Gray Matter Oligodendrocyte Progenitors and Neurons Die Caspase-3 Mediated Deaths Subsequent to Mild Perinatal Hypoxic/Ischemic Insults

Abstract

With significant improvements in neonatal care, fewer infants sustain severe injury as a consequence of hypoxia/ischemia (H/I). However, the majority of experimental studies have inflicted moderate to severe injuries, or they have assessed damage to the caudal forebrain; therefore, to better understand how a mild H/I episode affects the structures and cells of the rostral forebrain, we assessed the relative vulnerabilities of cells in the neocortex, striatum, corpus callosum, choroid plexus and subventricular zone (SVZ). To inflict mild H/I injury, the right common carotid artery was ligated followed by 1 h of hypoxia (8% O₂) at 37°C. Regional vulnerabilities were assessed using TUNEL, active caspase-3 and hematoxylin and eosin staining at 24 and 48 h of recovery. Scattered columns of cell death were observed in the neocortex with deep-layer neurons more vulnerable than more superficial neurons. The majority of these dying neurons appeared to be dying apoptotic rather than necrotic deaths. In addition, approximately 1/3 of the apoptotic cells in the neocortex were O4+ oligodendrocyte progenitors. We also observed a decrease in NG2 staining within the affected regions of the forebrain. By contrast, active caspase-3+/S-100β+ astrocytes were not observed. Neurons and O4+ oligodendrocyte progenitors also died apoptotic deaths within the striatum. The lining cells of the choroid plexus also sustained damage. Elevated numbers of apoptotic cells were observed in the most lateral region of the SVZ and some of these dying cells were O4+. The most novel finding of this study, that oligodendrocyte progenitors in the gray matter are damaged and eliminated as a consequence of perinatal H/I, provides new insights into the histopathology and neurological deficits observed in infants who sustain mild H/I brain injuries.

Hypoxia-Ischemia Upregulates TRAIL and TRAIL Receptors in the Immature Rat Brain

“…Moreover, neurons were not the only dying cells in the immature rat brain after HI insult. It has previously been reported that both oligodendrocyte progenitor cells and neurons die in a caspase-3-dependent manner in the cortex in a similar HI model [41]. …”

Hypothermic neuroprotection

“…48 Generally apoptosis-like or programmed cell death seems to be more important in the developing brain than in adults. 56,57,[61][62][63][64][65][66] Regardless of the precise pattern of delayed death, the concept remains an important one, since if neuronal and glia cell death is an active response (preprogrammed or functionally mediated by secondary mechanisms such as cytotoxin exposure), then it should logically be possible to interrupt these events.…”

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

“…[30][31][32] Although acute cellular necrosis occurs, apoptotic cell death appears to be a more significant contributor to abnormal outcome for the developing brain of the term infant. 33,34 After the secondary phase of injury, there is another chronic phase of injury where there is further loss of brain cells. 35 Emerging evidence in animal models of neonatal brain injury and evidence from advanced neuroimaging techniques in infants with HIE, suggest that areas of the brain that are connected to areas of initial injury suffer evolving pathology.…”