The Synergic Effect of Tetramethylpyrazine Phosphate and Borneol for Protecting Against Ischemia Injury in Cortex and Hippocampus Regions by Modulating Apoptosis and Autophagy

• Published in: Journal of molecular neuroscience 2017-09, Vol.63 (1), p.70-83
• Main Authors: Yu, Bin, Ruan, Ming, Liang, Tao, Huang, Shi-Wen, Yu, Yun, Cheng, Hai-Bo, Shen, Xiang-Chun
• Format: Article
• Language: English
• Subjects: Adenosine kinase; Adenosine monophosphate; AMP; Animals; Apoptosis; Autophagy; Autophagy-Related Protein-1 Homolog - metabolism; BAX protein; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Beclin-1 - metabolism; Biomedical and Life Sciences; Biomedicine; Bornanes - administration & dosage; Bornanes - pharmacology; Bornanes - therapeutic use; Borneol; Calcium; Calcium (intracellular); Caspase; Caspase-3; Cell Biology; Cerebral blood flow; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Combined treatment; Drug Synergism; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hypoxia-Ischemia, Brain - drug therapy; Intracellular; Ischemia; Kinases; Male; Neurochemistry; Neurology; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Occlusion; p53 Protein; Phagocytosis; Phosphates; Protein kinase; Protein Kinases - metabolism; Proteomics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrazines - administration & dosage; Pyrazines - pharmacology; Pyrazines - therapeutic use; Rapamycin; Rats; Rats, Sprague-Dawley; Reperfusion; Rodents; Signal transduction; Switching; TOR protein; TOR Serine-Threonine Kinases - metabolism; Ultrastructure
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-017-0958-1

This study aimed to investigate the synergic effects of tetramethylpyrazine phosphate (TMPP) and borneol (BO) for protecting against ischemia in the cortex and hippocampus. A rat model of global cerebral ischemia-reperfusion (GCIR) was induced by four-vessel occlusion. The results showed that TMPP (13.3 mg/kg), BO (0.16 g/kg), and their combination improved the ultrastructure of neurons, reduced the apoptosis index, and reduced the intracellular calcium content in both the cortex and hippocampus. TMPP and the combined treatment increased cortex autophagy by modulating phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) in the pAMPK-mammalian target of rapamycin (mTOR)-Unc-51-like kinase 1 (ULK1) signaling pathway, whereas BO only regulated ULK1. Moreover, BO increased neuron autophagy in the hippocampus by modulating mTOR, whereas TMPP targeted both mTOR and Beclin1. Similarly, the combination targeted both pAMPK and Beclin1. All three treatments decreased the expression of p53 and caspase-3 in the two areas. Additionally, TMPP and the combined therapy regulated Bax and Bcl-2. These results demonstrated the synergic effects between TMPP and BO for treating ischemia-reperfusion injury in the cortex and hippocampus regions. Their neuroprotective effects could be partly attributed to switching from apoptosis to protective autophagy. Additionally, the potential mechanism triggering this switching could be ascribed to the reduction of intracellular calcium content.