A Novel Extract From Ginkgo biloba Inhibits Neuroinflammation and Maintains White Matter Integrity in Experimental Stroke.

Ginkgo biloba L. leaf extract (GBE) has been added in many commercial herbal formulations such as EGb 761 and Shuxuening Injection to treat cardiovascular diseases and stroke worldwide. However, the comprehensive effects of GBE on cerebral ischemia remained unclear. Using a novel GBE (nGBE), which consists of all the compounds of traditional (t)GBE and one new compound, pinitol, we investigated its effect on inflammation, white matter integrity, and long-term neurological function in an experimental stroke model. Both transient middle cerebral artery occlusion (MCAO) and distal MCAO were conducted in male C57/BL6 mice. We found that nGBE significantly reduced infarct volume at 1, 3, and 14 days after ischemia. Sensorimotor and cognitive functions were superior in nGBE treated mice after MCAO. nGBE inhibited the release of IL-1ß in the brain, promoted microglial ramification, and regulated the microglial M1 to M2 phenotype shift at 7 days post injury. In vitro analyses showed that nGBE treatment reduced the production of IL-1ß and TNFα in primary microglia. Administration of nGBE also decreased the SMI-32/MBP ratio and enhanced myelin integrity, thus exhibiting improved white matter integrity at 28 days post stroke. These findings demonstrate that nGBE protects against cerebral ischemia by inhibiting microglia-related inflammation and promoting white matter repair, suggesting that nGBE is a promising therapeutic strategy for long-term recovery after stroke.

A preclinical randomized controlled study of ischemia treated with Ginkgo biloba extracts: Are complex components beneficial for treating acute stroke?

The rigorous design of preclinical experimental studies of candidate neuroprotectants for the treatment of acute ischemic stroke is crucial for the success of subsequent randomized clinical trials. The efficacy of Ginkgo biloba extracts (GBEs) in complex mixtures for the treatment of acute ischemic stroke remains unclear. In this preclinical randomized controlled trail (pRCT), the effects of a novel (n)GBE containing pinitol versus traditional (t)GBE without pinitol were evaluated on the mouse models of acute transient and permanent stroke, separately. The sample size, an important aspect of study design, was calculated based on our experimental data. Mice with ischemia that were induced by transient middle cerebral artery occlusion (tMCAO) or permanent distal middle cerebral artery occlusion (pdMCAO), were treated with vehicle, nGBE, tGBE, or pinitol alone by tail-vein injection. Our results showed that nGBE significantly reduced infarct size in mice with tMCAO compared with vehicle-treated control mice. Both nGBE and tGBE significantly reduced infarct size in mice with pdMCAO compared with the vehicle-treated controls. None of the three treatments rescued weight loss or prevented the neurological deficits in either the tMCAO- or pdMCAO-model mice. These findings suggest that nGBE, which includes all of the components of tGBE and pinitol, is neuroprotective in two ischemic stroke models. Additional studies of complex GBE mixtures for stroke treatment compared to single component medications are undergoing evaluation.

Angioedema and Hemorrhage After 4.5-Hour tPA (Tissue-Type Plasminogen Activator) Thrombolysis Ameliorated by T541 via Restoring Brain Microvascular Integrity.

Background and Purpose- tPA (tissue-type plasminogen activator) is the only recommended intravenous thrombolytic agent for ischemic stroke. However, its application is limited because of increased risk of hemorrhagic transformation beyond the time window. T541 is a Chinese compound medicine with potential to attenuate ischemia and reperfusion injury. This study was to explore whether T541-benefited subjects underwent tPA thrombolysis extending the time window. Methods- Male C57BL/6 N mice were subjected to carotid artery thrombosis by stimulation with 10% FeCl3 followed by 10 mg/kg tPA with/without 20 mg/kg T541 intervention at 4.5 hours. Thrombolysis and cerebral blood flow were observed dynamically until 24 hours after drug treatment. Neurological deficit scores, brain edema and hemorrhage, cerebral microvascular junctions and basement membrane proteins, and energy metabolism in cortex were assessed then. An in vitro hypoxia/reoxygenation model using human cerebral microvascular endothelial cells was used to evaluate effect of T541 on tight junctions and F-actin in the presence of tPA. Results- tPA administered at 4.5 hours after carotid thrombosis resulted in a decrease in thrombus area and survival rate, whereas no benefit on cerebral blood flow. Study at 24 hours after tPA administration revealed a significant angioedema and hemorrhage in the ischemia hemisphere, a decreased expression of junction proteins claudin-5, zonula occludens-1, occludin, junctional adhesion molecule-1 and vascular endothelial cadherin, and collagen IV and laminin. Meanwhile, ADP/ATP, AMP/ATP, and ATP5D (ATP synthase subunit) expression and activities of mitochondria complex I, II, and IV declined, whereas malondialdehyde and 8-Oxo-2'-deoxyguanosine increased and F-actin arrangement disordered. All the insults after tPA treatment were attenuated by addition of T541 dose dependently. Conclusions- The results suggest T541 as a potential remedy to attenuate delayed tPA-related angioedema and hemorrhage and extend time window for tPA treatment. The potential of T541 to upregulate energy metabolism and protect blood-brain barrier is likely attributable to its effects observed.

QiShenYiQi Pills, a compound in Chinese medicine, protects against pressure overload-induced cardiac hypertrophy through a multi-component and multi-target mode.

The present study aimed to explore the holistic mechanism for the antihypertrophic effect of a compound in Chinese medicine, QiShenYiQi Pills (QSYQ) and the contributions of its components to the effect in rats with cardiac hypertrophy (CH). After induction of CH by ascending aortic stenosis, rats were treated with QSYQ, each identified active ingredient (astragaloside IV, 3, 4-dihydroxy-phenyl lactic acid or notoginsenoside R1) from its 3 major herb components or dalbergia odorifera, either alone or combinations, for 1 month. QSYQ markedly attenuated CH, as evidenced by echocardiography, morphology and biochemistry. Proteomic analysis and western blot showed that the majority of differentially expressed proteins in the heart of QSYQ-treated rats were associated with energy metabolism or oxidative stress. Each ingredient alone or their combinations exhibited similar effects as QSYQ but to a lesser extent and differently with astragaloside IV and notoginsenoside R1 being more effective for enhancing energy metabolism, 3, 4-dihydroxy-phenyl lactic acid more effective for counteracting oxidative stress while dalbergia odorifera having little effect on the variables evaluated. In conclusion, QSYQ exerts a more potent antihypertrophic effect than any of its ingredients or their combinations, due to the interaction of its active components through a multi-component and multi-target mode.