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.
Highlights
Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain
To determine whether angiogenesis occurs in the spinal cord, we evaluated vascular endothelial growthgrowth factor (VEGF)
= 0.006; 19.9 ± 2.7 vs. 29.5 ± 1.2 s, p = 0.015; and 18.7 ± 2.3 vs. 28.9 ± 1.9 s, p = 0.013, respectively; Figure 5A). These results suggest that fumagillin is more efficient than the antivs. 11.8 ± 0.3, 2.1 ± 0.5 vs. 11.8 ± 0.9, 2.8 ± 0.7 vs. 12.2 ± 0. 5, 2.2 ± 1.0 vs. 11.5 ± 1.3, VEGF-A antibody in suppressing constriction injury (CCI)-induced thermal hyperalgesia the differ2.2 ± 0.6 vs. 12.2 ± 1.0, and 2.0 ± 0.8 vs. 11.8 ± 0.9 g at post-operative day (POD) 5, 7, 9, 11, 13, and 14, ence was not statistically significant
Summary
Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. The central nervous system (CNS) is composed of various cells, including neurons and glial cells. It consumes a large amount of oxygen and energy under normal (20% of the total body oxygen demand at rest) and pathological conditions. Astrocytes, the most abundant glial cells in the CNS, extend processes in contact with blood vessels and synapses and play supportive roles in regulating blood flow and synaptic transmission, maintaining synaptic homeostasis in physiological conditions, and distributing metabolism substrates in pathological situations, including stroke, seizure, neuroinflammation, and central sensitization in chronic pain [7,8,9,10,11,12]
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