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Opening of microglial K(ATP) channels inhibits rotenone-induced neuroinflammation
Fang Zhou1, Hong-Hong Yao, Jia-Yong Wu
1Jiangsu Key Laboratory of Neurodegeneration, Department of Anatomy Histology, Pharmacology Nanjing Medical University Nanjing, Jiangsu, P. R. China.
Abstract:
As activated microglia (MG) is an early sign that often precedes and triggers neuronal death, inhibition of microglial activation and reduction of subsequent neurotoxicity may offer therapeutic benefit. The present study demonstrates that rat primary cultured MG expressed Kir6.1 and SUR2 subunits of K(ATP) channel, which was identical to that expressed in BV-2 microglial cell line. The classic K(ATP) channel opener pinacidil and selective mitochondrial K(ATP) (mito-K(ATP)) channel opener diazoxide prevented rotenone-induced microglial activation and production of pro-inflammatory factors (tumour necrosis factor[TNF]-alpha and prostaglandin E(2)[PGE(2)]). And the effects of pinacidil and diazoxide were reversed by mito-K(ATP) blocker 5-hydroxydecanoate (5-HD), indicating that mito-K(ATP) channels participate in the regulation of microglial activation. Moreover, the underlying mechanisms involved the stabilization of mitochodrial membrane potential and inhibition of p38/c-Jun-N-terminal kinase (JNK) activation in microglia. Furthermore, the in vivo study confirmed that diazoxide exhibited neuroprotective effects against rotenone along with the inhibition of microglial activation and neuroinflammation. Thus, microglial mito-K(ATP) channel might be a novel prospective target for the treatment of neuroinflammation-related degenerative disorders such as Parkinson's disease.
Insights
Mitochondrial K(ATP) channels in microglia can be targeted to reduce neuroinflammation. Activating these channels with diazoxide protects against rotenone-induced neurodegeneration and microglial activation.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Activated microglia contribute to neurodegeneration.
- Targeting microglial activation may offer therapeutic benefits for neuroinflammatory disorders.
Purpose of the Study:
- To investigate the role of K(ATP) channels in microglial activation.
- To explore the therapeutic potential of K(ATP) channel modulators in neuroinflammation.
Main Methods:
- Primary rat microglia and BV-2 cell line were used.
- K(ATP) channel openers (pinacidil, diazoxide) and blockers (5-HD) were applied.
- Rotenone was used to induce microglial activation and neurotoxicity.
- Mitochondrial membrane potential and inflammatory markers were assessed.
- In vivo studies in a rotenone-induced neuroinflammation model were conducted.
Main Results:
- Microglia express Kir6.1 and SUR2 K(ATP) channel subunits.
- Diazoxide and pinacidil inhibited rotenone-induced microglial activation and pro-inflammatory factor release.
- These effects were mediated by mitochondrial K(ATP) channels.
- Diazoxide stabilized mitochondrial membrane potential and inhibited p38/JNK activation.
- Diazoxide demonstrated neuroprotection in vivo by inhibiting microglial activation and neuroinflammation.
Conclusions:
- Mitochondrial K(ATP) channels are key regulators of microglial activation.
- Targeting microglial mitochondrial K(ATP) channels offers a potential therapeutic strategy for neuroinflammation.
- Diazoxide shows promise for treating neurodegenerative diseases like Parkinson's.
