Role of Matrix Metalloproteinases in Myelin Abnormalities and Mechanical Allodynia in Rodents with Diabetic Neuropathy

Mingzheng Wu,Pingchuan Ma,Huabao Liao,Xueting Deng,Xue-Jun Song

doi:10.14336/ad.2021.0126

Mingzheng Wu, Pingchuan Ma + Show 3 more

Open Access

https://doi.org/10.14336/ad.2021.0126

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Abstract

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.

Highlights

The treatment of diabetic neuropathic pain (DNP) is a major clinical challenge
The results showed that the systematic administration of a single dose of α-lipoic acid (α-LA) (i.p., each at 30 mg/kg, 100 mg/kg, and 200 mg/kg, respectively) 21 days after STZ treatment produced a dose-dependent inhibition of the established STZ-induced mechanical allodynia in wild type (WT) mice
Our gelatin zymography analysis showed that the activity of Matrix metalloproteinases (MMPs)-9 in the dorsal root ganglion (DRG) (Fig. 5B) and dorsal horn (DH) (Fig. 5C) was significantly inhibited by the repetitive, systematic administration of α-LA in three groups treated with different doses of α-LA (10 mg/kg, 30 mg/kg, and 100 mg/kg, respectively, daily on days 19, 20, and 21)

Summary

Introduction

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. Systematic administration of αlipoic acid significantly suppressed STZ-induced mechanical allodynia by inhibiting MMP-9 and rescuing MMP2 activity These findings support a new mechanism underlying the pathogenesis of diabetic neuropathy and suggest a potential target for DNP treatment. We hypothesized and have provided evidence that MMP-9 and MMP-2 in the dorsal root ganglion (DRG) and dorsal horn (DH) of the spinal cord may play an important role in the pathogenesis of diabetic neuropathy and associated DNP. This finding suggests a potential target for DNP treatment. This finding provides mechanistic insights into the action of a therapeutically promising compound derived from natural products

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