Astragaloside IV Reduces Neuronal Apoptosis and Parthanatos in Ischemic Injury by Preserving Mitochondrial Hexokinase-II

Abstract

Background: Cerebral ischemia induces neuronal cell death in different ways and mitochondrial dysfunction is an important cause. Astragaloside IV (AIV) is a natural saponin abandent in Astragalus membranaceus and this study aims to find if AIV protects neuronal survival via preserving mitochondrial hexokinase-II (HK-II). Methods: The primary cortical neuron were prepared to observe the effects of AIV on neuroprotection with focus on the regulation of mitochondrial HK-II via Akt activation. Meanwhile, we also observed the protection in mice MCAO model. Results: Glutamate stimulation induced HK-II dissociation from mitochondria and impaired mitochondrial function, indicated by the opening of the mitochondrial permeability transition pore and the collapse of mitochondrial membrane potential. Accompanied with apoptosis, oxidative DNA damage, PAR formation and nuclear translocation of apoptosis inducing factor (AIF) indicated the presence of parthanatos. AIV activated Akt and protected mitochondrial HK-II via promoting the binding of Akt to HK-II. As a consequence of preserved mitochondrial HK-II, AIV reduced the release of pro-apoptotic proteins and AIF, resultantly protected neurons from apoptosis and parthanatos. Moreover, the neuroprotective effects of AIV were also reproduced in mice subjected to middle cerebral artery occlusion to support the findings in vitro. Interpretation: Glutamate excitotoxicity impaired mitochondrial HK-II and simultaneously induced apoptosis and parthanatos owing to mitochondrial dysfunction. AIV activated Akt to promote HK-II binding to mitochondria, and the structural and functional integrity of mitochondria contributed to protecting neurons from apoptosis and DNA damage. These findings address the important role of mitochondrial HK-II in neuronal protection. Funding:This study is funded by National Natural Science Foundation of China (Grant No. 81703738) and Foundation of The Science and Technology Department of Henan Province (Grant No. 182102310169) Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The animal care and all experimental procedures were approved by Animal Ethics Committee of China Pharmaceutical University.