Therapeutic Hypothermia After Cardiac Arrest: Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection.

Abstract

Therapeutic hypothermia is neuroprotective after cardiac arrest (CA) via poorly understood mechanisms. It may prevent mitochondrial permeability transition pore (PTP) opening, an event which plays a pivotal role in ischemia-reperfusion injury. PTP is the main end-effector of the reperfusion injury salvage kinase (RISK) signaling pathway. We hypothesized that therapeutic hypothermia activates the RISK pathway, thereby preventing PTP opening and its deleterious neurological consequences after CA. Four groups of New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion: Control, HT (hypothermia at 32°-34°C), NIM (specific PTP inhibition with N-methyl-4-isoleucine-cyclosporine at the onset of reperfusion), and HT+NIM. A Sham group only underwent surgery. The following measurements were taken: pupillary reflexes and brain damage biomarkers (NSE and S100β), RISK pathway activation in brain cortex (total and phosphorylated forms of both protein kinase B [Akt] and extracellular signal-regulated kinase [ERK]) and PTP opening in isolated brain mitochondria. Therapeutic hypothermia and pharmacological PTP inhibition preserved the pupillary reflexes and prevented the increase in both NSE and S100β (P < 0.05 vs. controls). These two interventions also enhanced (P < 0.05 vs. controls) the phospho-Akt/Akt ratio to a similar extent while preventing a CA-induced increase in phospho-ERK/ERK ratio. This Akt activation in the HT and NIM groups was associated with an attenuation of CA-induced PTP opening. In this model, therapeutic hypothermia promoted the activation of the RISK signaling pathway via Akt and limited CA-induced brain injury by preventing PTP opening.

• Authors: Vincent Jahandiez, Martin Cour, Maryline Abrial, Joseph Loufouat, Michel Ovize, Laurent Argaud
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 52 Issue 2 Pg. 224-229 (08 2019) ISSN: 1540-0514 [Electronic] United States
• PMID: 30052584 (Publication Type: Journal Article)

Chemical References

• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore

Topics

• Animals
• Heart Arrest (genetics, metabolism, therapy)
• Hypothermia, Induced (methods)
• Male
• Mitochondria (metabolism)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore
• Myocardium (metabolism)
• Neuroprotection (physiology)
• Oxidative Phosphorylation
• Rabbits
• Signal Transduction (genetics, physiology)