背景:刺猬(Shh),对其在早期神经发生和大脑发育中的作用进行了广泛的研究,最近已经认识到其在神经元损伤后的神经保护潜力。这项研究检查了早期给药Shh对大鼠急性脊髓损伤后局部炎症反应的直接影响。
方法:34只雌性Wistar大鼠在T9水平接受假手术(椎板切除术;n=10)或夹钳压迫/挫伤脊髓损伤(SCI)。随后植入渗透泵和硬膜下导管,以连续鞘内递送Shh(n=12)或安慰剂(NaCl;n=12)。使用Basso评估受伤后3天和7天(dpi)的运动功能,Beattie,和Bresnahan(BBB)评分和Gridwalk测试。3或7天后使动物安乐死,用于局部炎症反应和免疫细胞迁移的免疫组织化学分析。
结果:Shh处理的大鼠在损伤后7天表现出明显的后肢运动和协调改善,与对照组相比。这种增强伴随着脊髓病变内免疫细胞存在和血浆产物的显着减少。提示Shh在调节免疫细胞迁移和维持血脊髓屏障完整性方面的双重作用。分别,这些Shh处理的大鼠还显示巨噬细胞的M(IL-4)极化增加,进一步强调Shh在伤后恢复中的潜在治疗影响。值得注意的是,这些影响在损伤后3天并不明显.
结论:伤后7天应用Shh显示免疫调节作用,可能通过增强血脊髓屏障的完整性,减少免疫细胞迁移,和增加抗炎免疫细胞分化。这些机制共同有助于增强的运动恢复。
BACKGROUND: Sonic Hedgehog (Shh), extensively researched for its role in early neurogenesis and brain development, has recently been recognized for its neuroprotective potential following neuronal injuries. This study examines the immediate impact of early administered Shh on the local inflammatory response post-acute spinal cord injury in rats.
METHODS: Thirty-four female Wistar rats underwent either sham surgery (laminectomy; n = 10) or clip compression/contusion spinal cord injury (SCI) at the T9 level. This was followed by implantation of an osmotic pump and a subdural catheter for continuous intrathecal delivery of Shh (n = 12) or placebo (NaCl; n = 12). Locomotor function was assessed at 3- and 7-days post-injury (dpi) using the Basso, Beattie, and Bresnahan (BBB) score and the Gridwalk test. Animals were euthanized after 3 or 7 days for immunohistochemical analysis of the local inflammatory reaction and immune cell migration.
RESULTS: Shh-treated rats demonstrated significant hindlimb movement and coordination improvements at 7 days post-injury, compared to controls. This enhancement was accompanied by a significant reduction in both immune cell presence and blood plasma products within spinal cord lesions, suggesting Shh\'s dual role in modulating immune cell migration and maintaining the integrity of the blood-spinal cord barrier. Separately, these Shh-treated rats also showed an increase in M(IL-4) polarization of macrophages, further underlining the potential therapeutic impact of Shh in post-injury recovery. Notably, these effects were not evident at three days post-injury.
CONCLUSIONS: Shh application at 7 days post-injury showed immunomodulatory effects, possibly via enhanced blood-spinal cord barrier integrity, reduced immune cell migration, and increased anti-inflammatory immune cell differentiation. These mechanisms collectively contribute to enhanced locomotor recovery.