Abstract
Cerebral energy deficiency is a key pathophysiologic cascade that results in neuronal injury and necrosis after ischemic stroke. Shengui Sansheng San (SSS) has been used to treat stroke for more than 300 years. In present study, we investigated the therapeutic efficacy and mechanism of SSS extraction on cerebral energy deficiency post-stroke. In permanent middle cerebral artery occlusion (pMCAo) model of rats, it suggested that SSS extraction in dose-dependent manner improved neurological function, cerebral blood flow (CBF), 18F-2-deoxy-glucose uptake and the density and diameter of alpha smooth muscle actin (α-SMA) positive vasculature in ipsilateral area, as well as decreased infarcted volume. Meanwhile, the metabolomics study in cerebrospinal fluid (CSF) was performed by using 5-(diisopropylamino)amylamine (DIAAA) derivatization-UHPLC-Q-TOF/MS approach. Eighty-eight endogenous metabolites were identified, and mainly involved in citrate cycle, fatty acid biosynthesis, aminoacyl-tRNA biosynthesis, amino acids metabolism and biosynthesis, etc. The remarkable increase of citrate in CSF after treatment with three dosages indicated that the therapeutic mechanism of SSS extraction might be related with citrate cycle. Simultaneously, it showed that high dosage group significantly increased peripheral blood glucose level, the expressions of glucose transporter (GLUT) 1, GLUT3, and monocarboxylic acid transporter 1 (MCT1), which contributed to the transportation of glucose and lactate. By the regulations of phosphorylated pyruvate dehydrogenase E1-alpha (p-PDHA1), acetyl CoA synthetase and citrate synthetase (CS), the levels of citrate and its upstream molecules (pyruvate and acetyl CoA) in peri-infarction zone further enhanced, which ultimately caused the massive yield of adenosine triphosphate (ATP). Our study first demonstrated that SSS extraction could ameliorate cerebral energy deficiency after ischemia by citrate cycle, which is characterized by the enhancements of glucose supply, transportation, utilization, and metabolism.
Highlights
The data of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010 Country Collabration, 2013) indicates that the amount of people with first stroke and stroke related deaths significantly increase from 1990 to 2010 in low-income and middle-income countries (Feigin et al, 2014)
These results suggested that Sansheng San (SSS) extraction could attenuate cerebral ischemic injury
We demonstrated that SSS extraction effectively enhanced the expression of GLUT1 and GLUT3 in ischemic boundary zone at day 7 after cerebral ischemia, which meant that more glucose was successfully transported into neuronal and non-neuronal cells
Summary
The data of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010 Country Collabration, 2013) indicates that the amount of people with first stroke and stroke related deaths significantly increase from 1990 to 2010 in low-income and middle-income countries (Feigin et al, 2014). Due to the obstruction of CBF, a cascade of complex pathophysiological process emerges including energy failure, intracellular calcium overload, imbalance of ion homeostasis, neuronal excitotoxicity, inflammatory cell infiltration and so on, which leads to the neuronal apoptosis, necrosis, and neurological functional deficiency. In these pathological events, energy failure is one of the main causes of cerebral ischemic damage, because it disrupts the homeostatic mechanisms of governing the cellular volume and astrocyte/endothelial ion transport, sequentially inflicts cerebral edema and cellular death (Khanna et al, 2014; Song and Yu, 2014). When ischemic stroke occurs, decreased glucose delivery directly produces the severe consequences of citrate attenuation and mitochondria functional deficiency, which causes the yield of ATP to fall to less than 35% in infarcted core, and advances neuronal death and Abbreviations: α-SMA, alpha smooth muscle actin; ACS, acetyl-CoA synthetase; ATP, adenosine triphosphate; CBF, cerebral blood flow; CS, citrate synthetase; CSF, cerebrospinal fluid; DIAAA, 5-(diisopropylamino)amylamine; EPI, echo-planar imaging; 18F-FDG, 2-deoxy-2-[fluorine-18] fluoro-D-glucose; FOV, field of view; GLUT, glucose transporter; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N’,N’tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole hydrate; MCAo, middle cerebral artery occlusion; MCT1, monocarboxylic acid transporter 1; mNSS, modified neurological severity score; MRI, magnetic resonance imaging; PLS-DA, Partial least squares discriminant analysis; PET/CT, positron emission tomography/computed tomography; p-PDHA1, phosphorylated pyruvate dehydrogenase E1-alpha; SSS, Shengui Sansheng San; TE, echo time; TEA, triethylamine; TR, repetition time; UHPLC-Q-TOF/MS, ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry
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