Shengui Sansheng San Ameliorates Cerebral Energy Deficiency via Citrate Cycle After Ischemic Stroke

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), 18 F-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.

Notoginsenoside R1 ameliorates mitochondrial dysfunction to circumvent neuronal energy failure in acute phase of focal cerebral ischemia

“…Combined with exaltation in the expressions of GLUT1/3, MCT1 and CS, NGR1 treatment is likely to exert continuous energy supply by promoting energy substrates and enzyme activity in the ischemic zone, which contributes to the reduction of cerebral infarct volume and recovery of neurological function after acute stroke. This is similar to our previous study of Chinese Medicine formulae Shengui Sansheng San on brain glucose utilization and metabolism at day 7 in pMCAo rats (Luo et al, 2019).…”

Phenylacetylglutamine, a Novel Biomarker in Acute Ischemic Stroke

“…Studies have hypothesized that purine metabolism may be related to oxidative stress and that it occurs after ischemic injury ( 16 ). Cerebral energy disturbance is an important pathophysiological cascade after IS, and dysregulation of the TCA cycle after stroke is in line with previous studies ( 21 , 22 ). The pantothenate and CoA biosynthesis pathways play an essential role in energy metabolism and the TCA cycle, which could contribute to ischemic pathophysiology ( 23 ).…”

Hippocampal Sector–Specific Metabolic Profiles Reflect Endogenous Strategy for Ischemia-Reperfusion Insult Resistance

“…Perhaps this is one of the most important distinguishing features of CA1 and CA2–4,DG. Following this line of thought, an activation of protein synthesis might be closely related with the neuronal protection showed in permanent middle cerebral artery occlusion (pMCAo) model of rats, where pathways of aminoacyl t-RNA synthesis and amino acid metabolisms were modulated by a traditional Chinese herbal formula and positively influenced cerebral energy metabolism [ 61 ].…”