Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine

Yamanaka, Gaku; Suzuki, Shinji; Morishita, Natsumi; Takeshita, Mika; Kanou, Kanako; Takamatsu, Tomoko; Suzuki, Shunsuke; Morıchı, Shinichiro; Watanabe, Yusuke; Ishida, Yu; Go, Soken; Oana, Shingo; Kashiwagi, Yasuyo; Kawashima, Hisashi

doi:10.3390/ijms22168929

Cited by 44 publications

(28 citation statements)

References 120 publications

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“…However, due to the limited access of IgG antibodies to central sites within the BBB, an effective central effect of CGRP-targeting antibodies appears unlikely. Moreover, despite some controversial clinical observations, no convincing evidence supports the assumption that migraine attacks enhance the permeability of the BBB, allowing the passage of chemical substances from the blood into the brain tissue [ 75 ]. Therefore, trigeminal ganglion neurons and satellite cells and the dura mater innervated by the peripheral axons of the trigeminal afferents—structures not protected by the BBB—are the most likely targets of the antibody treatment.…”

Section: Discussionmentioning

confidence: 99%

The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow

Dux

Vogler

Kuhn

et al. 2022

Cells

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Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) belong to a new generation of therapeutics that are effective in the prevention of migraine. CGRP, a potent vasodilator, is strongly implicated in the pathophysiology of migraine, but its role remains to be fully elucidated. The hemisected rat head preparation and laser Doppler flowmetry were used to examine the effects on CGRP release from the dura mater and meningeal blood flow of the subcutaneously injected anti-CGRP monoclonal antibody fremanezumab at 30 mg/kg, when compared to an isotype control antibody. Some rats were administered glycerol trinitrate (GTN) intraperitoneally to produce a migraine-like sensitized state. When compared to the control antibody, the fremanezumab injection was followed by reduced basal and capsaicin-evoked CGRP release from day 3 up to 30 days. The difference was enhanced after 4 h of GTN application. The samples from the female rats showed a higher CGRP release compared to that of the males. The increases in meningeal blood flow induced by acrolein (100 µM) and capsaicin (100 nM) were reduced 13–20 days after the fremanezumab injection, and the direct vasoconstrictor effect of high capsaicin (10 µM) was intensified. In conclusion, fremanezumab lowers the CGRP release and lasts up to four weeks, thereby lowering the CGRP-dependent meningeal blood flow. The antibody may not only prevent the released CGRP from binding but may also influence the CGRP release stimulated by noxious agents relevant for the generation of migraine pain.

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Section: Discussionmentioning

confidence: 99%

The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow

Dux

Vogler

Kuhn

et al. 2022

Cells

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“…Sensory nerve fibers contain neuropeptides coming from the trigeminal ganglion (TG) that innervate the dura, generating neurogenic inflammation in the dura. The direct conduction of TG neurons can activate c-fos in the TNC, resulting in a pain sensation that is eventually experienced as a headache ( 77 ). Furthermore, evidence from mice and rat studies showed that parenchymal neuroinflammatory signaling between neurons, astrocytes, and microglia, which finally migrates to the meninges ( 65 , 66 , 78 , 80 – 85 ), might be the potential pathway of transferring a non-homeostatic activity in the unconscious brain to pain-sensitive meninges ( 86 , 87 ).…”

Section: Methodsmentioning

confidence: 99%

Immunologic aspects of migraine: A review of literature

et al. 2022

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Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.

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“…Our data demonstrated that saracatinib reduced IL-1β, CCL2, and CXCL1 release promoted by CGRP in the TG ( Figure 3 A–C). All these proteins are associated with pain hypersensitivity and migraine [ 61 , 62 , 63 , 64 , 65 ]. We therefore further investigated whether SFKs activity promotes cytokines production machinery by examining the effect of the SFKs inhibitor saracatinib on their CGRP-induced gene expression.…”

Section: Resultsmentioning

confidence: 99%

Src Family Kinases Facilitate the Crosstalk between CGRP and Cytokines in Sensitizing Trigeminal Ganglion via Transmitting CGRP Receptor/PKA Pathway

Nie

Sun

Gong

et al. 2022

Cells

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The communication between calcitonin gene-related peptide (CGRP) and cytokines plays a prominent role in maintaining trigeminal ganglion (TG) and trigeminovascular sensitization. However, the underlying regulatory mechanism is elusive. In this study, we explored the hypothesis that Src family kinases (SFKs) activity facilitates the crosstalk between CGRP and cytokines in sensitizing TG. Mouse TG tissue culture was performed to study CGRP release by enzyme-linked immunosorbent assay, cytokine release by multiplex assay, cytokine gene expression by quantitative polymerase chain reaction, and phosphorylated SFKs level by western blot. The results demonstrated that a SFKs activator, pYEEI (YGRKKRRQRRREPQY(PO3H2)EEIPIYL) alone, did not alter CGRP release or the inflammatory cytokine interleukin-1β (IL-1β) gene expression in the mouse TG. In contrast, a SFKs inhibitor, saracatinib, restored CGRP release, the inflammatory cytokines IL-1β, C-X-C motif ligand 1, C-C motif ligand 2 (CCL2) release, and IL-1β, CCL2 gene expression when the mouse TG was pre-sensitized with hydrogen peroxide and CGRP respectively. Consistently with this, the phosphorylated SFKs level was increased by both hydrogen peroxide and CGRP in the mouse TG, which was reduced by a CGRP receptor inhibitor BIBN4096 and a protein kinase A (PKA) inhibitor PKI (14–22) Amide. The present study demonstrates that SFKs activity plays a pivotal role in facilitating the crosstalk between CGRP and cytokines by transmitting CGRP receptor/PKA signaling to potentiate TG sensitization and ultimately trigeminovascular sensitization.

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Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine

Cited by 44 publications

References 120 publications

The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow

The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow

Immunologic aspects of migraine: A review of literature

Src Family Kinases Facilitate the Crosstalk between CGRP and Cytokines in Sensitizing Trigeminal Ganglion via Transmitting CGRP Receptor/PKA Pathway

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