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Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis

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Abstract

Increasing evidence corroborates the fundamental role of neuroinflammation in the development of epilepsy. Proinflammatory cytokines (PICs) are crucial contributors to the inflammatory reactions in the brain. It is evidenced that epileptic seizures are associated with elevated levels of PICs, particularly interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), which underscores the impact of neuroinflammation and PICs on hyperexcitability of the brain and epileptogenesis. Since the pathophysiology of epilepsy is unknown, determining the possible roles of PICs in epileptogenesis could facilitate unraveling the pathophysiology of epilepsy. About one-third of epileptic patients are drug-resistant, and existing treatments only resolve symptoms and do not inhibit epileptogenesis; thus, treatment of epilepsy is still challenging. Accordingly, understanding the function of PICs in epilepsy could provide us with promising targets for the treatment of epilepsy, especially drug-resistant type. In this review, we outline the role of neuroinflammation and its primary mediators, including IL-1β, IL-1α, IL-6, IL-17, IL-18, TNF-α, and interferon-γ (IFN-γ) in the pathophysiology of epilepsy. Furthermore, we discuss the potential therapeutic targeting of PICs and cytokine receptors in the treatment of epilepsy.

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Abbreviations

CNS:

Central nervous system

BBB:

Blood–brain barrier

PIC:

Proinflammatory cytokines

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

SLE:

Systemic lupus erythematosus

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

TNFR1:

TNF receptor-1

MS:

Multiple sclerosis

APP:

Amyloid precursor protein

Aβ:

β-Amyloid

NF-кB:

Nuclear factor-кB

TLR:

Toll-like receptor

HMGB1:

High Mobility Group Box 1

NMDA:

N-methyl-D-aspartate, NMDAR, N-methyl-D-aspartate receptor

TLE:

Temporal lobe epilepsy

KA:

Kainic acid

PI3K/Akt/mTOR:

Phosphoinositide 3-kinase/Akt/mammalian target of rapamycin

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

TGF-β:

Transforming growth factor-β

PGE2:

Prostaglandin E2

IL-1R:

IL-1 family receptor

Ig:

Immunoglobulin

TIR:

Toll/IL-1 receptor

IL-1RA:

IL-1 receptor antagonist

ICV:

Intracerebroventricular

N-Smase:

Neutral sphingomyelinase

NO:

Nitric oxide

SYN:

Synaptophysin

LPS:

Lipopolysaccharide

GABA:

Gamma-aminobutyric acid

GAT-1:

GABA transporter type 1

FIRES:

Febrile infection-related epilepsy syndrome

ICE/caspase 1:

IL-1β converting enzyme

IL-6R:

IL-6 receptor

gp130:

130 KDa glycoprotein

JAK/STAT:

Janus kinase/signal transducer and activator of transcription

MAPK:

Mitogen-activated protein kinase

mIL-6R:

Membrane-bound IL-6R

sIL-6R:

Soluble IL-6R

sgp130:

Soluble form of gp130

XLE:

Extra-temporal lobe epilepsy

ADAM:

A Disintegrin and Metalloproteinase

tmTNF-α:

Transmembrane TNF-α

TACE:

TNF-α converting enzyme

sTNF-α:

Soluble TNF-α

TRADD:

TNFR1-associated death domain

TRAF:

TNF receptor-associated factor

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors

TRPV1:

Transient receptor potential vanilloid 1

Sema7A:

Semaphoring7A

HIF-1α:

Hypoxia-inducible factor subtype 1α

IFN-γ:

Interferon-γ

NK cells:

Natural killer cells

APC:

Antigen-presenting cell

IFN-γR:

Interferon-γ receptor

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Acknowledgements

We thank Dr. A. Vezzani for reading this manuscript during its preparation.

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  1. Students′ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Alireza Soltani Khaboushan & Niloufar Yazdanpanah

  2. Research Center for Immunodeficiencies, Children′s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Niloufar Yazdanpanah & Nima Rezaei

  3. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Alireza Soltani Khaboushan, Niloufar Yazdanpanah & Nima Rezaei

  4. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  5. Children′s Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, 14194, Tehran, Iran

    Nima Rezaei

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ASK conceptualized the title, prepared the first draft, and designed the figures. NY conceptualized the title, edited and revised the manuscript and prepared the final draft. NR conceptualized the title, critically revised the manuscript, edited and finalized the draft, and supervised the project. All the authors have read and approved the final draft of the manuscript.

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Soltani Khaboushan, A., Yazdanpanah, N. & Rezaei, N. Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis. Mol Neurobiol 59, 1724–1743 (2022). https://doi.org/10.1007/s12035-022-02725-6

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