Abstract
BackgroundAccumulating evidence suggests that neuroinflammation plays an important role in the progression of Parkinson’s disease (PD). Excessively activated microglia produce several pro-inflammatory enzymes and pro-inflammatory cytokines, leading to damage to surrounding neurons and eventually inducing neurodegeneration. Therefore, the inhibition of microglial overactivation may be a potential therapeutic strategy to prevent the further progression of PD. β-Hydroxybutyric acid (BHBA) has been shown to suppress lipopolysaccharide (LPS)-induced inflammation in BV-2 cells and to protect dopaminergic neurons in previous studies, but the underlying mechanisms remain unclear. Thus, in this study, we further investigated this mechanism in LPS-induced in vivo and in vitro PD models.MethodsFor the in vitro experiments, primary mesencephalic neuron-glia cultures were pretreated with BHBA and stimulated with LPS. [3H]dopamine (DA) uptake, tyrosine hydroxylase-immunoreactive (TH-ir) neurons and morphological analysis were evaluated and analyzed in primary mesencephalic neuron-glia cultures. In vivo, microglial activation and the injury of dopaminergic neurons were induced by LPS intranigral injection, and the effects of BHBA treatment on microglial activation and the survival ratio and function of dopaminergic neurons were investigated. Four our in vitro mechanistic experiment, primary microglial cells were pretreated with BHBA and stimulated with LPS; the cells were then assessed for the responses of pro-inflammatory enzymes and pro-inflammatory cytokines, and the NF-κB signaling pathway was evaluated and analyzed.ResultsWe found that BHBA concentration-dependently attenuated the LPS-induced decrease in [3H]DA uptake and loss of TH-ir neurons in the primary mesencephalic neuron/glia mixed culture. BHBA treatment significantly improved the motor dysfunction of the PD model rats induced by intranigral injection of LPS, and this beneficial effect of BHBA was attributed to the inhibition of microglial overactivation and the protection of dopaminergic neurons in the substantia nigra (SN). Our in vitro mechanistic study revealed that the inhibitory effect of BHBA on microglia was mediated by G-protein-coupled receptor 109A (GPR109A) and involved the NF-κB signaling pathway, causing the inhibition of pro-inflammatory enzyme (iNOS and COX-2) and pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) production.ConclusionsIn conclusion, the present study supports the effectiveness of BHBA in protecting dopaminergic neurons against inflammatory challenge.
Highlights
Accumulating evidence suggests that neuroinflammation plays an important role in the progression of Parkinson’s disease (PD)
Effect of β-hydroxybutyric acid on lipopolysaccharideinduced degeneration of dopaminergic neurons To investigate whether the LPS-induced damage of dopaminergic neurons could be prevented by BHBA, rat mesencephalic neuron-glia cultures were pretreated for 30 min with vehicle or BHBA (0, 0.5, 1, or 1.5 mM) before treatment with 10 ng/ml LPS
In the cultures pretreated with 1.5 mM BHBA before LPS stimulation, the tyrosine hydroxylase (TH)-ir neurons were more numerous and appeared less affected compared with the LPS-treated cultures (Figure 1A)
Summary
Accumulating evidence suggests that neuroinflammation plays an important role in the progression of Parkinson’s disease (PD). Activated microglia produce several pro-inflammatory enzymes and pro-inflammatory cytokines, leading to damage to surrounding neurons and eventually inducing neurodegeneration. Β-Hydroxybutyric acid (BHBA) has been shown to suppress lipopolysaccharide (LPS)-induced inflammation in BV-2 cells and to protect dopaminergic neurons in previous studies, but the underlying mechanisms remain unclear. Accumulating evidence suggests that neuroinflammation plays an important role in the progression of PD [9,10]. Excessive activation of microglia and the consequent release of several pro-inflammatory cytokines and/or pro-inflammatory enzymes, such as TNF-α, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), are believed to contribute to neurodegenerative processes [14,15]. Inhibition of microglial overactivation may be a potential therapeutic strategy to prevent further progression of PD
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