Protective Effects And Its Mechanisms Of β-hydroxybutyric Acid In LPS-induced Parkinson’s Disease Models

Accumulating evidence suggests that neuroinflammation plays animportant role in the progression of Parkinson’s disease (PD). Excessivelyactivated microglia produce several pro-inflammatory enzymes (iNOS andCOX-2) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), leading todamage to surrounding neurons and eventually inducing neurodegeneration.Therefore, inhibition of microglial overactivation may be a potentialtherapeutic strategy to prevent further progression of PD. As an importantintermediate of amino acid and fatty acid catabolism, β-hydroxybutyric acid(BHBA) is similar to glucose in that it can be used by the brain to provideenergy, particularly for suckling newborns. In addition, BHBA has been shownto protect dopaminergic neurons in previous studies, but the underlyingmechanisms remain unclear. Accumulating data have demonstrated a stronganti-inflammatory activity of BHBA in macrophages and monocytes. So, wehypothesized that BHBA has the potential to act directly on microglia to inhibitproinflammatory proteins that may contribute to its neuroprotective effects invivo. Thus, in this study, we further investigated this mechanism inLPS-induced in vivo and in vitro PD models.The results showed that BHBA significantly reduced LPS-induced proteinand mRNA expression levels of iNOS, COX-2, TNF-α, IL-1β, and IL-6.Blocking of GPR109A by PTX or siRNA resulted in a loss of thisanti-inflammatory effect in BV-2cells and primary microglial cells. Westernblot analysis showed that BHBA reduced LPS-induced degradation of IκB-αand translocation of NF-κB, while no effect was observed on MAPKsphosphorylation in BV-2cells; reduced LPS-induced phosphorylation of NF-κB in primary microglial cells, and this effect was blocked byGPR109A-siRNA. All results imply that BHBA significantly reducesLPS-induced inflammation by inhibition of the GPR109A/NF-κB signalingpathway.In this study, we investigated whether BHBA is neuroprotective toinflammation-mediated neurodegenerative diseases. Pretreatment with BHBAreduced the degeneration of dopaminergic neurons induced by LPS inmesencephalic neuron-glia cultures in a dose-dependent manner. Theneuroprotective effect of BHBA was attributed to the inhibition of microglialactivation, since BHBA significantly inhibited the production of iNOS、COX-2、TNF-α、IL-1β and IL-6from LPS-stimulated microglia.Further in vivo study, we found BHBA administration improvedapomorphine-induced rotation in the LPS-induced PD model rats; BHBAadministration can also attenuates depletion of DA and DOPAC in the striatuminduced by LPS intranigral injection. In addition, BHBA treatment increasedthe number of tyrosine hydroxylase (TH)-positive cells and TH expression inthe substantia nigra of LPS-induced Parkinson’s disease model rats. Further,BHBA treatment inhibited microglial activation induced by LPS intranigralinjectionIn conclusion, BHBA significantly reduces LPS-induced inflammation byinhibition of the GPR109A/NF-κB signaling pathway; BHBA treatmentimproves LPS-induced behavioral dysfunction and protects dopaminergicneurons through inhibiting microglia-mediated neuroinflammation both in vitroand in vivo. Thus, GPR109A-mediated signaling pathways may representpotential targets for therapeutic intervention to prevent or slow the progressionof PD.