Therapeutic Hypothermia After Cardiac Arrest: Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue Shock Année : 2019

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

Résumé

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 degrees -34 degrees 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 S100beta), 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 S100beta (P \textless 0.05 vs. controls). These two interventions also enhanced (P \textless 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.

Dates et versions

hal-02195235 , version 1 (26-07-2019)

Identifiants

Citer

V. Jahandiez, M. Cour, M. Abrial, J. Loufouat, M. Ovize, et al.. Therapeutic Hypothermia After Cardiac Arrest: Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection. Shock, 2019, 52 (2), pp.224--229. ⟨10.1097/shk.0000000000001234⟩. ⟨hal-02195235⟩
12 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More