Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways.
The mechanism of neuronal death induced by ischemic injury remains unknown. We investigated whether autophagy and p53 signaling played a role in the apoptosis of hippocampal neurons following global cerebral ischemia-reperfusion (I/R) injury, in a rat model of 8-min asphyxial cardiac arrest (CA) and resuscitation. Increased autophagosome numbers, expression of lysosomal cathepsin B, cathepsin D, Beclin-1, and microtubule-associated protein light chain 3 (LC3) suggested autophagy in hippocampal cells. The expression of tumor suppressor protein 53 (p53) and its target genes: Bax, p53-upregulated modulator of apoptosis (PUMA), and damage-regulated autophagy modulator (DRAM) were upregulated following CA. The p53-specific inhibitor pifithrin-α (PFT-α) significantly reduced the expression of pro-apoptotic proteins (Bax and PUMA) and autophagic proteins (LC3-II and DRAM) that generally increase following CA. PFT-α also reduced hippocampal neuronal damage following CA. Similarly, 3-methyladenine (3-MA), which inhibits autophagy and bafilomycin A1 (BFA), which inhibits lysosomes, significantly inhibited hippocampal neuronal damage after CA. These results indicate that CA affects both autophagy and apoptosis, partially mediated by p53. Autophagy plays a significant role in hippocampal neuronal death induced by cerebral I/R following asphyxial-CA.
Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai 200233, China.|Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Derong
D
Cui
Department of Neurosurgery, Shanghai Ruijin Hospital Affiliated with Medical School of Shanghai Jiaotong University, Shanghai 200025, China.
Hanbing
H
Shang
Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai 200233, China.
Xiaoli
X
Zhang
Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai 200233, China.
Wei
W
Jiang
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.|Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Xiaofeng
X
Jia
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D052160:Benzothiazoles / Q000494:pharmacology; D015415:Biomarkers; D001784:Blood Gas Analysis; D016923:Cell Death; D004195:Disease Models, Animal; D015870:Gene Expression; D006323:Heart Arrest / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D052160:Benzothiazoles; D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D014050:Toluene; D016159:Tumor Suppressor Protein p53; C526109:Anxa3 protein, rat; C121565:pifithrin