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A Time-dependent Glia cell-Mediated Neuroprotective Effects of Kv7/KCNQ channel opener QO-83 in Ischemic Stroke: Mechanisms of Action and Therapeutic Potential

ABSTRACT: This study investigates the protective role of Kv7 channel opener QO-83 in mouse brain injury induced by ischemia-reperfusion and permanent ischemia. QO-83 shows promise in enhancing survival rates, reducing infarction area, cerebral edema, and maintaining the blood-brain barrier. Furthermore, QO-83 administration correlates with enhanced cognition, memory, and fibrotic scar mitigation. Notably, these protective effects extend beyond the 4-6-hour post-reperfusion window. Single-nucleus RNA sequencing unveils distinct microglial and astrocyte clusters influenced by QO-83, potentially mediated via KCNQ3/5 targets. Notably, QO-83's influence on nestin-positive cell differentiation underscores its potential in limiting fibrotic scar formation. This study highlights QO-83 as a protective agent against ischemic brain injury, showcasing its multifaceted effects and potential as a therapeutic strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE244576 | GEO | 2025/09/19

REPOSITORIES: GEO

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Project description:Astrocytes are abundant glial cells in the central nervous system (CNS) that play important roles in cerebral ischemia-reperfusion injury. Following brain ischemia, astrocytes can trigger endogenous neuroprotective mechanisms such as neurogenesis, regulation of inflammation, transfer of mitochondria, and defense against oxidative stress. Transforming growth factor beta 1 (TGF-β1) is known as an injury-related cytokine, particularly associated with neurogenesis, neuronal migration, inflammatory reactions, and astrocyte scar formation in response to brain injury. TGF-β1 is closely related to ischemia-reperfusion brain injury and plays a significant role as both effectors and targets of I/R brain injury. Upregulation of endogenous TGF-β1 in neurons may contribute to preventing apoptosis after ischemic insult. TGF-β1 exerts dynamic effects in tissues through autocrine and paracrine signaling pathways as a secretory factor. The current study suggests that the multiple functions exerted by astrocytes might potentially be mediated by TGF-β1 signaling, raising the idea that astrocytes could be a potential therapeutic target for neuroprotection as sources or targets of TGF-β1. However, few studies are currently available on the effects of TGF-β1 on astrocytes after ischemia-reperfusion brain injury. Although current research shows that transforming growth factor-beta acts as a neuroprotective agent in cerebral ischemia, its specific mechanism is still not completely clear. In this study, RNA sequencing analysis was performed to investigate the potential mechanism of astrocytes pretreated with TGF-β1. Our study found that TGF-β1 mediates the upregulation of DUSP4 in astrocytes, which plays a neuroprotective role after ischemia-reperfusion injury. Overexpression of TGF-β1 inhibits the activation of astrocytes, accompanied by decreased levels of inflammatory factors and reactive oxygen species (ROS), while promoting the transfer of mitochondria between astrocytes and neurons. This enhanced neuron survival and axonal regeneration after injury. Hence, this study provides further insights into strategies for inhibiting neurological impairment and suggests a potential therapeutic target after ischemia-reperfusion injury.

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A Time-dependent Glia cell-Mediated Neuroprotective Effects of Kv7/KCNQ channel opener QO-83 in Ischemic Stroke: Mechanisms of Action and Therapeutic Potential

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