Clinical, Cellular and Molecular Aspects of Brain Injury in the Premature Infant
The two major forms of brain injury in premature infants are periventricular leukomalacia (PVL) and periventricular hemorrhagic infarction (PHI), a form of severe germinal matrix/intraventricular hemorrhage (GMH-IVH). Research in this IDDRC from the early 1990's to the present has addressed the pathogenesis of this injury in living infants and the mechanisms of cell death of the cellular target in white matter, the developing oligodendrocyte. The research was carried out primarily by Drs. Volpe, du Plessis and Rosenberg and represents a stunning example of how the IDDRC has fostered research that ranges all the way from the bedside to the laboratory bench (for key initial work see N. Engl. J. Med., 1991; J. Neurosci., 1993; Pediatrics, 1994; Ann. Neurol., 1995). The major results of this work were: application of near-infrared spectroscopy to the study in vivo of cerebral hemodynamics in the critically ill premature infant at high risk for the development of brain injury; demonstration of parallel changes in cerebral blood volume and arterial blood pressure, consistent with impaired cerebrovascular autoregulation, in the premature infant; and demonstration of a relation between impaired cerebrovascular autoregulation and subsequent occurrence of ultrasonographically identified PVL and GMH-IVH. In parallel with this clinical research, basic neuroscientific findings were: development of a system of primary cultures of differentiating oligodendroglia to model the cell that is the target in periventricular white matter injury of the premature infant.; discovery that glutamate is highly toxic to differentiating oligodendroglia in culture and that the toxicity is caused by activation of a glutamate-cystine exchange system, leading to cystine and thereby glutathione depletion, and ultimately to apoptotic death induced by oxidative stress; and demonstration that differentiating oligodendroglia are highly vulnerable to oxidative stress, in part because of the acquisition of iron during differentiation, and that the toxicity with oxidative stress is totally preventable by exposure to such clinically safe agents as vitamin E. This work has led to a remarkable confluence of basic and clinical research in this IDDRC. The research has involved the study of living infants by advanced near-infrared spectroscopic and magnetic resonance techniques, the characterization of postmortem human brain by modern immunocytochemical approaches, and studies of cellular and whole animal systems by sophisticated cellular and molecular biological approaches. The research has defined the molecular basis for the vulnerability to oxidative and nitrosative stress and the importance of both excitotoxic and inflammatory (microglia-mediated) injury in the white matter injury. Novel preventative therapies based on this research are currently under investigation (Volpe, Kinney, Rosenberg, Jensen and Vartanian).