Role of Matrix Metalloproteinases in Myelin Abnormalities and Mechanical Allodynia in Rodents with Diabetic Neuropathy.
Role of Matrix Metalloproteinases in Myelin Abnormalities and Mechanical Allodynia in Rodents with Diabetic Neuropathy.
复制标题
基质金属蛋白酶在糖尿病神经病啮齿动物髓磷脂异常和机械性异常性疼痛中的作用
DOI：
10.14336/ad.2021.0126
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发表时间：
2021-10
影响因子：
7.4
通讯作者：
Song XJ
中科院分区：
文献类型：
--
作者：
Deng X;Ma P;Wu M;Liao H;Song XJ
糖尿病神经性疼痛（DNP）的治疗是一个重大的临床挑战。糖尿病神经病变的潜在机制尚不清楚，治疗方法有限。在这里，我们报告明胶酶MMP-9和MMP-2在啮齿类动物的轴突脱髓鞘和DNP中起关键作用。MMP-9可能通过诱导轴突脱髓鞘和脊髓中枢敏感化而参与链脲佐菌素（STZ）诱导的DNP，而MMP-2可能作为负性调节剂。在STZ诱导的DNP大鼠，MMP-9的活性增加，而MMP-2在背根神经节和脊髓中的活性降低。脊髓抑制MMP-9，但不是MMP-2，大大抑制了行为和神经化学的迹象DNP，而管理的MMP-2减轻机械异常性疼痛。在小鼠中，除了机械性异常性疼痛外，STZ治疗还导致外周坐骨神经和脊髓背角的轴突脱髓鞘。MMP-9-/-小鼠的这些神经病理性改变显著减少。最后，系统给予α-硫辛酸通过抑制MMP-9和拯救MMP-2活性显著抑制STZ诱导的机械性异常性疼痛。这些发现支持了糖尿病神经病变发病机制的新机制，并提出了DNP治疗的潜在靶点。明胶酶MMP-9和MMP-2在糖尿病神经病变的发病机制中起关键作用，并可能作为潜在的治疗靶点。MMP-9/2是α-硫辛酸在糖尿病神经病变中的作用机制，为开发新型镇痛抗炎药物提供了潜在的靶点。
The treatment of diabetic neuropathic pain (DNP) is a major clinical challenge. The underlying mechanisms of diabetic neuropathy remain unclear, and treatment approaches are limited. Here, we report that the gelatinases MMP-9 and MMP-2 play a critical role in axonal demyelination and DNP in rodents. MMP-9 may contribute to streptozotocin (STZ)-induced DNP via inducing axonal demyelination and spinal central sensitization, while MMP-2 may serve as a negative regulator. In STZ-induced DNP rats, the activity of MMP-9 was increased, while MMP-2 was decreased in the dorsal root ganglion and spinal cord. Spinal inhibition of MMP-9, but not MMP-2, greatly suppressed the behavioral and neurochemical signs of DNP, while administration of MMP-2 alleviated mechanical allodynia. In mice, STZ treatment resulted in axonal demyelination in the peripheral sciatic nerves and spinal dorsal horn, in addition to mechanical allodynia. These neuropathic alterations were significantly reduced in MMP-9-/- mice. Finally, systematic administration of α-lipoic acid significantly suppressed STZ-induced mechanical allodynia by inhibiting MMP-9 and rescuing MMP-2 activity. These findings support a new mechanism underlying the pathogenesis of diabetic neuropathy and suggest a potential target for DNP treatment. Gelatinases MMP-9 and MMP-2 play a critical role in the pathogenesis of diabetic neuropathy and may serve as a potential treatment target. MMP-9/2 underlies the mechanism of α-lipoic acid in diabetic neuropathy, providing a potential target for the development of novel analgesic and anti-inflammatory drugs.