Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice

Dehghani, Anisa; Phisonkunkasem, Thas; Özcan, Sinem Yilmaz; Dalkara, Turgay; Maagdenberg, Arn M. J. M. van den; Tolner, Else A.; Karataş, Hülya

doi:10.1016/j.nbd.2021.105424

Cited by 14 publications

(28 citation statements)

References 32 publications

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“…Our observation of CSD-induced elevated anti-inflammatory lipid mediators DPAn-3, EPA, ALA, and DHA in WT (that were not altered in FHM1 mutant mice), suggests a reduced anti-inflammatory response in the context of hemiplegic migraine and CSD. This is in line with earlier work in which we observed specific CSD-related neuroinflammatory changes in the brain of FHM1 mutant mice [ 12 , 13 ]. In the context of treatment regimes, our findings appear in line with the use of NSAIDs in acute migraine treatment [ 60 ].…”

Section: Discussionsupporting

confidence: 93%

“…In the brain, EPA and DHA inhibit neuroinflammatory processes in several ways, that is, (1) inhibition of the production of neuroinflammatory proteins such as tumor necrosis factor alpha (TNF-α) and various interleukins in various cell types, (2) reduction in the activity of mitogen-activated protein kinases (MAPKs), and (3) inhibition of signaling pathways resulting in lower macrophage responses [ 53 ]. FHM1 mutant mice, compared to WT, show more widespread neuroinflammatory changes in the brain at 30 min following CSD [ 12 ], as well as a unique cortical neuroinflammatory gene expression profile at 24 h following CSD [ 13 ]. Our finding of increased plasma levels of anti-inflammatory lipid metabolites at 24 h in WT mice, but not in FHM1 mutant mice, suggests a reduced anti-inflammatory response in FHM1 mutants.…”

Section: Discussionmentioning

confidence: 99%

“…FHM1 mutant knock-in mice carrying the human pathogenic R192Q missense mutation (‘R192Q mutant mice’) exhibit an enhanced Ca V 2.1 channel function and consequently a higher level of glutamatergic neurotransmission in the cortex, resulting in an enhanced susceptibility to experimentally induced CSD [ 9 , 10 , 11 ]. In the FHM1 mutant mice, CSDs are associated with an increased neuroinflammatory response, either immediately following CSD [ 12 ] or lasting for at least one day after CSD [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine

et al. 2022

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Metabolite levels in peripheral body fluids can correlate with attack features in migraine patients, which underscores the potential of plasma metabolites as possible disease biomarkers. Migraine headache can be preceded by an aura that is caused by cortical spreading depolarization (CSD), a transient wave of neuroglial depolarization. We previously identified plasma amino acid changes after CSD in familial hemiplegic migraine type 1 (FHM1) mutant mice that exhibit increased neuronal excitability and various migraine-related features. Here, we aimed to uncover lipid metabolic pathways affected by CSD, guided by findings on the involvement of lipids in hemiplegic migraine pathophysiology. Using targeted lipidomic analysis, we studied plasma lipid metabolite levels at different time points after CSD in wild-type and FHM1 mutant mice. Following CSD, the most prominent plasma lipid change concerned a transient increase in PGD2, which lasted longer in mutant mice. In wild-type mice only, levels of anti-inflammatory lipid mediators DPAn-3, EPA, ALA, and DHA were elevated 24 h following CSD compared to Sham-treated animals. Given the role of PGs and neuroinflammation in migraine pathophysiology, our findings underscore the potential of monitoring peripheral changes in lipids to gain insight in central brain mechanisms.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine

et al. 2022

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“…Further studies confirmed the neuronal presence of P2X7 and showed that the roles of these receptors in the glia or neurons are not always mutually exclusive 40 . Here, we investigated P2X7 immunostaining signal following CSD and we have found an increase in the P2X7 signal in cortex, thalamus, striatum, hypothalamus and hippocampus following CSD in neurons, effecting both hemispheres, concordant with the neuroinflammation 41 . In addition, P2X7 antagonism thus blockage of the inflammatory cascade halted this increase in the neuronal cytoplasmic P2X7 signal in all of the aforementioned cortical and subcortical regions.…”

Section: Discussionmentioning

confidence: 88%

The Effect of P2X7 Antagonism on Subcortical Spread of Optogenetically-Triggered Cortical Spreading Depression and Neuroinflammation

Uzay

Demir

Özcan

et al. 2022

Preprint

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Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in the opening of pannexin-1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7 antagonist, JNJ-47965567. P2X7 antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD showing that ATP acts as a mediator in the subcortical spread. P2X7 antagonism also prevented hypothalamic neuronal activation following CSD, revealed by bilateral decrease in hypothalamic c-fos positive neuron count. P2X7 antagonism further stopped the CSD-induced neuroinflammation revealed by decreased nuclear translocation of NF-kappa B-p65 in astrocytes and decreased HMGB1 release. Following CSD we observed an increase in neuronal cytoplasmic P2X7R signal in the cortex and subcortical structures (thalamus, hypothalamus, striatum, hippocampus) concordant with the neuroinflammation which is also prevented by P2X7R antagonism. In conclusion, our data suggest that P2X7R plays an imperative role in CSD-induced neuroinflammation, the subcortical spread of CSD, and CSD-induced hypothalamic neuronal activation hence can be a potential target in migraine treatment.

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“…CSD has been shown to activate neuronal pannexin1 channels and initiate the downstream inflammatory signaling following formation of the inflammasome complex ( Karatas et al, 2013 ; Ghaemi et al, 2016 ; Takizawa et al, 2016 ; Chen et al, 2017 ; Eising et al, 2017 ; Ghaemi et al, 2018 ; Bu et al, 2020 ; Takizawa et al, 2020b ). Inflammasome formation causes release of pro-inflammatory mediators such IL1-ß and HMGB1 from neurons, which triggers translocation of inflammatory transcription factor NF-kappaB to the nucleus in astrocytes ( Karatas et al, 2013 ; Takizawa et al, 2016 ; Dehghani et al, 2021 ). NF-kappaB induces hundreds of transcripts including tens of inflammatory mediators such as iNOS, COX2, and cytokines ( https://www.bu.edu/nf-kb/gene-resources/target-genes/ ).…”

Section: Introductionmentioning

confidence: 99%

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Eren-Koçak

Dalkara

2021

Front. Pharmacol.

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Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K+, Na+, and Ca+2 channels, have been reported to be disturbed in both depression and migraine. Ion channels and energy supply to synapses not only change excitability of neurons but can also mediate the induction and maintenance of inflammatory signaling implicated in the pathophysiology of both disorders. In this respect, Pannexin-1 and P2X7 large-pore ion channel receptors can induce inflammasome formation that triggers release of pro-inflammatory mediators from the cell. Here, the role of ion channels involved in the regulation of excitation-inhibition balance, synaptic energy homeostasis as well as inflammatory signaling in migraine and depression will be reviewed.

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Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice

Cited by 14 publications

References 32 publications

Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine

Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine

The Effect of P2X7 Antagonism on Subcortical Spread of Optogenetically-Triggered Cortical Spreading Depression and Neuroinflammation

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

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