Abstract
BackgroundMicroglia-mediated neuroinflammation is associated with epilepsy. Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for mitigating epileptogenesis. We previously found that dynorphins protected against epilepsy via activation of kappa opioid receptor (KOR). Here, this study aims to investigate the role and the mechanism of dynorphin in regulating microglial polarization.MethodsA pilocarpine-induced rat model of epilepsy was established and lipopolysaccharide (LPS)-activated BV-2 microglial cells were used as an inflammatory model to explore the mechanism of dynorphin regulating microglial polarization.ResultsOverexpression of the dynorphin precursor protein prodynorphin (PDYN) alleviated the pilocarpine-induced neuronal apoptosis, promoted microglial polarization to the M2 phenotype, and inhibited pilocarpine-induced Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway in the hippocampi of epileptic rats. Dynorphin activation of KOR promoted microglial M2 polarization via inhibiting TLR4/NF-κB pathway in LPS-stimulated BV-2 microglial cells. Moreover, dynorphin/KOR regulated microglial M2 polarization inhibited apoptosis of the primary mouse hippocampal neurons.ConclusionIn conclusion, dynorphin activation of KOR promotes microglia polarization toward M2 phenotype via inhibiting TLR4/NF-κB pathway.
Highlights
IntroductionWe previously found that dynorphins protected against epilepsy via activation of kappa opioid receptor (KOR)
TdT‐mediated dUTP Nick‐End Labeling (TUNEL) staining demonstrated that intra-hippocampus injection of LV-PDYN markedly attenuated the pilocarpine-induced hippocampal neuronal apoptosis (Fig. 1c)
We examined the microglia state in the pilocarpineinduced epilepsy rats and found that these epilepsy model rats exhibited a significant increase in the number of ionized calcium binding adaptor molecule-1 (Iba-1)+inducible NO synthase (iNOS)+ cells (M1) and Iba-1+Arg-1+ cells (M2) in rat hippocampus when compared with the control rats, indicating microglial activation
Summary
We previously found that dynorphins protected against epilepsy via activation of kappa opioid receptor (KOR). The M2 phenotype is characterized by increased expression of several proteins such as arginase-1 (Arg-1) and mannose receptor (MR/CD206), as well as increased production of anti-inflammatory cytokines IL-4 and IL-10 [1, 3]. Convincing evidence has suggested that the pro- and anti-inflammatory states of microglia determine the outcomes of many CNS diseases, including epilepsy. Toll-like receptor 4 (TLR4) is primarily expressed in microglia and mediates microglial activation [7]. TLR4 induces activation of nuclear factor-kappa B (NF-κB) via the myeloid differentiation factor 88 (MyD88)/ TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathway, and increasing cytokine expression and inflammatory injury [8]. A recent study showed that betaine induced polarization of the microglia to the M2 phenotype by possibly inhibiting the TLR4/NF-κB pathway [3], reinforcing the important role of the TLR4/NF-κB pathway in regulating microglia polarization
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