Abstract
Microglial phagocytosis benefits neurological recovery after stroke. Large-conductance Ca2+-activated K+ currents are expressed in activated microglia, and BK channel knockout aggravates cerebral ischemic injury. However, the effect of BK channels on microglial phagocytosis after ischemic stroke remains unknown. Here, we explored whether BK channel activation is beneficial for neurological outcomes through microglial phagocytosis after ischemic stroke. ICR mice after transient middle cerebral artery occlusion (tMCAO) were treated with dimethyl sulfoxide (DMSO), BK channel activator NS19504, and inhibitor Paxilline. The results showed a decrease in BK channel expression after tMCAO. BK channel activator NS19504 alleviates neurological deficit after experimental modeling of tMCAO in mice compared to the control. Furthermore, we treated primary microglia with DMSO, NS19504, and Paxilline after oxygen glucose deprivation (OGD). NS19504 promoted primary microglial phagocytosing fluorescent beads and neuronal debris, which reduced neuronal apoptosis after stroke. These effects could be reversed by BK channel inhibitor Paxilline. Finally, NS19504 increased relative phosphorylated extracellular signal-regulated kinase 1/2 expression compared to the Paxilline group at the third day after stroke. Our findings indicate that microglial BK channels are a potential target for acute stage of ischemic stroke therapy.
Highlights
Stroke is the major cause of death and long-term neurological disability, seriously threatening quality of life in China and across the world (Wu et al, 2019)
The results showed that BK channels were mainly expressed in microglia and neurons, not in astrocytes (Figure 2A)
At 3 days after transient middle cerebral artery occlusion (tMCAO), we found that most BK channels were located in microglia, while few with neurons and astrocytes (Figure 2C), which suggested that BK channels on microglia play a major role after stroke
Summary
Stroke is the major cause of death and long-term neurological disability, seriously threatening quality of life in China and across the world (Wu et al, 2019). Ischemic stroke, comprising 80% of all stroke cases, annually affects about 4 million people in China (Wang et al, 2019). Current therapeutic approaches for ischemic stroke (recombinant tissue plasminogen activator and thrombolysis) are limited by short time window and the risk of hemorrhage transformation (Xiong et al, 2019; Chang et al, 2021). Treatment in the acute stage of ischemic stroke could effectively limit infarct volume and rescue neuronal death in the peri-focal region (Chamorro et al, 2020). Microglial phagocytosis plays an important role in maintaining CNS homeostasis. Microglial pruning overproduced synapses and myelin along
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