CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice

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.