MicroRNA-155-5p promotes neuroinflammation and central sensitization via inhibiting SIRT1 in a nitroglycerin-induced chronic migraine mouse model

Abstract

Background Previous studies have confirmed that the microglial activation and subsequent inflammatory responses in the trigeminal nucleus caudalis (TNC) are involved in the central sensitization of chronic migraine (CM). MicroRNA-155-5p has been shown to modulate the polarization of microglia and participate in inflammatory processes in a variety of neurological diseases. However, its role in CM remains unclear. The purpose of this study was to determine the precise role of miR-155-5p in CM. Methods A model of CM in C57BL/6 mice was established by recurrent intraperitoneal injection of nitroglycerin (NTG). Mechanical and thermal hyperalgesia were evaluated by Von Frey filaments and radiant heat. The expression of miR-155-5p was examined by qRT-PCR, and the mRNA and protein levels of silent information regulator 1(SIRT1) were measured by qRT-PCR, Western blotting (WB) and immunofluorescence (IF) analysis. The miR-155-5p antagomir, miR-155-5p agomir, SRT1720 (a SIRT1 activator) and EX527 (a SIRT1 inhibitor) were administered to confirm the effects of miR-155-5p and SIRT1 on neuroinflammation and the central sensitization of CM. ELISA, WB and IF assays were applied to evaluate the expression of TNF-α, myeloperoxidase (MPO), IL-10, p-ERK, p-CREB, calcitonin gene-related peptide (CGRP), c-Fos and microglial activation. The cellular localization of SIRT1 was illustrated by IF. Results After the NTG-induced mouse model of CM was established, the expression of miR-155-5p was increased. The level of SIRT1 was decreased, and partly colocalized with Iba1 in the TNC. The miR-155-5p antagomir and SRT1720 downregulated the expression of p-ERK, p-CREB, CGRP, and c-Fos, alleviating microglial activation and decreasing inflammatory substances (TNF-α, MPO). The administration of miR-155-5p agomir or EX527 exacerbated neuroinflammation and central sensitization. Importantly, the miR-155-5p agomir elevated CGRP and c-Fos expression and microglial activation, which could subsequently be alleviated by SRT1720. Conclusions These data demonstrate that upregulated miR-155-5p in the TNC participates in the central sensitization of CM. Inhibiting miR-155-5p alleviates neuroinflammation by activating SIRT1 in the TNC of CM mice.

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain

“…Recently, miR-155-5p has been identified as involved in intense neuropathic pain and neuronal inflammation. 31 Subsequently, we verified whether miR-155-5p is a key molecule in nociceptive hypersensitivity behaviors ( Figure 2(a) for the timeline of drug administration and testing). To investigate the potential spinal miR-155-5p modulatory role in the bone cancer-induced nociceptive response, we first collected Sham and BCP group spinal dorsal horn tissues and detected microRNA expression.…”

β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

“…Since β–lactam RGM8-51 possesses analgesic activity in other animal models, we considered also its evaluation in a mouse model of chronic migraine characterized by mechanical hypersensitivity and induced by administration of nitroglycerin (NTG), a known vasodilator used in the treatment of angina pectoris [ 55 ]. This model has been used to evaluate the effects of known acute and preventive migraine therapies and to demonstrate the role of miR155-5p upregulation in the pathological mechanism of chronic migraine [ 56 , 57 ].…”

Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine

“…The role of miR-155-5p in TNC in chronic migraine using an NTG-induced chronic migraine mouse model was determined [ 100 ]. NTG caused hyperalgesia, upregulated CGRP, fos proto-oncogene, and AP-1 transcription factor subunit (c-FOS), increased the level of miR-155-5p, and decreased the mRNA and protein levels of SIRT1.…”