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Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats after Chronic Constriction Injury.

ABSTRACT:

Introduction

Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzes the impact of angiogenesis on spinal neuroinflammation in neuropathic pain.

Methods

Rats with chronic constriction injury (CCI) to the sciatic nerve underwent the implantation of an intrathecal catheter. Fumagillin or vascular endothelial growth factor-A antibody (anti-VEGF-A) was administered intrathecally. Nociceptive behaviors, cytokine immunoassay, Western blot, and immunohistochemical analysis assessed the effect of angiogenesis inhibition on CCI-induced neuropathic pain.

Results

VEGF, cluster of differentiation 31 (CD31), and von Willebrand factor (vWF) expressions increased after CCI in the ipsilateral lumbar spinal cord compared to that in the contralateral side of CCI and control rats from post-operative day (POD) 7 to 28, with a peak at POD 14. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations, but not IL-10 levels, also increased in the ipsilateral spinal cord after CCI. Fumagillin and anti-VEGF-A reduced CCI-induced thermal hyperalgesia from POD 5 to 14 and mechanical allodynia from POD 3 to 14. Fumagillin reduced CCI-upregulated expressions of angiogenic factors and astrocytes. Furthermore, fumagillin decreased TNF-α and IL-6 amounts and increased IL-10 levels at POD 7 and 14, but not IL-1β concentrations.

Conclusions

Fumagillin significantly ameliorates CCI-induced nociceptive sensitization, spinal angiogenesis, and astrocyte activation. Our results suggest that angiogenesis inhibitor treatment suppresses peripheral neuropathy-induced central angiogenesis, neuroinflammation, astrocyte activation, and neuropathic pain.

SUBMITTER: Wen ZH

PROVIDER: S-EPMC8470034 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have previously demonstrated that the Thymus algeriensis and Thymus fontanesii extracts have powerful anti-inflammatory, antipyretic, and analgesic effects against acute pain models. We profiled their chemical composition and found many phenolic acids, flavonoids, and phenolic diterpenes. In this work, we investigated their antioxidant properties on HaCaT cells exposed to UVA-induced oxidative stress and examined their effects against chronic neuropathic pain and the underlying mechanisms. Through a rat chronic constriction injury (CCI) model, we induced chronic neuropathic pain by placing 4 loose ligatures around the right sciatic nerve for 14 days. Thermal and mechanical hyperalgesia in addition to cold and dynamic allodynia were tested on the day before surgery and on the 7th and 14th post-surgery days. Key markers of the nitrosative and oxidative stresses, in addition to markers of inflammation, were measured at day 14 post surgery. Histopathological examination and immunostaining of both synaptophysin and caspase-3 of sciatic nerve and brain stem were also performed. Results of this study showed that T. algeriensis extract suppresses UVA oxidative stress in HaCaT cells via activation of the Nrf-2 pathway. Both extracts attenuated hyperalgesia and allodynia at 7- and 14-days post-surgery with more prominent effects at day 14 of surgery. Their protective effects against neuropathic pain were mediated by inhibiting NOX-1, iNOS, by increasing the enzyme activity of catalase, and inhibition of inflammatory mediators, NF-κB, TNF-α, lipoxygenase, COX-2 enzymes, and PGE2. Furthermore, they improved deleterious structural changes of the brainstem and sciatic nerve. They also attenuated the increased caspase-3 and synaptophysin. The data indicate that both extracts have neuroprotective effects against chronic constriction injury-induced neuropathic pain. The observed protective effects are partially mediated through attenuation of oxidative and nitrosative stress and suppression of both neuroinflammation and neuronal apoptosis, suggesting substantial activities of both extracts in amelioration of painful peripheral neuropathy.