Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
Sci Rep. 2022 Feb 28;12(1):3344. doi: 10.1038/s41598-022-07253-w.
Incomplete functional recovery after peripheral nerve injury (PNI) often results in devastating physical disabilities in human patients. Despite improved progress in surgical and non-surgical approaches, achieving complete functional recovery following PNI remains a challenge. This study demonstrates that phentolamine may hold a significant promise in treating nerve injuries and denervation induced muscle atrophy following PNI. In a sciatic nerve crush injury mouse model, we found that phentolamine treatment enhanced motor and functional recovery, protected axon myelination, and attenuated injury-induced muscle atrophy in mice at 14 days post-injury (dpi) compared to saline treatment. In the soleus of phentolamine treated animals, we observed the downregulation of phosphorylated signal transducer and activator of transcription factor 3 (p-STAT3) as well as muscle atrophy-related genes Myogenin, muscle ring finger 1 (MuRF-1), and Forkhead box O proteins (FoxO1, FoxO3). Our results show that both nerve and muscle recovery are integral components of phentolamine treatment-induced global functional recovery in mice at 14 dpi. Moreover, phentolamine treatment improved locomotor functional recovery in the mice after spinal cord crush (SCC) injury. The fact that phentolamine is an FDA approved non-selective alpha-adrenergic blocker, clinically prescribed for oral anesthesia reversal, hypertension, and erectile dysfunction makes this drug a promising candidate for repurposing in restoring behavioral recovery following PNI and SCC injuries, axonal neuropathy, and muscle wasting disorders.
周围神经损伤 (PNI) 后的不完全功能恢复常常导致人类患者遭受严重的身体残疾。尽管在手术和非手术方法方面取得了进展，但在 PNI 后实现完全功能恢复仍然是一个挑战。本研究表明，酚妥拉明在治疗 PNI 后的神经损伤和去神经支配引起的肌肉萎缩方面可能具有重要意义。在坐骨神经挤压损伤小鼠模型中，我们发现与生理盐水处理相比，酚妥拉明治疗在损伤后 14 天 (dpi) 增强了运动和功能恢复，保护了轴突髓鞘形成，并减轻了损伤引起的肌肉萎缩。在酚妥拉明处理动物的比目鱼肌中，我们观察到磷酸化信号转导和转录激活因子 3 (p-STAT3) 以及肌肉萎缩相关基因 Myogenin、肌肉环指 1 (MuRF-1) 和 Forkhead 盒 O 蛋白 (FoxO1、FoxO3) 的下调。我们的结果表明，在损伤后 14 天，神经和肌肉恢复都是酚妥拉明治疗诱导小鼠整体功能恢复的组成部分。此外，酚妥拉明治疗改善了脊髓挤压 (SCC) 损伤后小鼠的运动功能恢复。酚妥拉明是一种已获美国食品和药物管理局 (FDA) 批准的非选择性α-肾上腺素能阻滞剂，临床上用于口腔麻醉逆转、高血压和勃起功能障碍，这一事实使其成为一种有前途的候选药物，可用于恢复 PNI 和 SCC 损伤、轴突神经病变和肌肉消耗性疾病后的行为恢复。
