Novel surface imprinted magnetic mesoporous silica as artificial antibodies for efficient discovery and capture of candidate nNOS–PSD-95 uncouplers for stroke treatment†
In the search for novel efficient nNOS–PSD-95 (nitric oxide synthase–postsynaptic density protein-95) uncouplers from natural products for stroke treatment, highly selective surface molecular imprinted polymers based on sandwich structured magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@MIPs, MMS@MIPs) were designed and optimized as artificial antibodies. The resultant polymers exhibited satisfactory adsorption performance and excellent recyclability, and were successfully utilized as sorbents to capture candidate uncouplers from natural products. Furthermore, the biological activity and the functional mechanism of the obtained candidates were investigated in vivo and in vitro. Consequently, coptisine, chelerythrine and nitidine chloride presented both potent neuroprotective effects on glutamate-injured PC12 cells and uncoupling activity targeting nNOS–PSD-95 in vitro. Simultaneously, they effectively ameliorated neurological deficit and reduced infarct volume of MCAO/R (middle cerebral artery occlusion and reperfusion) rats. Therefore, coptisine, chelerythrine and nitidine chloride were considered the most promising nNOS–PSD-95 uncouplers for further preclinical studies of ischemic stroke treatment.