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Tetramethylpyrazine phosphate and borneol combination therapy synergistically attenuated ischemia-reperfusion injury of the hypothalamus and striatum via regulation of apoptosis and autophagy in a rat model.

ABSTRACT: The combination of tetramethylpyrazine (TMP) and borneol (BO) has shown promise for treatment of cerebral ischemia in clinical and experimental studies. However, the mechanism for the synergistic effect of these compounds is unclear. In this study, global cerebral ischemia-reperfusion (GCIR) was induced in rats that were subsequently treated with tetramethylpyrazine phosphate (TMPP) (13.3 mg/kg), BO (0.16 g/kg), or the combination TMPP + BO. Neuronal ultrastructure and intracellular calcium [Ca2+]i levels were evaluated in hypothalamus and striatum. Neuron autophagy was evaluated by expression of LC3 II/I, ULK1, Beclin1, BNIP3, mTOR, and pAMPK. Neuron apoptosis was examined via apoptosis index (AI) and expression of p53, Bcl-2, Bax, and caspase-3. Both monotherapies significantly improved neuronal ultrastructure, reduced numbers of apoptotic neurons and AI, attenuated [Ca2+]i overload, increased expression of pAMPK, ULK1, and LC3 II/I, and markedly reduced expression of mTOR, p53, and caspase-3 in hypothalamus and striatum. In hypothalamus, TMPP increased Bcl-2 expression and decreased Bax expression. In striatum, TMPP and BO increased Beclin1 expression while TMPP increased Bcl-2 expression and decreased Bax expression. TMPP + BO combination therapy enhanced expression of LC3 II/I, pAMPK, mTOR, and ULK1 in hypothalamus, and pAMPK, mTOR, ULK1, Beclin1, and Bax in striatum compared to the monotherapies. Combination therapy synergistically modulated p53 and adjusted Bcl-2 in striatum compared to TMPP and BO monotherapies, respectively. These results demonstrated a synergistic effect of TMPP + BO in protecting against hypothalamus and striatum in rats from ischemia-reperfusion injury and suggested that the mechanism involved shifting neurons from harmful apoptosis to protective autophagy and reducing neuronal [Ca2+]i.

SUBMITTER: Yu B

PROVIDER: S-EPMC5714767 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Tetramethylpyrazine phosphate and borneol combination therapy synergistically attenuated ischemia-reperfusion injury of the hypothalamus and striatum via regulation of apoptosis and autophagy in a rat model.

Yu Bin B Ruan Ming M Liang Tao T Huang Shi-Wen SW Liu Sheng-Jin SJ Cheng Hai-Bo HB Shen Xiang-Chun XC

American journal of translational research 20171115 11

The combination of tetramethylpyrazine (TMP) and borneol (BO) has shown promise for treatment of cerebral ischemia in clinical and experimental studies. However, the mechanism for the synergistic effect of these compounds is unclear. In this study, global cerebral ischemia-reperfusion (GCIR) was induced in rats that were subsequently treated with tetramethylpyrazine phosphate (TMPP) (13.3 mg/kg), BO (0.16 g/kg), or the combination TMPP + BO. Neuronal ultrastructure and intracellular calcium [Ca< ...[more]

PMID: 29218081

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Project description:BackgroundPrevention of diabetic heart myocardial ischemia-reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5'-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI.MethodsDiabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46 mg/kg/h without or with SAA at 10 mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24 h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12 h.ResultsDiabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5 μM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25 μM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol- and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression.ConclusionsCombinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.

Dataset Information

Tetramethylpyrazine phosphate and borneol combination therapy synergistically attenuated ischemia-reperfusion injury of the hypothalamus and striatum via regulation of apoptosis and autophagy in a rat model.

Publications

Tetramethylpyrazine phosphate and borneol combination therapy synergistically attenuated ischemia-reperfusion injury of the hypothalamus and striatum via regulation of apoptosis and autophagy in a rat model.

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