Abstract
BackgroundOveractivated microglia is involved in various kinds of neurodegenerative diseases. Suppression of microglial overactivation has emerged as a novel strategy for treatment of neuroinflammation-based neurodegeneration. In the current study, anti-inflammatory effects of oxytocin (OT), which is a highly conserved nonapeptide with hormone and neurotransmitter properties, were investigated in vitro and in vivo.MethodsBV-2 cells and primary microglia were pre-treated with OT (0.1, 1, and 10 μM) for 2 h followed by LPS treatment (500 ng/ml); microglial activation and pro-inflammatory mediators were measured by Western blot, RT-PCR, and immunofluorescence. The MAPK and NF-κB pathway proteins were assessed by Western blot. The intracellular calcium concentration ([Ca2+]i) was determined using Fluo2-/AM assay. Intranasal application of OT was pre-treated in BALB/C mice (adult male) followed by injected intraperitoneally with LPS (5 mg/kg). The effect of OT on LPS-induced microglial activation and pro-inflammatory mediators was measured by Western blot, RT-PCR, and immunofluorescence in vivo.ResultsUsing the BV-2 microglial cell line and primary microglia, we found that OT pre-treatment significantly inhibited LPS-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, OT inhibited phosphorylation of ERK and p38 but not JNK MAPK in LPS-induced microglia. OT remarkably reduced the elevation of [Ca2+]i in LPS-stimulated BV-2 cells. Furthermore, a systemic LPS-treated acute inflammation murine brain model was used to study the suppressive effects of OT against neuroinflammation in vivo. We found that pre-treatment with OT showed marked attenuation of microglial activation and pro-inflammatory factor levels.ConclusionsTaken together, the present study demonstrated that OT possesses anti-neuroinflammatory activity and might serve as a potential therapeutic agent for treating neuroinflammatory diseases.
Highlights
Overactivated microglia is involved in various kinds of neurodegenerative diseases
OT receptor (OTR) protein expressions measured by Western blot analysis were increased at 60 min after LPS administration, reached the peak point at 2 h, and remained elevated at 24 h in BV-2 cells (Fig. 1c)
The present study demonstrated that OT suppressed the expression of tumor necrosis factor-α (TNF-α), IL-1β, COX-2, and inducible nitric oxide synthase (iNOS) at the messenger RNA (mRNA) and proteins levels and reduced the elevation of [Ca2+]i in LPS-stimulated microglia cells
Summary
Overactivated microglia is involved in various kinds of neurodegenerative diseases. Suppression of microglial overactivation has emerged as a novel strategy for treatment of neuroinflammation-based neurodegeneration. Microglial activation can be induced by lipopolysaccharide (LPS), interferon (IFN)-γ, or β-amyloid and results in overproduction of inflammatory cytokines. These inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin (IL) -6, IL-1β, glutamate, nitric oxide, and reactive oxygen species, can collectively lead to neuronal damage, resulting in the progress of neurodegenerative diseases [3]. During this process, ramified resting microglia undergo morphological transformations including deramification, process shortening and thickening, and development into its activated amoeboid form [4]. Anti-inflammatory treatment via inhibition of microglial activation is regarded as a promising strategy for preventing neurodegenerative diseases in the clinic
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