FKN/CX3CR1 axis facilitates migraine-Like behaviour by activating thalamic-cortical network microglia in status epilepticus model rats

Zhou, Yanjie; Zhang, Lily; Hao, Yuyan; Yang, Lu; Fan, Shanghua; Xiao, Zheman

doi:10.1186/s10194-022-01416-w

Cited by 20 publications

(17 citation statements)

References 59 publications

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“…Most murine studies investigated purinergic receptors (e.g., P2X/P2Y), which is plausible given the metabolic aspects of migraine pathophysiology, including neuronal energy de ciency (20). The involvement of the fraktalkine pathway was only recently suggested in another mouse model of migraine and was also associated with impaired neuronal signalling in thalamo-cortical networks (21). We found that CX3CL1, the ligand to the fractalkine receptor, is increased in humans irrespective of the headache status.…”

Section: Serum T-tau As a Potential Biomarker For Disease Activity In...mentioning

confidence: 62%

Discrete state-dependent profiles of increased CX3CL1 in cerebrospinal fluid and serum t-Tau elevations in migraine: results from a cross-sectional case-control study

Süße,

Kloetzer,

Strauß

et al. 2023

Preprint

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Background & Objectives: To date, migraine is diagnosed exclusively based on clinical criteria, but fluid biomarkers are desirable to gain insight into pathophysiological processes and inform clinical management. We investigated the state-dependent profile of fluid biomarkers for neuroaxonal damage and microglial activation as two potentially relevant aspects in human migraine pathophysiology. Methods: This exploratory study included serum and cerebrospinal fluid (CSF) samples of patients with migraine during the headache phase (ictally) (n=23), between attacks (interictally) (n=16), and age/sex-matched controls (n=19). Total Tau (t-Tau) protein, glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NfL) were measured with the Neurology 4-plex kit on a Single Molecule Array SR-X Analyzer (Simoa® SR-X, Quanterix Corp., Lexington, MA). Markers of microglial activation, C-X3-C motif chemokine ligand 1 (CX3CL1) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), were assessed using an immunoassay. Results: Concentrations of CX3CL1 but not sTREM2 were significantly increased both ictally and interictally in CSF but not in serum in comparison to the control cohort (p=0.039). ROC curve analysis provided an AUC of 0.699 (95% CI 0.563 to 0.813, p=0.007). T-Tau in serum but not in CSF was significantly increased in samples from patients taken during the headache phase, but not interictally (effect size: η²=0.121, p=0.038). ROC analysis of t-Tau protein in serum between ictal and interictal collected samples provided an AUC of 0.729 (95% CI 0.558 to 0.861, p=0.006). The other determined biomarkers for axonal damage were not significantly different between the cohorts in either serum or CSF. Discussion: CX3CL1 in CSF is a novel potential fluid biomarker of migraine that is unrelated to the headache status. Serum t-Tau is linked to the headache phase but not interictal migraine. These data need to be confirmed in a larger hypothesis-driven prospective study.

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Section: Serum T-tau As a Potential Biomarker For Disease Activity In...mentioning

confidence: 62%

Discrete state-dependent profiles of increased CX3CL1 in cerebrospinal fluid and serum t-Tau elevations in migraine: results from a cross-sectional case-control study

Süße,

Kloetzer,

Strauß

et al. 2023

Preprint

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“…The surgical procedure was conducted as described previously [ 34 , 35 ]. Rats were anesthetized with a ketamine-xylazine mixture (100 mg/kg ketamine, 10 mg/kg xylazine) and fixed on a stereotaxic apparatus (68,002, RWD Life Science).…”

Section: Methodsmentioning

confidence: 99%

PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine

et al. 2023

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Aims Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. Methods Sprague–Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. Results The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. Conclusions Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine.

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“…After the IS (or saline) injection, we immediately recorded the number of head scratching for 1 h, which represented a nociceptive behavior resulting by IS. The periorbital mechanical threshold was evaluated by a von Frey test, using an up-and-down approach according to previous report [ 33 , 34 ]. A positive reaction was defined as rapid withdrawal of the head.…”

Section: Materials and Methodsmentioning

confidence: 99%

SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1α positive feedback loop

Shan,

Wang,

Qiu

et al. 2023

J Headache Pain

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Migraine is the second highest cause of disability worldwide, bringing a huge socioeconomic burden. Improving mitochondrial function has promise as an effective treatment strategy for migraine. Szeto-Schiller peptide (SS-31) is a new mitochondria-targeted tetrapeptide molecule that has been shown to suppress the progression of diseases by restoring mitochondrial function, including renal disease, cardiac disease, and neurodegenerative disease. However, whether SS-31 has a therapeutic effect on migraine remains unclear. The aim of this study is to clarify the treatment of SS-31 for headache and its potential mechanisms. Here we used a mouse model induced by repeated dural infusion of inflammatory soup (IS), and examined roles of Sirt3/Pgc-1α positive feedback loop in headache pathogenesis and mitochondrial function. Our results showed that repeated IS infusion impaired mitochondrial function, mitochondrial ultrastructure and mitochondrial homeostasis in the trigeminal nucleus caudalis (TNC). These IS-induced damages in TNC were reversed by SS-31. In addition, IS-induced nociceptive responses were simultaneously alleviated. The effects of SS-31 on mitochondrial function and mitochondrial homeostasis (mainly mitochondrial biogenesis) were attenuated partially by the inhibitor of Sirt3/Pgc-1α. Overexpression of Sirt3/Pgc-1α increased the protein level of each other. These results indicated that SS-31 alleviated nociceptive responses and restored mitochondrial function in an IS-induced headache mouse model via Sirt3/Pgc-1α positive feedback loop. SS-31 has the potential to be an effective drug candidate for headache treatment. Graphical Abstract

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FKN/CX3CR1 axis facilitates migraine-Like behaviour by activating thalamic-cortical network microglia in status epilepticus model rats

Cited by 20 publications

References 59 publications

Discrete state-dependent profiles of increased CX3CL1 in cerebrospinal fluid and serum t-Tau elevations in migraine: results from a cross-sectional case-control study

Discrete state-dependent profiles of increased CX3CL1 in cerebrospinal fluid and serum t-Tau elevations in migraine: results from a cross-sectional case-control study

PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine

SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1α positive feedback loop

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