Abstract
BackgroundPrevious 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.MethodsA 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.ResultsAfter 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.ConclusionsThese 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.
Highlights
Chronic migraine (CM) is a common debilitating neurological disorder characterized by unilateral or bilateral pulsatile headache, with at least 15 attack days perWen et al Journal of Neuroinflammation (2021) 18:287 month [1, 2]
The administration of NTG caused hyperalgesia and upregulated the levels of calcitonin gene-related peptide (CGRP) and c‐Fos After the NTG-induced mouse model of chronic migraine (CM) was established (Fig. 1A), mechanical allodynia, thermal hyperalgesia and the protein levels of CGRP and c-Fos were measured to evaluate the reliability of our model
CGRP is involved in the occurrence and maintenance of migraine [37]. c-Fos is regarded as a sign of neuronal activation in response to nociceptive stimulation, which is closely related to the pathological mechanism of migraine [38]
Summary
Chronic migraine (CM) is a common debilitating neurological disorder characterized by unilateral or bilateral pulsatile headache, with at least 15 attack days perWen et al Journal of Neuroinflammation (2021) 18:287 month [1, 2]. Following the recognition of infection, injury or protein aggregates, microglia become rapidly ‘‘activated’’ and transform to an ameboid morphology, releasing TNFα, IL-1β and other inflammatory mediators [7]. These mediators bind to specific receptors of neurons and promote central sensitization, resulting in spontaneous pain, hyperalgesia and abnormal pain [10]. 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). The purpose of this study was to determine the precise role of miR-155-5p in CM
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