Novel roles of phentolamine in protecting axon myelination, muscle atrophy, and functional recovery following nerve injury

Scientific Reports, 2022 · DOI: 10.1038/s41598-022-07253-w · Published: February 18, 2022

Pharmacology Neurology Regenerative Medicine & Stem Cells

Simple Explanation

This study investigates the potential of phentolamine, an FDA-approved drug, in treating nerve injuries and muscle atrophy following peripheral nerve injury (PNI). The research demonstrates that phentolamine treatment enhances motor and functional recovery in mice with sciatic nerve crush injury. Phentolamine treatment also protects axon myelination and reduces injury-induced muscle atrophy. The study shows that phentolamine improves locomotor functional recovery in mice after spinal cord crush (SCC) injury, suggesting its potential for restoring behavioral recovery following PNI and SCC injuries. Researchers found that phentolamine treatment robustly enhanced DRG neuronal outgrowth in vitro in the presence of growth inhibitors, aggrecan, and CSPG. The drug's ability to overcome growth inhibition suggests a mechanism beyond its known alpha-receptor blocking activity.

Study Duration

14 days

Participants

Mice (C57BL/6J and Thy1-YFP)

Evidence Level

Not specified

Key Findings

1
Phentolamine treatment significantly enhanced functional recovery in mice at 14 days post-injury (dpi) following peripheral nerve injury, as evidenced by improved rotarod performance and sciatic function index (SFI).
2
Phentolamine treatment protects myelination and the number of axons after sciatic nerve injury, suggesting a protective effect on nerve structure upon peripheral nerve injury.
3
Phentolamine treatment attenuated muscle atrophy in both soleus and tibialis anterior (TA) muscles at 14 dpi in mice after sciatic nerve injury, indicated by improved muscle cross-section area (CSA) and minimal Feret’s diameter (MFD).

Research Summary

The study demonstrates that phentolamine treatment enhances functional recovery after peripheral nerve injury (PNI) in mice. This includes improved motor function, protection of axon myelination, and attenuation of muscle atrophy. Phentolamine modulates the expression of muscle atrophy genes, specifically downregulating Myogenin, FoxO1, and FoxO3 in the soleus muscle, and suppresses the activation of STAT3, which contributes to the downregulation of ubiquitin-proteasome and autophagy pathways. The research extends findings to central nervous system (CNS) injury, showing that phentolamine enhances behavioral recovery in mice following spinal cord crush (SCC) injury, suggesting its potential for treating both PNS and CNS injuries.

Practical Implications

Therapeutic Repurposing

Phentolamine, an FDA-approved drug, could be repurposed as a potential therapy for restoring injury-related functional recovery, neuropathy, and muscle-wasting disorders.

Targeted Treatment

The study identifies specific molecular targets, such as STAT3 and muscle atrophy-related genes, that can be modulated by phentolamine to improve muscle phenotype.

Broad Application

Phentolamine shows promise for treating both peripheral and central nervous system injuries, offering a potential therapeutic option for conditions where functional recovery is limited.

Study Limitations

1
The study has not evaluated the effects of different dose concentrations in vivo.
2
The effects of phentolamine in permanent denervation mouse models were not studied.
3
The study does not include muscle electrophysiological measurements to validate muscle function.

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