Department of Orthopedic Surgery, National Defense Medical College, Tokorozawa, Japan.
Department of Medicine, University of Otago Medical School, Dunedin, New Zealand.
PLoS One. 2020 Aug 11;15(8):e0237156. doi: 10.1371/journal.pone.0237156. eCollection 2020.
Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.
缺血性神经病变在肢体严重缺血患者中很常见，常导致慢性神经性疼痛。然而，尽管恢复了足够的血流，缺血引起的神经性疼痛仍然难以控制。在这里，我们使用缺血再灌注神经损伤（IRI）大鼠模型来研究肝细胞生长因子（HGF）对缺血性神经病变的可能作用。含有 HGF 编码质粒的日本血凝病毒（HVJ）脂质体通过逆行轴突运输递送至外周神经系统，方法是在右侧后肢的胫骨前肌中反复注射。首先在 IRI 后立即进行 HGF 基因转移，并在 1、2 和 3 周后重复。IRI 大鼠表现出明显的机械性痛觉过敏和热痛觉过敏、血流量和皮肤温度降低以及后爪足底刺激阈值降低。HGF 基因转移显著改善了这些症状，坐骨神经传导速度和肌肉动作电位幅度也得到了改善。组织学上，HGF 基因转移导致坐骨神经和胫神经的神经内膜微血管显著增加，并促进了神经再生，这通过形态计量学分析得到了证实。在周围神经的对侧也观察到了新生血管化。此外，IRI 使坐骨神经、背根神经节和脊髓中 P2X3 和 P2Y1 受体以及瞬时受体电位香草酸受体亚型 1（TRPV1）的 mRNA 水平升高，HGF 基因转移抑制了这些升高的水平。总之，HGF 基因转移是治疗再灌注损伤引起的急性缺血性神经病变的有效候选药物，因为它具有强大的血管生成和增强的神经再生作用。
