Ozaki Tomoya, Sugie Takahiro, Suzuki Yuji, Uchimura Kenji, Suzui Masumi, Sakamoto Kazuma, Shirane Michiko, Kadomatsu Kenji
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-ku, Nagoya 467-8603, Japan; Department of Neurotoxicology, Institute of Brain Science, Nagoya city University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan; Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Neurosci Res. 2025 Mar;212:11-19. doi: 10.1016/j.neures.2024.12.001. Epub 2024 Dec 3.
Spinal cord injury (SCI) results in damage to neural circuits that cause long-term locomotor and sensory disability. The objective of the present study is to evaluate whether a clinical drug, protamine, can be employed as a therapeutic agent for SCI. First, we examined the rescue effect of protamine on dystrophic endballs (DEs) cultured on a chondroitin sulfate (CS) gradient coating. Consequently, axons with DE, which are unable to grow through the CS barrier, resumed growth after protamine treatment and were able to pass through the barrier. In addition, we tested whether protamine resolves the DE phenotype, accumulation of autophagosomes. The results demonstrated that protamine has significantly reduced the density of LC3 in DEs. Subsequently, mice were administered 1 mg/kg protamine via the tail vein one week following a contusion injury to the thoracic spinal cord. The hindlimb movements of the mice were evaluated in order to assess the therapeutic effect of protamine. Eleven venous administrations of protamine improved the symptoms. The current study has demonstrated that protamine cancels the CS inhibitory effect on axonal regrowth. Administrations of protamine were observed to alleviate hindlimb motor dysfunction in SCI mice. Our results suggest an effective therapeutic agent for SCI and a possibility for drug repositioning. It would be of interest to see if protamine also exerts a therapeutic effect in brain injury.
脊髓损伤（SCI）会导致神经回路受损，从而引起长期的运动和感觉功能障碍。本研究的目的是评估一种临床药物鱼精蛋白是否可作为脊髓损伤的治疗药物。首先，我们研究了鱼精蛋白对在硫酸软骨素（CS）梯度涂层上培养的营养不良终球（DEs）的挽救作用。结果，带有DE的轴突原本无法穿过CS屏障生长，在接受鱼精蛋白治疗后恢复了生长并能够穿过该屏障。此外，我们测试了鱼精蛋白是否能解决DE表型，即自噬体的积累问题。结果表明，鱼精蛋白显著降低了DEs中LC3的密度。随后，在小鼠胸段脊髓挫伤损伤一周后，通过尾静脉给小鼠注射1 mg/kg鱼精蛋白。为了评估鱼精蛋白的治疗效果，对小鼠的后肢运动进行了评估。静脉注射11次鱼精蛋白改善了症状。当前研究表明，鱼精蛋白消除了CS对轴突再生的抑制作用。观察到注射鱼精蛋白可减轻脊髓损伤小鼠的后肢运动功能障碍。我们的结果提示了一种治疗脊髓损伤的有效药物以及药物重新定位的可能性。鱼精蛋白在脑损伤中是否也发挥治疗作用将是一个有趣的研究方向。
