Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.

Abstract

Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling ( n ϭ 9) or sham cooling ( n ϭ 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 Њ C, and a fall in esophageal temperature of 1.5-3 Њ C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema ( P Ͻ 0.001).

Hypothermic neuroprotection

“…78 For example, in the near-term fetal sheep, moderate hypothermia induced 90 minutes after reperfusion, in the early latent phase, and continued until 72 hours after ischemia, prevented secondary cytotoxic edema, and improved electroencephalographic recovery. 27 There was a concomitant substantial reduction in parasagittal cortical infarction and improvement in neuronal loss scores in all regions. When the start of hypothermia was delayed until just before the onset of secondary seizures in this paradigm (5.5 hours after reperfusion) partial neuroprotection was seen ( Figure 3).…”

“…19,21 At term equivalent, this secondary deterioration is often marked by the onset of seizures (figure 2), 26,27 secondary cytotoxic edema, 24 accumulation of excitotoxins, 23 failure of cerebral mitochondrial activity 21 and ultimately, cell death. 27,28 Surprisingly, although there are extensive data describing the timing and development of the delayed failure of mitochondrial oxidative metabolism after acute insults, its precise pathogenic significance remains highly controversial. For example, there is a close correlation between histological loss of the key mitochondrial cytochromes and neuronal loss, 29 -31 and between the timing of loss of cytochrome activity after severe anoxia in the cat and subsequent delayed onset of neurological deterioration.…”

“…51 The intracytoplasmic stage of apoptosis involves alterations in the ratio of various intracellular factors such as the proto-oncogene Bcl-2, which inhibits apoptosis, and From approximately 6 h after reperfusion there is a rapid onset of intense delayed seizures and cytotoxic edema, which begin to resolve from 36 h. The profound suppression of the EEG after resolution of seizures correlates strongly with loss of cortical neurons. 27 Bax, which promotes apoptosis, 52 and activation of cysteine proteases (caspases). 53 The final, irreversible execution phase of apoptosis is intranuclear, involving endonuclease mediated DNA fragmentation.…”

Comparative Effects of Glucose- and Mannitol-Induced Osmolar Stress on Blood—Brain Barrier Function in Ovine Fetuses and Lambs

“…The fetuses at 60% of gestation were a mean of 88 (range 87 to 88) days of gestation, preterm lambs were 138 (range 136 to 142) days of gestation and the newborn lambs 4 (range 3 to 5) days of age on the day of study. Although the relative maturation of the ovine and human brain cannot be compared precisely, the sheep brain at 80% to 85% of gestation is generally thought to be similar to the newborn infant at term (Back et al, 2006;Gunn et al, 1997). Hence, the relative brain maturation of the fetuses at 60% of gestation would be approximately similar to preterm human infants at 22 to 25 weeks of gestation (Back et al, 2006), the premature lambs at 90% of gestation similar to full term to several week-old infants and the newborn lambs to several weeks to a month-of-age infants.…”

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

“…As hypoxic-ischemic brain injury is often unpredictable, the primary approach is to develop post-insult therapies to ameliorate ongoing or secondary injury [17,29] . In this regard, many studies have been carried out to identify new therapeutic strategies that diminish brain damage caused by hypoxia-ischemia [30][31][32] .…”