Differential effects of slow rewarming after cerebral hypothermia on white matter recovery after global cerebral ischemia in near-term fetal sheep.

It is widely believed that rewarming slowly after therapeutic hypothermia for hypoxic-ischemic (HI) encephalopathy can improve outcomes, but its impact on white matter injury after HI is unclear. Fetal sheep (0.85 gestation) received 30 min ischemia-normothermia (n = 8), or hypothermia from 3-48 h with rapid spontaneous rewarming over 1 h (ischemia-48 h hypothermia, n = 8), or 48 h with slow rewarming over 24 h (ischemia-slow rewarming, n = 7) or 72 h with rapid rewarming (ischemia-72 h hypothermia, n = 8). Ischemia was associated with loss of total and mature oligodendrocytes and reduced area fraction of myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase; immature/mature oligodendrocytes) and increased microglia and astrocytes. Total numbers of oligodendrocytes were increased by all hypothermia protocols but only ischemia-72 h hypothermia attenuated loss of mature oligodendrocytes. All hypothermia protocols similarly increased the area fraction of MBP, whereas there was only an intermediate effect on the area fraction of CNPase. Microglia were suppressed by all hypothermia protocols, with the greatest reduction after ischemia-72 h hypothermia, and an intermediate effect after ischemia-slow rewarming. By contrast, induction of astrocytes was significantly reduced only after ischemia-slow rewarming. In conclusion, slow rewarming after hypothermia did not improve oligodendrocyte survival or myelination or suppression of microgliosis compared to fast rewarming, but modestly reduced astrocytosis.

Potential neuroprotective strategies for perinatal infection and inflammation.

Preterm born infants have high rates of brain injury, leading to motor and neurocognitive problems in later life. Infection and resulting inflammation of the fetus and newborn are highly associated with these disabilities. However, there are no established neuroprotective therapies. Microglial activation and expression of many cytokines play a key role in normal brain function and development, as well as being deleterious. Thus, treatment must achieve a delicate balance between possible beneficial and harmful effects. In this review, we discuss potential neuroprotective strategies targeting systemic infection or the resulting systemic and central inflammatory responses. We highlight the central importance of timing of treatment and the critical lack of studies of delayed treatment of infection/inflammation.

Battle of the hemichannels--Connexins and Pannexins in ischemic brain injury.

Perinatal ischemic brain injury can occur as a result of a global ischemic insult or focal ischemic stroke in the preterm or full-term neonate. One of the most striking features of HI injury is that, after initial recovery of cellular oxidative metabolism, there is a delayed, 'secondary' mitochondrial failure that spreads over time from the most severely damaged areas outwards, into previously undamaged regions. This secondary failure is accompanied by transient seizure activity and cytotoxic edema. The specific mechanisms of this spread are poorly understood, but it is at least partly associated with spreading waves of depression that can trigger cell death in neighboring uninjured tissues. Both Connexin and Pannexin hemichannels may mediate release of paracrine molecules that in turn propagate cell death messages by releasing intracellular mediators, such as ATP, NAD(+), or glutamate or by abnormally prolonged opening to allow cell edema. This review will discuss the controversy around the relative contribution of both Connexin and Pannexin hemichannels and mechanisms by which they may contribute to the spread of ischemic brain injury.

Connexin hemichannel blockade is neuroprotective after, but not during, global cerebral ischemia in near-term fetal sheep.

There is increasing evidence that connexin hemichannels, the half gap junctions that sit unopposed in the cell membrane, can open during ischemia and that blockade of connexin43 hemichannels after cerebral ischemia can improve neural outcomes. However, it is unclear whether connexin blockade during ischemia is protective. In the present study global cerebral ischemia was induced by 30 min of bilateral carotid artery occlusion in near-term (128 ± 1 day gestation age) fetal sheep. A specific mimetic peptide that blocks connexin43 hemichannels was infused into the lateral ventricle for either 1h before and during ischemia (intra-ischemia group, n=6) or for 25 h starting 90 min after the end of ischemia (post-ischemia group, n=7). The vehicle was infused in the ischemia-vehicle group (n=6) and sham-controls received sham occlusion plus vehicle (n=10). The post-ischemia group showed enhanced recovery of EEG power from day five until the end of the experiment (-5 ± 1.6 dB) compared to ischemia-vehicle (-13 ± 1.9 dB, p<0.05) and intra-ischemia infusion (-14.4 ± 3.6 dB, p<0.05). Post-ischemic infusion was associated with higher neuronal counts compared to ischemia-vehicle and intra-ischemia in the cortex (p<0.05) but not the CA1 and CA3 regions of the hippocampus. Oligodendrocyte cell counts in the intragyral and periventricular white matter were significantly higher in the post-ischemia group compared to ischemia-vehicle and intra-ischemia infusion (p<0.05). These large animal data support the hypothesis that connexin hemichannel opening after, but not during, ischemia contributes to the spread of white and gray matter injury of the developing brain.