Hypoxic-Ischemic Oligodendroglial Injury in Neonatal Rat Brain

Abstract

Neonatal periventricular white matter injury is a major contributor to chronic neurologic dysfunction. In a neonatal rat stroke model, myelin basic protein (MBP) immunostaining reveals acute periventricular white matter injury. Yet, the extent to which myelin proteins can recover after neonatal hypoxicischemic injury is unknown. We developed a quantitative method to correlate the severity of the hypoxic-ischemic insult with the magnitude of loss of MBP immunostaining. Seven-day-old (P7) rats underwent right carotid ligation, followed by exposure to 8% oxygen for 1, 1.5, 2, or 2.5 h. On both P12 and P21, white matter integrity was evaluated by densitometric analysis of MBP immunostaining, and the amount of tissue injury was evaluated by morphometric measurements of cerebral hemisphere areas. The most severe hypoxic-ischemic insults (2.5 h) elicited marked reductions in MBP immunostaining ipsilaterally on both P12 and P21. In contrast, in mildly lesioned animals (1.5 h), MBP immunostaining was reduced ipsilaterally on P12, but 2 wk after lesioning, on P21, there was a substantial restoration of MBP immunostaining. The restoration in MBP immunostaining could reflect either functional recovery of injured oligodendroglia or proliferation and maturation of oligodendroglial precursors. Our data demonstrate that quantitative measurement of MBP immunostaining provides a sensitive indicator of acute oligodendroglial injury. Most importantly, we show that in this neonatal rodent stroke model, restoration of myelin proteins occurs after moderate, but not after more severe, cerebral hypoxia-ischemia. Considerable clinical and experimental data demonstrate that immature oligodendroglia are highly susceptible to HI injury (1-5). There is also growing recognition that oligodendroglial injury in the immature nervous system may have profound adverse effects on neuronal development (6). Among the mechanisms implicated as contributing to the vulnerability of immature oligodendroglia to HI are increased susceptibility to excitotoxicity (1, 7), oxidative stress (2), and inflammation (8 -9), and propensity for induction of apoptosis (10).In a widely used neonatal rat stroke model, elicited by unilateral carotid artery ligation and timed exposure to moderate hypoxia (8% oxygen) in 7-d-old (P7) rats, ipsilateral white matter injury occurs, together with more widespread tissue injury (11)(12)(13)(14)(15). In this model, lengthening the duration of hypoxic exposure results in a progressive increase in the severity of brain damage (12); the temporal threshold to elicit tissue injury is at approximately 1.5 h, and more prolonged HI (2-2.5 h) commonly elicits extensive neuronal loss in the ipsilateral cortex, hippocampus, striatum, and thalamus (13). Additional neuropathologic features of the HI lesion include an acute and sustained microglial and monocyte infiltrate (13, 14), reactive gliosis (13, 15), and the evolution of cortical cavitary infarcts (13).Although the original description of histopathology in this model documented the vulner...

Neural Stem/Progenitor Cells Participate in the Regenerative Response to Perinatal Hypoxia/Ischemia

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