Intraischemic mild hypothermia prevents neuronal cell death and tissue loss after neonatal cerebral hypoxia–ischemia

Abstract

The effectiveness of hypothermia in preventing ischemic brain damage depends on when it is started. The purpose of this study was to investigate the effects of temperature reduction during a hypoxic-ischemic (HI) insult on brain injury and signalling pathways of neuronal cell death and survival. Seven-day-old mice were subjected to left common carotid artery ligation and hypoxia (10% oxygen) at different temperatures (37, 36 or 34 degrees C) for 50 min. Brain injury at 7 days post-HI was significantly reduced from 67.4% at 37 degrees C to 31.6% at 36 degrees C and 10% at 34 degrees C, with no observable injury in the cortex of the 34 degrees C group. Cytochrome c release, caspase-3 activation and apoptosis-inducing factor translocation from mitochondria to nuclei were all significantly inhibited after intraischemic temperature reduction. Concurrently, the cell survival signalling pathway involving Akt was significantly sustained (the phosphorylated form of Akt was maintained) when the hypoxia temperature was decreased. These results indicate that intraischemic hypothermia diminished apoptosis through inhibition of both caspase-dependent and caspase-independent neuronal cell death pathways and promoted cell survival by inhibition of phosphorylated Akt dephosphorylation in the neonatal brain, thereby preventing neuronal cell death.

Sex Differences in Behavioral Outcomes Following Temperature Modulation During Induced Neonatal Hypoxic Ischemic Injury in Rats

“…For example, a preterm fetal sheep model has demonstrated that hypothermia following induced HI is associated with an overall reduction in hypoxia-induced loss of immature oligodendrocytes, as well as reduction in energy expenditure [ 69 ]. Benefits of lower body temperatures have also been substantiated in other animal studies, showing for example that cooling during an ischemic insult is associated with more favorable long-term outcomes [ 70 , 71 , 72 ]. However, benefits are bounded by evidence that extremely low body temperatures (approximately 5 °C lower than normal) also lead to a higher incidence of cell death in a piglet model [ 73 ].…”

Whole body hypothermia broadens the therapeutic window of intranasally administered IGF-1 in a neonatal rat model of cerebral hypoxia–ischemia

“…For example, in an adult focal brain ischemia model, hypothermia blocked the ischemia-induced pAkt changes and maintained pAkt activity (Zhao et al, 2005). In a neonatal HI model, hypothermia was found to enhance pAkt activity at 24 h after HI and blocked cytochrome C release from the mitochondria and caspase activation (Zhu et al, 2006). However, there are other reports that showed reduced pAkt levels following hypothermia treatment in a neonatal HI model (Tomimatsu et al, 2001).…”

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

“…However, we did achieve a 45% reduction of injury after hypothermia as well as a 26% reduction in injury after delayed hypothermia in Casp2 −/− mice as compared with WT normothermic mice. Zhu et al (34) found that a minor lowering of body temperature to 34 °C during HI in mice provided complete protection in the cerebral cortex. Due to a smaller body volume we expected mice to be more vulnerable than rats, which was the rationale behind using a protocol of moderate hypothermia in this study.…”