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

Abstract

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.

Role of macrophage autophagy in postoperative pain and inflammation in mice

“…Autophagy, an intracellular self-degradation system, is an essential biological process that removes unnecessary cytosol, cytoplasmic organelles, and even microbes from cells [ 10 – 12 ]. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation in various diseases, including atherosclerosis [ 13 , 14 ], inflammatory bowel disease [ 15 ], uveitis [ 16 ], infection [ 17 – 19 ], peripheral neuronal injury [ 20 ], and brain ischemia [ 21 ]. Considering that macrophages are key cells in the generation and resolution of inflammatory pain [ 1 , 22 , 23 ], autophagy in macrophages can be expected to play pivotal roles in postoperative pain and inflammation as well as their resolution, and is therefore a potential therapeutic target.…”

Ultrastructural Evidence of Synapse Preservation and Axonal Regeneration Following Spinal Root Repair with Fibrin Biopolymer and Therapy with Dimethyl Fumarate

“…For that, the establishment of animal models of root avulsion allowed the advance in understanding the several reactions to proximal axotomy as well as aspects of the regeneration process [4][5][6][7][8][9][10][11]. Thus, ventral root avulsion (VRA) in rats has become an animal model widely used since it can recapitulate both acute and chronic phases following injury [3,[12][13][14][15][16][17][18][19][20][21].…”

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

“…Following publication of the original article [ 1 ], the authors identified that the article note about co-first author and equal contribution were missing.…”