Apamin Suppresses LPS-Induced Neuroinflammatory Responses by Regulating SK Channels and TLR4-Mediated Signaling Pathways.

Jihyun Park,Kyung Mi Jang,Kwan-Kyu Park

doi:10.3390/ijms21124319

Jihyun Park, Kyung Mi Jang + Show 1 more

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https://doi.org/10.3390/ijms21124319

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Abstract

Neuroinflammation plays a vital role in neurodegenerative conditions. Microglia are a key component of the neuroinflammatory response. There is a growing interest in developing drugs to target microglia and thereby control neuroinflammatory processes. Apamin (APM) is a specifically selective antagonist of small conductance calcium-activated potassium (SK) channels. However, its effect on neuroinflammation is largely unknown. We examine the effects of APM on lipopolysaccharide (LPS)-stimulated BV2 and rat primary microglial cells. Regarding the molecular mechanism by which APM significantly inhibits proinflammatory cytokine production and microglial cell activation, we found that APM does so by reducing the expression of phosphorylated CaMKII and toll-like receptor (TLR4). In particular, APM potently suppressed the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription (STAT)3 and phosphorylated mitogen-activated protein kinases (MAPK)-extracellular signal-regulated kinase (ERK). In addition, the correlation of NF-κB/STAT3 and MAPK-ERK in the neuroinflammatory response was verified through inhibitors. The literature and our findings suggest that APM is a promising candidate for an anti-neuroinflammatory agent and can potentially be used for the prevention and treatment of various neurological disorders.

Highlights

Neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases including ischemic stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD) [1]
To investigate the influence of tumor necrosis factor α (TNFα) on LPS-induced microglial activation, BV2 cells were treated with different concentrations of LPS for 12 h and analyzed by an established Enzyme-Linked Immunosorbent Assay (ELISA) assay
The microglial proinflammatory response is attributed to the activation of Ca2+-activated SK channels and TLR4 by LPS, which triggers downstream inflammatory signaling pathways, leading to protein phosphorylation, nuclear translocation, and, to proinflammatory cytokines mediators [4,6,8,18,30,34]

Summary

Introduction

Neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases including ischemic stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD) [1]. The resident immune cells of the central nervous system (CNS), play an important role in neuroprotection and are involved in various neurodegenerative pathologies [2]. Activated microglia produce neuroinflammatory responses by releasing various proinflammatory cytokines and mediators including tumor necrosis factor α (TNFα), interleukin 1β (IL1β), interleukin 6 (IL6), and cyclooxygenases-2 (COX2) [4]. These neuroinflammatory responses are strongly correlated with neurodegenerative diseases and lead to synaptic degeneration, neuronal cell death, and cognitive dysfunction [5]. The increased neuroinflammatory response activates the ability to kill neurons through a peroxy-nitrite-mediated mechanism [7]. The modulation of neuroinflammatory responses represents a potential therapeutic strategy for a wide range of pathological conditions, including neurodegenerative diseases

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