Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways.

Derong Cui,Derong Cui,Derong Cui,Hanbing Shang,Wei Jiang,Xiaoli Zhang,Xiaofeng Jia

doi:10.1038/srep27642

Abstract

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.

Highlights

The transcription of Damage-Regulated Autophagy Modulator (DRAM), which in turn triggers autophagy as well as p53-mediated apoptosis[21,22]
The current study demonstrates that ischemic Cardiac arrest (CA) injury leads to cell death and increased autophagic activity, marked by accumulation of autophagosomes, autolysosomes, and other biomarkers
Our findings further indicate autophagic mechanisms in hippocampal neuronal injury during cerebral ischemia following CA

Summary

Introduction

The transcription of Damage-Regulated Autophagy Modulator (DRAM), which in turn triggers autophagy as well as p53-mediated apoptosis[21,22]. Preventing autophagy partially reduced pyramidal neuronal death, suggesting its role in ischemic injury[7]. Whether p53 induction of autophagy in an ischemic brain following CA was adaptive, maladaptive, or mediated by cellular effectors common to apoptosis, is unknown. Autophagy is involved in both the promotion and inhibition of cell survival. The signaling pathways that regulate these cellular events remain poorly defined, underscoring the need for determination of other factors in autophagy and its impact on cell survival, in the context of cerebral ischemia following CA. We explored the role of autophagy involving hippocampal apoptosis triggered by global cerebral I/R injury following CA. We identified new therapeutic targets for the inhibition of neuronal cell death and associated clinical therapeutic windows following CA for possible future clinical translation

Methods

Results

Conclusion