Upregulation of silent information regulator 1 alleviates mitochondrial dysfunction in the trigeminal nucleus caudalis in a rat model of chronic migraine

Abstract Background: The mechanism of chronic migraine (CM) is still unclear and mitochondrial dysfunction plays a possible role in migraine pathophysiology. Silent information regulator 1 (SIRT1) plays a vital role in mitochondrial dysfunction in many diseases, but there is no information about SIRT1 in CM.The aim of this study was to explore the role of SIRT1 in mitochondrial dysfunction in CM. Methods： A rat model was established through repeated dural infusions of inflammatory soup (IS) for seven days to simulate CM attacks. Cutaneous hyperalgesia caused by the repeated infusions of IS was detected using the von Frey test. Then, we detected SIRT1 expression in the trigeminal nucleus caudalis (TNC). To explore the effect of SIRT1 on mitochondrial dysfunction in CM rats, we examined whether SRT1720, an activator of SIRT1, altered mitochondrial dysfunction in CM rats. Results： Repeated infusions of IS resulted in cutaneous hyperalgesia accompanied bydownregulation of SIRT1.SRT1720 significantly alleviated the cutaneous hyperalgesia induced by repeated infusions of IS. Furthermore, activation of SIRT1 markedly increased the expression of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha(PGC-1α), transcription factor A (TFAM), nuclear respiratory factor 1 (NRF-1), and nuclear respiratory factor 2(NRF-2) mitochondrial DNA (mtDNA) and increased the ATP content and mitochondrial membrane potential. Conclusions ：Our results indicate that SIRT1 may have an effect on mitochondrial dysfunction in CM rats. Activation of SIRT1 has a protective effect on mitochondrial function in CM rats.

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Functional mitochondrial analysis in acute brain sections from adult rats reveals mitochondrial dysfunction in a rat model of migraine

AJP Cell Physiology ◽

10.1152/ajpcell.00332.2013 ◽

2014 ◽

Vol 307 (11) ◽

pp. C1017-C1030 ◽

Cited By ~ 23

Author(s):

Nathan T. Fried ◽

Cynthia Moffat ◽

Erin L. Seifert ◽

Michael L. Oshinsky

Keyword(s):

Mitochondrial Dysfunction ◽

Rat Model ◽

Neurological Disorders ◽

Atp Synthesis ◽

Brain Regions ◽

Adult Brain ◽

Trigeminal Nucleus ◽

Adult Rats ◽

Trigeminal Nucleus Caudalis ◽

Adult Rat

Mitochondrial dysfunction has been implicated in many neurological disorders that only develop or are much more severe in adults, yet no methodology exists that allows for medium-throughput functional mitochondrial analysis of brain sections from adult animals. We developed a technique for quantifying mitochondrial respiration in acutely isolated adult rat brain sections with the Seahorse XF Analyzer. Evaluating a range of conditions made quantifying mitochondrial function from acutely derived adult brain sections from the cortex, cerebellum, and trigeminal nucleus caudalis possible. Optimization of this technique demonstrated that the ideal section size was 1 mm wide. We found that sectioning brains at physiological temperatures was necessary for consistent metabolic analysis of trigeminal nucleus caudalis sections. Oxygen consumption in these sections was highly coupled to ATP synthesis, had robust spare respiratory capacities, and had limited nonmitochondrial respiration, all indicative of healthy tissue. We demonstrate the effectiveness of this technique by identifying a decreased spare respiratory capacity in the trigeminal nucleus caudalis of a rat model of chronic migraine, a neurological disorder that has been associated with mitochondrial dysfunction. This technique allows for 24 acutely isolated sections from multiple brain regions of a single adult rat to be analyzed simultaneously with four sequential drug treatments, greatly advancing the ability to study mitochondrial physiology in adult neurological disorders.

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P2Y12 receptor mediates microglial activation via RhoA/ROCK pathway in the trigeminal nucleus caudalis in a mouse model of chronic migraine

Journal of Neuroinflammation ◽

10.1186/s12974-019-1603-4 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 6

Author(s):

Feng Jing ◽

Yixin Zhang ◽

Ting Long ◽

Wei He ◽

Guangcheng Qin ◽

...

