Lovastatin induces neuroprotection by inhibiting inflammatory cytokines in 6-hydroxydopamine treated microglia cells.
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This study aims to investigate the impact of lovastatin on neuroinflammation in 6-OHDA-treated microglia cells.6-Hydroxydopamine (6-OHDA)-treated microglia cells were used to investigate the neuroprotective nature of lovastatin. After incubation with 6-OHDA and/or lovastatin for 24 h, test kits were used to detect the levels of LDH and glutamate, which were released from PC12 cells exposed to different culture media. The mRNA levels of TNF-α, IL-6 and IL-1β were determined by RT-PCR and the protein levels were analyzed by Western blot.LDH and glutamate levels in 6-OHDA-incubated PC12 cells increased, when compared with those in the controls, while incubation with lovastatin inhibited this elevation. The expression levels of TNF-α IL-6 and IL-1β were significantly upregulated after treatment with 6-OHDA. The 6-OHDA-stimulated mRNA and protein levels of TNF-α IL-6 and IL-1β were reduced by lovastatin.Our results suggest that Lovastatin is able to induce neuroprotection by inhibiting inflammatory cytokines. The data provide direct evidence of the potential application of lovastatin for the treatment of neuroinflammatory diseases.Keywords:
Lovastatin
Hydroxydopamine
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This study aims to investigate the impact of lovastatin on neuroinflammation in 6-OHDA-treated microglia cells.6-Hydroxydopamine (6-OHDA)-treated microglia cells were used to investigate the neuroprotective nature of lovastatin. After incubation with 6-OHDA and/or lovastatin for 24 h, test kits were used to detect the levels of LDH and glutamate, which were released from PC12 cells exposed to different culture media. The mRNA levels of TNF-α, IL-6 and IL-1β were determined by RT-PCR and the protein levels were analyzed by Western blot.LDH and glutamate levels in 6-OHDA-incubated PC12 cells increased, when compared with those in the controls, while incubation with lovastatin inhibited this elevation. The expression levels of TNF-α IL-6 and IL-1β were significantly upregulated after treatment with 6-OHDA. The 6-OHDA-stimulated mRNA and protein levels of TNF-α IL-6 and IL-1β were reduced by lovastatin.Our results suggest that Lovastatin is able to induce neuroprotection by inhibiting inflammatory cytokines. The data provide direct evidence of the potential application of lovastatin for the treatment of neuroinflammatory diseases.
Lovastatin
Hydroxydopamine
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MPTP
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Background: Chronic inflammation in central nervous system is a conspicuous hallmark in Alzheimer’s disease (AD) and microglial activation is now accepted as a key factor in neuroinflammation. SCM‐198 is an alkaloid extracted from Herba leonuri. In the present study, we investigated its direct and indirect neuroprotective effects in neurons and in animal AD models. Methods and Results: (1) Pretreatment of microglia with SCM‐198 could reduce nitric oxide elevation and inhibit iNOS, TNF‐α, IL‐1β mRNA and protein expressions induced by LPS or Aβ1‐40. NF‐κB translocation induced by LPS was effectively mitigated by SCM‐198 in BV‐2 cells. Western blot results showed that IκBα degradation, NF‐κB p65 activation, phosphorylations of JNK1/2 and tau protein were also inhibited in BV‐2 cells. (2) Microglia/neuron co‐culture assay showed that pretreatment of activated microglia with SCM‐198 could significantly increase neuronal survival and alleviate excessive tau phosphorylation and synaptophysin loss in neurons. (3) Pretreatment of primary neurons with SCM‐198 before Aβ1‐40 challenge could reduce lactase dehydrogenase release, inhibit Bax protein elevation, prevent caspase‐3 and ‐9 activations, increase Bcl‐2 protein expressions in neurons. Besides, neuritic morphology was largely preserved under the intervention of SCM‐198. (4) Animal studies demonstrated that SCM‐198 could ameliorate cognitive deficits of both SD rats injected with Aβ1‐40 and APP/PS1 mice in Morris water maze and novel object recognition tests. Suppression of microglial activation could be observed in brain slices of SD rats and less neuronal loss in hippocampus and cortex were found in APP/PS1 mice. Conclusions: Our findings are the first to report that SCM‐198 could directly protect neurons from apoptosis and indirectly protect neurons by inhibiting microglial overactivation through JNK and NF‐κB pathways. Therefore, SCM‐198 might be a new potential drug candidate for AD therapy in the future. Grant Funding Source : This study was supported by the National Science fund for Distinguished Young Scholars of China
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Abstract Neuroinflammation is a key factor that contributes to the secondary injury after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5(CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC,APEXBIO,UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion(MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) with different doses (5, 20, or 50 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia were stimulated with different doses of MVC (0.2, 2, 20 or 200nM) for 12h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro . MVC significantly increased the viability of primary microglia after (OGD/R). The expression of pro-inflammatory cytokines (IL-1β and IL-6) in microglia were down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of IL-1β and IL-6 by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro . The JNK activator anisomycin (AN，Beyotime，SC0132-5mg) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials.
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