The novel compound CP-10 suppresses microglia-mediated neuroinflammation and neutrophil chemotaxis and attenuates ischemic brain injury by targeting FPR1

Abstract

Ischemic stroke represents a major neurological disorder characterized by significant morbidity, where neuroinflammation plays a central role in exacerbating cerebral injury. Following ischemic events, microglial activation and the subsequent infiltration of peripheral immune cells, particularly neutrophils, contribute to the disruption of the blood-brain barrier and amplify neuronal damage. In the present study, as a part of our ongoing screening experiment to evaluate the anti-inflammatory effects of new compounds, a novel compound, namely N-{2-[(7-chloro-4-oxo-4H-pyrido[1,2-a] pyrimidin-2-yl) methoxy] phenyl}-2,2-dimethylpropanamide (referred to as CP-10 in this study), to test whether it could target microglial activation and neutrophil chemotaxis, both critical contributors to ischemic brain injury. CP-10 exhibited no apparent cytotoxicity to primary microglia or neurons at concentrations up to 30 μM. Transcriptomic analysis revealed that CP-10 modulated a wide range of inflammatory and immune response genes, particularly those associated with neutrophil chemotaxis, such as Cxcl1, Cxcl2, Cxcl3, and Cxcl5. Mechanistically, CP-10 exerted its effects by interacting with formyl peptide receptor 1 (FPR1), a receptor involved in microglial activation and neutrophil recruitment. In vivo, CP-10 significantly reduced infarct volume and neurological deficits in a mouse model of middle cerebral artery occlusion (MCAO), accompanied by reduced neutrophil infiltration and microglial activation in the ischemic penumbra. Furthermore, CP-10 inhibited key inflammatory signaling pathways, including NF-κB and MAPK, downstream of FPR1 activation. These findings position CP-10 as a promising candidate for ischemic stroke therapy, targeting neuroinflammation and immune cell chemotaxis via FPR1 modulation.