1H NMR Spectroscopy-Based Metabolomics Approach to Study the Anti-Stroke Activity of G-3702, a Novel Better Alternative to DL-3-n-Butylphthalide.

Abstract

Cerebrovascular disease is the leading cause of disability and death, and ischemic stroke accounts for most stroke cases. However, few effective drugs are available for the treatment of ischemic stroke; thus, there is an urgent need to develop effective drugs to treat ischemic stroke. DL-3-n-butylphthalide (NBP) is clinically approved as an anti-ischemic drug in China, but its potential hepatotoxicity limits its use. G-3702 (a structural analogue of NBP) is synthesized with the boron hydroxyl group replacing carbonyl group. G-3702 significantly enhanced the survival of middle cerebral artery occlusion (MCAO) rats, decreased neurobehavioral deficit scores and cerebral infarct volume, comparable with NBP, which was also supported by tissue damage assessment, immunohistochemistry staining, biochemical parameters and ELISA assay. G-3702 showed better anti-stroke activity than NBP according to 1H NMR spectroscopy-based metabolomics analysis, demonstrating the feasibility of metabolomics approach to assess drug efficacy. G-3702 markedly ameliorated energy metabolism, attenuated oxidative and inflammatory stress during ischemia/reperfusion (I/R). G-3702 exhibited good neuroprotective effects against I/R induced injury and favorable little possibility of hepatotoxicity, which made it a promising anti-stroke drug and better NBP alternative.