Activation of pial and dural macrophages and dendritic cells by cortical spreading depression

Schain, Aaron; Melo‐Carrillo, Agustin; Borsook, David; Grutzendler, Jaime; Strassman, Andrew M.; Burstein, Rami

doi:10.1002/ana.25169

Cited by 66 publications

(49 citation statements)

References 57 publications

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“…It was recently used to image peripheral tissues such as immune cell infiltration in the bone after fracture, inflamed pannus tissue in osteoarthritis, the activation of macrophage and stroma in the synovial tissue of patients with rheumatoid arthritis, and in the neuroforamen of patients suffering from sciatica . Our findings in migraine demonstrate that inflammation is consistently present in a pain‐sensitive tissue, thereby reinforcing results from preclinical studies . From our results, however, we cannot conclude whether the elevated TSPO signals observed in MWA patients reflect increased protein expression, increased cellular density, or both.…”

Section: Discussionsupporting

confidence: 72%

Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Hadjikhani

Albrecht

Mainero

et al. 2020

Annals of Neurology

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Objective: Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. Methods: We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). Results: MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT.Interpretation: A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders.

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Section: Discussionsupporting

confidence: 72%

Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Hadjikhani

Albrecht

Mainero

et al. 2020

Annals of Neurology

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“…12 Dural macrophages line blood vessels and connective tissues, responding to inflammatory stimuli immediately. 29 A previous study found that cortical spreading depression-induced activation of pial and dural macrophages is more likely to increase inflammation in which meningeal nociceptors function. 29 In this study, we observed that EA significantly decreased the number of immune cells.…”

Section: Discussionmentioning

confidence: 98%

“…29 A previous study found that cortical spreading depression-induced activation of pial and dural macrophages is more likely to increase inflammation in which meningeal nociceptors function. 29 In this study, we observed that EA significantly decreased the number of immune cells. Therefore, we detected a reduction in neuropeptides and inflammatory factors using ELISA.…”

Section: Discussionmentioning

confidence: 98%

<p>Electroacupuncture Inhibits Hyperalgesia by Alleviating Inflammatory Factors in a Rat Model of Migraine</p>

Zhao¹,

Liu²,

Xu³

et al. 2020

JPR

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Objective: Acupuncture has a therapeutic effect similar to that of prophylactic drugs and can be considered a treatment option for migraineurs. However, the mechanism of acupuncture treatment's effect on migraine is uncertain. An approach based on anti-inflammatory effects is an important treatment strategy for migraine because non-steroidal anti-inflammatory drugs (NSAIDs) are usually used during migraine attacks. Meningeal inflammation is thought to be responsible for the activation of the trigeminovascular system. Our previous study found that electroacupuncture (EA) decreased neurogenic inflammation mediator expression in the trigeminal ganglion (TG) and alleviated hyperalgesia. The present study examined whether EA would inhibit hyperalgesia by alleviating neurogenic inflammatory factors.Methods: A rat model of migraine was established using dural electrical stimulation (DES). Five groups were analyzed in this study. The Model group received DES three times to mimic migraine attacks, a Control group had sham DES, and three groups received electroacupuncture after DES: a Non-Acu group at a non-acupuncture point, a GB20 group at GB20, and a GB20/34 group at GB20 and GB34 acupuncture points. We evaluated mechanical hyperalgesia using an electronic von Frey esthesiometer in the awake state. After sacrifice, the dura mater was analyzed using immunofluorescence. Serum calcitonin gene-related peptide, cyclooxygenase-2, brainderived neurotrophic factor, IL-1β, IL-6, and TNF levels were determined using enzymelinked immunosorbent assays to evaluate the anti-inflammatory effect of acupuncture. Results: After repeated DES, we observed facial and hind paw mechanical hyperalgesia, which was inhibited by electroacupuncture. Electrical stimulation increased the number of mast cells and macrophages and serum levels of inflammatory factors. GB20 and GB20/34 electroacupuncture significantly decreased the number of mast cells and macrophages and serum levels of inflammatory factors. Moreover, electroacupuncture at GB20/34 was superior to that at GB20 alone in inhibiting hyperalgesia and alleviating inflammatory factors. Conclusion: Electroacupuncture inhibits DES-induced hyperalgesia by alleviating inflammatory factors. Inhibition of dural mast cells, macrophages, and serum inflammatory factors may be one of the mechanisms involved in acupuncture treatment's effect on migraine.

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“…Note that the pial arterioles and veins are not connected to the dural vessels. Though these two vascular structures are physically adjacent, they form completely unconnected vascular networks 44 , 45 .…”

Section: Introductionmentioning

confidence: 99%

The pial vasculature of the mouse develops according to a sensory-independent program

Adams

Winder

Blinder

et al. 2018

Sci Rep

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The cerebral vasculature is organized to supply the brain’s metabolic needs. Sensory deprivation during the early postnatal period causes altered neural activity and lower metabolic demand. Neural activity is instructional for some aspects of vascular development, and deprivation causes changes in capillary density in the deprived brain region. However, it is not known if the pial arteriole network, which contains many leptomeningeal anastomoses (LMAs) that endow the network with redundancy against occlusions, is also affected by sensory deprivation. We quantified the effects of early-life sensory deprivation via whisker plucking on the densities of LMAs and penetrating arterioles (PAs) in anatomically-identified primary sensory regions (vibrissae cortex, forelimb/hindlimb cortex, visual cortex and auditory cortex) in mice. We found that the densities of penetrating arterioles were the same across cortical regions, though the hindlimb representation had a higher density of LMAs than other sensory regions. We found that the densities of PAs and LMAs, as well as quantitative measures of network topology, were not affected by sensory deprivation. Our results show that the postnatal development of the pial arterial network is robust to sensory deprivation.

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Activation of pial and dural macrophages and dendritic cells by cortical spreading depression

Cited by 66 publications

References 57 publications

Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

Extra‐Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura

<p>Electroacupuncture Inhibits Hyperalgesia by Alleviating Inflammatory Factors in a Rat Model of Migraine</p>

The pial vasculature of the mouse develops according to a sensory-independent program

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