Keyword(s):

Chronic Migraine ◽

Microglial Activation ◽

Morphological Changes ◽

Critical Role ◽

Radiant Heat ◽

P2y12 Receptor ◽

Trigeminal Nucleus ◽

Double Labeling ◽

Trigeminal Nucleus Caudalis

Abstract Background Microglial activation contributes to the development of chronic migraine (CM). The P2Y12 receptor (P2Y12R), a metabolic purinoceptor that is expressed on microglia in the central nervous system (CNS), has been indicated to play a critical role in the pathogenesis of chronic pain. However, whether it contributes to the mechanism of CM remains unknown. Thus, the present study investigated the precise details of microglial P2Y12R involvement in CM. Methods Mice subjected to recurrent nitroglycerin (NTG) treatment were used as the CM model. Hyperalgesia were assessed by mechanical withdrawal threshold to electronic von Frey and thermal withdrawal latency to radiant heat. Western blot and immunohistochemical analyses were employed to detect the expression of P2Y12R, Iba-1, RhoA, and ROCK2 in the trigeminal nucleus caudalis (TNC). To confirm the role of P2Y12R and RhoA/ROCK in CM, we systemically administered P2Y12R antagonists (MRS2395 and clopidogrel) and a ROCK2 inhibitor (fasudil) and investigated their effects on microglial activation, c-fos, and calcitonin gene-related peptide (CGRP) expression in the TNC. To further confirm the effect of P2Y12R on microglial activation, we preincubated lipopolysaccharide (LPS)-treated BV-2 microglia with MRS2395 and clopidogrel. ELISA was used to evaluate the levels of inflammatory cytokines. Results The protein levels of P2Y12R, GTP-RhoA, ROCK2, CGRP, c-fos, and inducible nitric oxide synthase (iNOS) in the TNC were increased after recurrent NTG injection. A double labeling study showed that P2Y12R was restricted to microglia in the TNC. MRS2395 and clopidogrel attenuated the development of tactile allodynia and suppressed the expression of CGRP, c-fos, and GTP-RhoA/ROCK2 in the TNC. Furthermore, fasudil also prevented hyperalgesia and suppressed the expression of CGRP in the TNC. In addition, inhibiting P2Y12R and ROCK2 activities suppressed NTG-induced microglial morphological changes (process retraction) and iNOS production in the TNC. In vitro, a double labeling study showed that P2Y12R was colocalized with BV-2 cells, and the levels of iNOS, IL-1β, and TNF-α in LPS-stimulated BV-2 microglia were reduced by P2Y12R inhibitors. Conclusions These data demonstrate that microglial P2Y12R in the TNC plays a critical role in the pathogenesis of CM by regulating microglial activation in the TNC via RhoA/ROCK pathway.

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PTEN inhibition preserves trigeminal nucleus caudalis neuron activation through tyrosine phosphorylation of the NR2B subunit at Tyr1472 of the NMDA receptor in a rat model of recurrent migraine

Neurological Research ◽

10.1080/01616412.2016.1145915 ◽

2016 ◽

Vol 38 (4) ◽

pp. 320-326 ◽

Cited By ~ 8

Author(s):

Guangcheng Qin ◽

Jingmei Xie ◽

Lixue Chen ◽

Baixue Wu ◽

Bei Gui ◽

...

Keyword(s):

Nmda Receptor ◽

Tyrosine Phosphorylation ◽

Rat Model ◽

Nr2b Subunit ◽

Trigeminal Nucleus ◽

Trigeminal Nucleus Caudalis ◽

Neuron Activation ◽

Pten Inhibition

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Expression of ASIC3 in the Trigeminal Nucleus Caudalis Plays a Role in a Rat Model of Recurrent Migraine

Journal of Molecular Neuroscience ◽

10.1007/s12031-018-1113-3 ◽

2018 ◽

Vol 66 (1) ◽

pp. 44-52 ◽

Cited By ~ 8

Author(s):

Sha Wang ◽

Bai-Xue Wu ◽

Chao-Yang Liu ◽

Guang-Cheng Qin ◽

Wen-Hui Yan ◽

...

Keyword(s):

Rat Model ◽

Trigeminal Nucleus ◽

Trigeminal Nucleus Caudalis

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Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation

The Journal of Headache and Pain ◽

10.1186/s10194-021-01302-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Feng Jing ◽

Qian Zou ◽

Yangyang Wang ◽

Zhiyou Cai ◽

Yong Tang

Keyword(s):

Chronic Migraine ◽

Western Blotting ◽

Central Sensitization ◽

Microglial Activation ◽

Morphological Changes ◽

Trigeminal Nucleus ◽

Trigeminal Nucleus Caudalis ◽

Tnf Α

Abstract Background Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway.

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