous enzyme that catalyzes fructose synthesis, positively correlates with the poor prognosis following cerebral ischemic injury, diabetic retinopathy and diabetic peripheral neuropathy. However, the role of AR in BPRA remains unknown. Herein, we used a mouse model and found that in the spinal cord of BPRA mice, the upregulation of AR correlated significantly with (1) an inactivated SIRT1-AMPK-mTOR pathway and disrupted autophagy; (2) increased byproducts accumulation of lipid peroxidation metabolism and neuroinflammation; and (3) increased MNs death. Furthermore, our results demonstrated the role of AR in BPRA injury whereby the absence of AR (AR knockout mice, AR ) prevented the hyper-neuroinflammation and disrupted autophagy as well as motor neuron death caused by BPRA injury. Finally, we further demonstrate that AR inhibitor epalrestat is neuroprotective against BPRA injury by increasing autophagy level, alleviating neuroinflammation and rescuing MNs death in mice. Collectively, our data demonstrate that the AR upregulation in the spinal cord is an important factor contributing to autophagy disruption, neuroinflammation and MNs death following brachial plexus roots avulsion in mice. Our study also provides a promising therapy drug to assist re-implantation surgery for the treatment of BPRA.