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CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
Hailin Liu1,2, Xiangnan Hu1, Rong Jiang3
1Department of Pharmacology, the Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China.
Abstract:
Excessive microglial activation-mediated neuroinflammation is closely involved in the pathogenesis of several neurological diseases. CQMUH-011, as a novel adamantane sulfonamide compound, has been shown anti-inflammatory properties in activated macrophages (RAW264.7). However, the role of CQMUH-011 in microglial activation-induced neuroinflammation and neuroprotective properties has yet to be elucidated. In the present study, we investigated the potential effects and mechanisms of CQMUH-011 on lipopolysaccharide (LPS)-stimulated primary microglia in vitro and transient middle cerebral artery occlusion (t-MCAO)-induced acute cerebral ischemia/reperfusion (I/R) injury in vivo. The results demonstrated that CQMUH-011 significantly suppressed the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β by LPS-stimulated primary microglia. In addition, CQMUH-011 inhibited the proliferation of activated microglia by arresting the cell cycle at the G1/S phase accompanied by downregulating the expression of cell cycle regulatory proteins such as proliferating cell nuclear antigen (PCNA) and cyclin D1. CQMUH-011 was seen to induce apoptosis in activated microglia by regulating the expression of Bax and Bcl-2. Furthermore, CQMUH-011 markedly attenuated the protein expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) as well as the phosphorylation levels of nuclear factor-kappa (NF-κB) subunit p65, inhibitory kappa B-alpha (IκBα), and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK) and p38 kinases. In vivo, CQMUH-011 administration significantly improved neurological function and infarct volume, and ameliorated the inflammatory cytokines and microglia amount around the injury site of mice. In conclusion, these results suggested that CQMUH-011 has a notable anti-inflammatory effect and protects mice from I/R injure. Thus, CQMUH-011 may be a candidate drug for the treatment of cerebral ischemia patients.
Insights
CQMUH-011, a novel compound, reduces neuroinflammation by suppressing microglial activation and protects against cerebral ischemia/reperfusion injury in mice. This suggests CQMUH-011
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Neuroinflammation, driven by microglial activation, contributes to neurological diseases.
- CQMUH-011, an adamantane sulfonamide, exhibits anti-inflammatory properties in macrophages.
- The role of CQMUH-011 in microglial activation and neuroprotection remains unclear.
Purpose of the Study:
- To investigate the effects of CQMUH-011 on lipopolysaccharide-stimulated primary microglia in vitro.
- To evaluate the neuroprotective potential of CQMUH-011 in a mouse model of cerebral ischemia/reperfusion injury.
- To elucidate the underlying mechanisms of CQMUH-011's action.
Main Methods:
- Primary microglia were stimulated with lipopolysaccharide (LPS) in vitro.
- CQMUH-011's effects on microglial activation, cell cycle, apoptosis, and signaling pathways (TLR4/MyD88/NF-κB/MAPKs) were assessed.
- Transient middle cerebral artery occlusion (t-MCAO) model was used for in vivo studies of cerebral ischemia/reperfusion injury.
Main Results:
- CQMUH-011 suppressed TNF-α and IL-1β production in LPS-stimulated microglia.
- It inhibited microglial proliferation by arresting the cell cycle and induced apoptosis.
- CQMUH-011 attenuated TLR4, MyD88, NF-κB, and MAPK signaling pathways.
- In vivo, CQMUH-011 improved neurological function, reduced infarct volume, and decreased neuroinflammation.
Conclusions:
- CQMUH-011 demonstrates significant anti-inflammatory effects on activated microglia.
- It exhibits neuroprotective properties against cerebral ischemia/reperfusion injury.
- CQMUH-011 shows potential as a therapeutic candidate for treating cerebral ischemia.
