Ginkgo Biloba Extract And Its Diterpene Ginkgolide Constituents Ameliorate The Metabolic Disturbances Caused By Recombinant Tissue Plasminogen Activator In Rat Prefrontal Cortex

Background Ischemic stroke is a serious disease that endangers human health and has a high fatality rate.Moreover,surviving patients also have a heavy burden on families and the community because of their limited mobility.Rt-PA is recognized as an effective drug for ischemic stroke.But there is a time window for rt-PA in the treatment of ischemic stroke with rt-PA within 3-4 hours of ischemic stroke,which was the limitation in the clinical when ischemic stroke occurs.In fact,most patients will miss this optimal therapeutic window and only about 5% of patients will be treated effectively.The neurotoxic effect shown after the rt PA treatment exacerbates bleeding and edema symptoms in stroke patients.Previous study showed the ginkgo biloba extract had neuroprotective effects.Based on the rt-PA neurotoxicity effect,we hypothesized that ginkgo biloba extract could alleviate neurotoxicity and compared with metabolites among multiple groups to further explore the mechanism of ginkgo biloba alleviating neurotoxicity.Objective Recombinant tissue plasminogen activator(rt PA)-induced toxicity or adverse effects have been reported in many studies.However,Ginkgo Biloba Extract(GBE)may provide neuroprotective effects against rt PA-induced toxicity.Methods in the present study,we investigated whether a single administration of rt PA caused neurotoxicity in the prefrontal cortex(PFC)of Sprague-Dawley rats and determined whether GBE or its diterpene ginkgolide(DG)constituents were neuroprotective against any rt PAinduced toxicity.A gas chromatography–mass spectrometry metabolomic approach and multivariate statistical were used to detect molecular changes in the PFC among the groups.Results We found 32 metabolites differentially altered that were primarily involved in neurotransmitter,amino acid,energy,lipid,and nucleotide metabolism.Our results indicated that a single rt PA administration caused metabolic disturbances in the PFC.Both GBE and DG effectively ameliorated these rt PA-induced disturbances,although DG better controlled the rt PA-induced glutamate and aspartate excitotoxicity and the activation of NMDA receptor.Conclusion Our results provide important novel mechanistic insights into the adverse effects of rt PA and offer directions for future exploration on the thrombolytic effects of rt PA combined with the administration of DG or GBE for treatment of acute ischemic stroke in humans.