Dataset Information

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex.

ABSTRACT:

Introduction

Although recombinant tissue plasminogen activator (rtPA) is a widely used therapy in patients with acute ischemic stroke, rtPA-induced toxicity or its adverse effects have been reported in our previous studies. However, Ginkgo biloba extract (GBE) may provide neuroprotective effects against rtPA-induced toxicity. Thus, in the present study, we investigated whether a single administration of rtPA caused neurotoxicity in the prefrontal cortex (PFC) of rats and determined whether GBE or its diterpene ginkgolide (DG) constituents were neuroprotective against any rtPA-induced toxicity.

Materials and methods

We randomly divided adult Sprague-Dawley rats into four groups that were intravenously administered saline, rtPA, rtPA+DG, or rtPA+GBE. The rats were sacrificed 24 hours later and the whole brain removed. A gas chromatography-mass spectrometry metabolomic approach was used to detect molecular changes in the PFC among the groups. Multivariate statistical and pathway analyses were used to determine the relevant metabolites as well as their functions and pathways.

Results

We found 32 metabolites differentially altered in the four groups that were primarily involved in neurotransmitter, amino acid, energy, lipid, and nucleotide metabolism. Our results indicated that a single rtPA administration caused metabolic disturbances in the PFC. Both GBE and DG effectively ameliorated these rtPA-induced disturbances, although DG better controlled the rtPA-induced glutamate and aspartate excitotoxicity and the activation of NMDA receptor.

Conclusion

Our results provide important novel mechanistic insights into the adverse effects of rtPA and offer directions for future exploration on the thrombolytic effects of rtPA combined with the administration of DG or GBE for the treatment of acute ischemic stroke in humans.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6037272 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex.

Chen Zhi Z Bai Shunjie S Hu Qingchuan Q Shen Peng P Wang Ting T Liang Zihong Z Wang Wei W Qi Xunzhong X Xie Peng P

Neuropsychiatric disease and treatment 20180704

<h4>Introduction</h4>Although recombinant tissue plasminogen activator (rtPA) is a widely used therapy in patients with acute ischemic stroke, rtPA-induced toxicity or its adverse effects have been reported in our previous studies. However, Ginkgo biloba extract (GBE) may provide neuroprotective effects against rtPA-induced toxicity. Thus, in the present study, we investigated whether a single administration of rtPA caused neurotoxicity in the prefrontal cortex (PFC) of rats and determined wheth ...[more]

PMID: 30013348

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Project description:Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier breakdown after ischaemic stroke and lead to lethal haemorrhagic transformation. The immune system is a dynamic modulator of stroke response, and excessive immune cell accumulation in the cerebral vasculature is associated with compromised integrity of the blood-brain barrier. We previously reported that regulatory T cells, which function to suppress excessive immune responses, ameliorated blood-brain barrier damage after cerebral ischaemia. This study assessed the impact of regulatory T cells in the context of tPA-induced brain haemorrhage and investigated the underlying mechanisms of action. The number of circulating regulatory T cells in stroke patients was dramatically reduced soon after stroke onset (84 acute ischaemic stroke patients with or without intravenous tPA treatment, compared to 115 age and gender-matched healthy controls). Although stroke patients without tPA treatment gradually repopulated the numbers of circulating regulatory T cells within the first 7 days after stroke, post-ischaemic tPA treatment led to sustained suppression of regulatory T cells in the blood. We then used the murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive regulatory T cell transfer against tPA-induced haemorrhagic transformation. Delayed administration of tPA (10 mg/kg) resulted in haemorrhagic transformation in the ischaemic territory 1 day after ischaemia. When regulatory T cells (2 × 106/mouse) were intravenously administered immediately after delayed tPA treatment in ischaemic mice, haemorrhagic transformation was significantly decreased, and this was associated with improved sensorimotor functions. Blood-brain barrier disruption and tight junction damages were observed in the presence of delayed tPA after stroke, but were mitigated by regulatory T cell transfer. Mechanistic studies demonstrated that regulatory T cells completely abolished the tPA-induced elevation of MMP9 and CCL2 after stroke. Using MMP9 and CCL2 knockout mice, we discovered that both molecules partially contributed to the protective actions of regulatory T cells. In an in vitro endothelial cell-based model of the blood-brain barrier, we confirmed that regulatory T cells inhibited tPA-induced endothelial expression of CCL2 and preserved blood-brain barrier integrity after an ischaemic challenge. Lentivirus-mediated CCL2 knockdown in endothelial cells completely abolished the blood-brain barrier protective effect of regulatory T cells in vitro. Altogether, our studies suggest that regulatory T cell adoptive transfer may alleviate thrombolytic treatment-induced haemorrhage in stroke victims. Furthermore, regulatory T cell-afforded protection in the tPA-treated stroke model is mediated by two inhibitory mechanisms involving CCL2 and MMP9. Thus, regulatory T cell adoptive transfer may be useful as a cell-based therapy to improve the efficacy and safety of thrombolytic treatment for ischaemic stroke.

Dataset Information

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex.

Introduction

Materials and methods

Results

Conclusion

Publications

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex.

Similar Datasets

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