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Glia Signaling and Brain Microenvironment in Migraine

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Abstract

Migraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function, neurotransmitter disturbances, cortical hyperexcitability, genetic factors, and endocrine system problems, are responsible for migraine. However, these mechanisms have not completely delineated the pathophysiology behind migraine, and they should be further studied. The brain microenvironment comprises neurons, glial cells, and vascular structures with complex interactions. Disruption of the brain microenvironment is the main culprit behind various neurological disorders. Neuron-glia crosstalk contributes to hyperalgesia in migraine. In the brain, microenvironment and related peripheral regulatory circuits, microglia, astrocytes, and satellite cells are necessary for proper function. These are the most important cells that could induce migraine headaches by disturbing the balance of the neurotransmitters in the nervous system. Neuroinflammation and oxidative stress are the prominent reactions glial cells drive during migraine. Understanding the role of cellular and molecular components of the brain microenvironment on the major neurotransmitters engaged in migraine pathophysiology facilitates the development of new therapeutic approaches with higher effectiveness for migraine headaches. Investigating the role of the brain microenvironment and neuroinflammation in migraine may help decipher its pathophysiology and provide an opportunity to develop novel therapeutic approaches for its management. This review aims to discuss the neuron-glia interactions in the brain microenvironment during migraine and their potential role as a therapeutic target for the treatment of migraine.

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Abbreviations

CNS:

Central nervous system

BBB:

Blood-brain barrier

IgE:

Immunoglobulin

TNF-α:

Tumor necrosis factor-α

IL:

Interleukin

CGRP:

Calcitonin gene–related peptide

NMDA:

N-methyl-D-aspartate

SGC:

Satellite glial cells

PICs:

Proinflammatory cytokines

TNC:

Trigeminal nucleus caudalis

PAG:

Periaqueductal gray

LC:

Locus coeruleus

RN:

Raphe nuclei

PI3K:

Phosphatidylinositol-3-kinase

CSD:

Cortical spreading depolarization

TRPA1:

Transient receptor potential ankyrin 1

NO:

Nitric oxide

TG:

Trigeminal ganglion

FHM:

Familial hemiplegic migraine

DRG:

Dorsal root ganglion

TRP:

Transient receptor potential

CRLR/CGRPR1:

Calcitonin receptor-like receptor/CGRP receptor 1

ROS:

Reactive oxygen species

TGF-β:

Transforming growth factor-β

BDNF:

Brain-derived neurotrophic factor

NLRP3:

NLR family pyrin domain containing 3

TLR:

Toll-like receptor

NF-Κb:

Nuclear factor kappa B

STAT:

Signal transducer and activator of transcription

IFN:

Interferon

iNOS:

Inducible nitric oxide synthase

P2XR:

P2X purinergic receptor

ATP:

Adenosine triphosphate

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

GABAA:

Gamma-aminobutyric acid A

GLT1:

Glutamate transporter 1

GluR1:

Glutamate receptor 1

Kir:

Inwardly rectifying potassium channels

EAAT2:

Excitatory amino acid transporters 2

EPK:

Eukaryotic protein kinase

RAMP:

Receptor activity modifying proteins

CASK:

Calmodulin-dependent serine protein kinase

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium-binding adaptor molecule 1

SNAP-25:

Synaptosomal-associated protein, 25 kDa

HK-1:

Hemokinin-1

pERK:

Extracellular signal-regulated kinase

PRR:

Pattern recognition receptors

JAK:

Janus kinase

CCL:

Chemokine ligand

Α7 nAChR:

α7 Nicotinic acetylcholine receptor

P-JNK:

Phosphorylated c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

SFRP1:

Secreted frizzled‐related protein 1

PACAP:

Pituitary adenylate cyclase–activating polypeptide

VIP:

Vasoactive intestinal peptide

Th:

T helper cells

PGI2:

Prostaglandin I2

GABA:

Gamma-aminobutyric acid

TRPV1:

Transient receptor potential cation channel subfamily V member 1

PAC1:

PACAP type I

AEG-1:

Astrocyte elevated gene-1

5-HT:

5-Hydroxytryptamine

nVNS:

Non-invasive vagus nerve stimulation

CADASIL:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

HERNS:

Hereditary endotheliopathy with retinopathy, nephropathy, and stroke

GDNF:

Glial cell line–derived neurotrophic factor

GFRα3:

Growth family receptor α3

NSAIDs:

Nonsteroidal anti-inflammatory drugs

FDA:

US Food and Drug Administration

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Authors and Affiliations

  1. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Hanieh Amani

  2. Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Alireza Soltani Khaboushan

  3. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Alireza Soltani Khaboushan & Abbas Tafakhori

  4. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

    Gisela M. Terwindt

  5. Department of Neurology, Imam Khomeini Hospital, Keshavarz Blvd., Tehran, Iran

    Abbas Tafakhori

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HA conceptualized the title, prepared the first draft, and designed the figures and tables. ASK conceptualized the title, prepared the first draft, edited the first draft, and prepared final draft. GMT conceptualized the title, critically revised the manuscript, and finalized the draft. AT conceptualized the title, supervised the project, critically revised the manuscript, and finalized the draft. All the authors have read the final manuscript and approved it.

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Amani, H., Soltani Khaboushan, A., Terwindt, G.M. et al. Glia Signaling and Brain Microenvironment in Migraine. Mol Neurobiol 60, 3911–3934 (2023). https://doi.org/10.1007/s12035-023-03300-3

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