Abstract
The “gold standard” treatment of patients with spinal root injuries consists of delayed surgical reconnection of nerves. The sooner, the better, but problems such as injury-induced motor neuronal death and muscle atrophy due to long-term denervation mean that normal movement is not restored. Herein we describe a preclinical model of root avulsion with delayed reimplantation of lumbar roots that was used to establish a new adjuvant pharmacological treatment. Chronic treatment (up to 6 months) with NeuroHeal, a new combination drug therapy identified using a systems biology approach, exerted long-lasting neuroprotection, reduced gliosis and matrix proteoglycan content, accelerated nerve regeneration by activating the AKT pathway, promoted the formation of functional neuromuscular junctions, and reduced denervation-induced muscular atrophy. Thus, NeuroHeal is a promising treatment for spinal nerve root injuries and axonal regeneration after trauma.
Highlights
In animal models of root avulsion, immediate reimplantation of the avulsed roots increases MN survival and allows some reinnervation of limb muscles with limited functional recovery that is worse in lumbar than in cervical root injuries, likely due to the differences in length[11,12,13,14]
The findings of this work indicate that NeuroHeal treatment after root avulsion and delayed reimplantation of the lumbar roots remarkably promoted regeneration resulting in (1) long-lasting protection of motoneurons from retrograde neurodegeneration; (2) activation of a pro-regenerative profile via pAKT-mTOR signaling; (3)
Histograms of weight ratio between ipsilateral and contralateral TA and GA muscles at 6 months post RE (n = 7–8; t-test, *p < 0.05 RE + NH vs. RE). (B) Representative microphotographs of cross and longitudinal TA and GA muscle sections with H&E staining from CTL, RE, and RE + NH groups at 6 months post RE. (C) Left, Means (±standard error of the mean (SEM)) of the fiber cross-sectional areas from GA muscles of indicated groups at 6 months post RE
Summary
In animal models of root avulsion (root avulsion, RA), immediate reimplantation of the avulsed roots increases MN survival and allows some reinnervation of limb muscles with limited functional recovery that is worse in lumbar than in cervical root injuries, likely due to the differences in length[11,12,13,14]. Grafting of mesenchymal stem cells into the injured spinal cord segments have shown some benefit[17,18]. Drugs, such as riluzole[13], lithium[19], and intracellular sigma peptide (ISP, a mimetic of the proteoglycan receptor PTPσ)[20], have been tested only after immediate reimplantation of the avulsed roots and so have limited translational potential. In order to bring efficient therapeutic strategies to the clinic, we developed a preclinical model based on RA plus delayed surgical reimplantation of lumbar roots to test a new promising drug combination called www.nature.com/scientificreports/. Results presented here evaluating NeuroHeal in a preclinical model demonstrate the promise of this coadjuvant agent for the clinical treatment of root and plexus injuries
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