BackgroundCortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural... Show moreBackgroundCortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation.MethodsCSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor.ResultsIn both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release.ConclusionsCSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine. Show less
Dehghani, A.; Phisonkunkasem, T.; Ozcan, S.Y.; Dalkara, T.; Maagdenberg, A.M.J.M. van den; Tolner, E.A.; Karatas, H. 2021
Neuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-KB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown... Show moreNeuroinflammatory changes involving neuronal HMGB1 release and astrocytic NF-KB nuclear translocation occur following cortical spreading depolarization (CSD) in wildtype (WT) mice but it is unknown to what extent this occurs in the migraine brain. We therefore investigated in familial hemiplegic migraine type 1 (FHM1) knock-in mice, which express an intrinsic hyperexcitability phenotype, the extent of neuroinflammation without and after CSD. CSD was evoked in one hemisphere by pinprick (single CSD) or topical KCl application (multiple CSDs). Neuroinflammatory (HMGB1, NF-KB) and neuronal activation (pERK) markers were investigated by immunohistochemistry in the brains of WT and FHM1 mutant mice without and after CSD. Effects of NMDA receptor antagonism on basal and CSD-induced neuroinflammatory changes were examined by, respectively, systemically administered MK801 and ifenprodil or topical MK801 application. In FHM1 mutant mice, CSD caused enhanced neuronal HMGB1 release and astrocytic NF-KB nuclear translocation in the cortex and subcortical areas that were equally high in both hemispheres. In WT mice such effects were only pronounced in the hemisphere in which CSD was induced. Neuroinflammatory responses were associated with pERK expression indicating neuronal activation. Upon CSD, contralateral cortical and striatal HMGB1 release was reduced by topical application of MK801 in the hemisphere contralateral to the one in which CSD was induced. This study reveals that neuroinflammatory activation after CSD is widespread and extends to the contralateral hemisphere, particularly in brains of FHM1 mutant mice. Effective blockade of CSD-induced neuroinflammatory responses in the contralateral hemisphere in FHM1 mice by local NMDA receptor antagonism suggests that neuronal hyperexcitability-related neuroinflammation is relevant in migraine pathophysiology, but possibly also other neurological disorders in which spreading depolarization is involved. Show less
There is increasing evidence for the involvement of high mobility group box 1 (HMGB1) in inflammation, angiogenesis, and tumorigenesis. However, no studies have reviewed the role of HMGB1 in... Show moreThere is increasing evidence for the involvement of high mobility group box 1 (HMGB1) in inflammation, angiogenesis, and tumorigenesis. However, no studies have reviewed the role of HMGB1 in musculoskeletal disease. This systematic review aimed to evaluate the literature regarding the potential roles of HMGB1 in musculoskeletal disease (joint, tendon, ligament, intervertebral disk, and bone). After searching PubMed, MEDLINE, and EMBASE databases up to 01-01-2020, 66 articles that measured HMGB1 expression in musculoskeletal disease were included. Immune and tissue-resident stromal cells expressed HMGB1, and both diseased human tissues and animal disease models showed increased HMGB1 expression relative to controls. Administration of recombinant HMGB1 to diseased musculoskeletal tissues induced inflammation, whereas blocking HMGB1 ameliorated histopathologic and clinical severity of disease. HMGB1 redox status was investigated in only 3% of the articles: Fully reduced HMGB1 promoted chemotaxis of leukocytes and tissue repair, whereas disulfide HMGB1 acted as a pro-inflammatory mediator. Our review highlights that while HMGB1 is an important mediator in musculoskeletal disease, its redox status remains understudied. Identification of HMGB1 redox status in musculoskeletal tissues is critical to advance understanding of the diverse biological functions of HMGB1 in musculoskeletal disease. Importantly, this will inform future therapeutic strategies to target HMGB1. Show less
