Mild hypothermia alleviates excessive autophagy and mitophagy in a rat model of asphyxial cardiac arrest

Abstract

Mild hypothermia is an effective therapeutic strategy to improve poor neurological outcomes in patients following cardiac arrest (CA). However, the underlying mechanism remains unclear. The aim of the study was to evaluate the effect of mild hypothermia on intracellular autophagy and mitophagy in hippocampal neurons in a rat model of CA. CA was induced in Sprague-Dawley (SD) rats by asphyxia for 5 min. After successful resuscitation, the surviving rats were randomly divided into two groups, the normothermia (NT) group and the hypothermia (HT) group. Mild hypothermia (32 °C) was induced following CA for 4 h, and animals were rewarmed at a rate of 0.5 °C/h. Neurologic deficit scores (NDS) were used to determine the status of neurological function. Cytoplasmic and mitochondrial protein from the hippocampus was extracted, and the expression of LC3B-II/I and Parkin were measured as markers of intracellular autophagy and mitophagy, respectively. Of the 60 rats that underwent CA, 44 were successfully resuscitated (73 %), and 33 survived until the end of the experiment (55 %). Mild hypothermia maintained eumorphism of nuclear and mitochondrial structures and significantly improved NDS (p < 0.05). Expression of LC3B-II/I and Parkin in hippocampal nerve cells were significantly increased (p < 0.05) in the NT group relative to the control. Meanwhile, mild hypothermia reduced the level of LC3B-II/I and Parkin (p < 0.05) relative to the NT group. Mild hypothermia protected mitochondria and improved neurological function following CA and resuscitation after ischemia/reperfusion (I/R) injury, likely by reducing excessive autophagy and mitophagy in neurons.

Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia‑reperfusion injury

“…They were provided food and water ad libitum, and housed at 25˚C, with freshly ventilator delivered atmosphere and a 12 h light/dark cycle. The procedure of animal CA and CPR were performed as described previously (4). Endotracheal intubation was performed prior to left/right femoral arteriovenous catheterization.…”

“…The principal pathological cause of organ damage is excessive apoptosis and autophagy (4,5), the extent of which has been found to correlate with poor neurological prognosis (6)(7)(8). A number of studies have demonstrated that hypothermia can attenuate neurological damage following I/R injury by reducing neural apoptosis and preventing autophagy overactivation (4,9,10). Therefore, it has been recommended as a potential treatment in patients who were successfully resuscitated following CA (11).…”

Effect of valproic acid combined with therapeutic hypothermia on neurologic outcome in asphyxial cardiac arrest model of rats

“…Fifth, the duration of HT treatment was 4 hours, which may be contrasted with clinical use of HT. The duration of HT treatment used in this study was similar to previous studies investigating the beneficial effect of HT in a cardiac arrest rat model [25,26]. Four hours of HT may not be enough to improve neurologic outcomes in cases of clinical HT, and more prolonged HT could result in diminishing beneficial effects of VPA.…”

Role of Mitophagy in Cardiovascular Disease

“…Certain environmental stimuli can inhibit or promote mitophagy and alter the content of the proteins related to this phenomenon. Mild hypothermia downregulated Parkin in hippocampal neurons in a cardiac arrest model, diminishing mitophagy in the neurons, protecting mitochondria, and improving neurological function after cardiac arrest [194]. Hypoxic preconditioning induced FUNDC1-dependent activation of mitophagy and decreased I/R-induced cardiac injury [96].…”