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Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis

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Abstract

Epileptic seizure-induced brain injuries include activation of neuroimmune response with activation of microglia, astrocytes cells releasing neurotoxic inflammatory mediators underlies the pathophysiology of epilepsy. A wide spectrum of neuroinflammatory pathways is involved in neurodegeneration along with elevated levels of inflammatory mediators indicating the neuroinflammation in the epileptic brain. Therefore, the neuroimmune response is commonly observed in the epileptic brain, indicating elevated cytokine levels, providing an understanding of the neuroinflammatory mechanism contributing to seizures recurrence. Clinical and experimental-based evidence suggested the elevated levels of cytokines responsible for neuronal excitation and blood–brain barrier (BBB) dysfunctioning causing the drug resistance in epilepsy. Therefore, the understanding of the pathogenesis of neuroinflammation in epilepsy, including migration of microglial cells releasing the inflammatory cytokines indicating the correlation of elevated levels of inflammatory mediators (interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) triggering the generation or recurrence of seizures. The current review summarized the knowledge regarding elevated inflammatory mediators as immunomodulatory response correlating multiple neuroinflammatory NF-kB, RIPK, MAPK, ERK, JNK, JAK-STAT signaling cascades in epileptogenesis. Further selective targeting of inflammatory mediators provides beneficial therapeutic strategies for epilepsy.

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Abbreviations

TNF α:

Tumour necrosis factor alpha

ERK:

Extracellular regulated kinase

JNK-c:

Jun N-terminal kinase

AP-1:

Activator protein-1

NF-κB:

Nuclear factor kappa light chain enhancer of activated B cells

HMGB1:

High mobility group box 1 protein

TRAF2:

TNF Receptor Associated Factor 2

JAK-STAT:

Janus kinases signal transducer and activator of transcription proteins

BBB:

Blood–brain barrier

NMDA:

N-Methyl-d-aspartic acid

BCL2:

B-cell lymphoma 2

COX-2:

Cyclooxygenase2

P-gp:

P-glycoprotein

AEDs:

Antiepileptic drugs

PGE2:

Prostaglandin E2

GABA:

Gamma-Aminobutyric acid

GPCR:

G-protein-coupled receptors

OS:

Oxidative stress

BDNF:

Brain-derived neurotrophic factor

ROS:

Reactive oxygen species

miRNA:

MicroRNAs

IL-1:

Interleukin-1

TBI:

Traumatic brain injury

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Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India for providing the necessary facilities to carry out the research work.

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  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India

    Shubham Vishwakarma, Shareen Singh & Thakur Gurjeet Singh

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  1. Shubham Vishwakarma
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  2. Shareen Singh
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Conceptualization: Conceived and designed the experiments: TGS. Analyzed the data: SS, TGS Wrote the manuscript: SV, SS Editing of the Manuscript: TGS critically reviewed the article: TGS. All authors read and approved the final manuscript.

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Correspondence to Thakur Gurjeet Singh.

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Vishwakarma, S., Singh, S. & Singh, T.G. Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis. Mol Biol Rep 49, 1437–1452 (2022). https://doi.org/10.1007/s11033-021-06896-8

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