Hypoxia ischemia update

Embryonic and perinatal hypoxic-ischemia (HI) is an increasingly major factor in the growing indicidence of behavioral, motor, and cognitive deficits expressed in preterm infants (Rice and Barone, 2000). One of better known consequences, cerebral palsy (CP), characterized by movement disorders, cognitive and behavioral deficits and first described by William John Little (Little, 1862) followed by linkage to development by S. Freud (Freud, 1897) and William Osler (Osler, 1899). A more recent description by Bax et al. (2005) is that “Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occur in the developing fetal or infant brain. The motor disorders of CP are often accompanied by disturbances of sensation, perception, cognition, communication, behavior, by epilepsy and by secondary musculoskeletal problems.” (Bax et al., 2005). Perinatal hypoxic-ischemic encephalopathy following neonatal hypoxia-ischemia (HI), can result in developmental neurological deficits such as cerebral palsy, and delayed cognitive and behavioral deficits (Boichot et al., 2006). In the United States, perinatal HI occurs in 0.2–0.4% of term infants, and up to 60% of preterm (< 37 weeks) or very low birth weight (< 1500 g) infants (Vannucci et al., 1999). Many of the advances made in our understanding of HI and its consequences are due to the use of mammalian experimental models. These have allowed for the cellular and molecular characterization of the events and consequences associated with the HI insult. They also take advantage of differences in the developmental timetable of events that take place in the embryonic stages as opposed to neonatal events of the different animal models compared to humans (Rice et al., 1981). In this Special Issue dedicated to hypoxia/ischemia, there are six papers addressing descriptions of anatomical, behavioral and motor coordination features of HI as it presents in animal models; cellular targets impacted by HI, molecular components, and putative therapeutic approaches to its treatment. Effects of HI on myelination are discussed by Singh et al and Snyder et al (see this issue). Singh et al (see this issue) address the importance of glial cell lineage with a focus on oligodendroglia, the cells responsible for myelination via the concerted action of a number of growth factors and other signaling molecules derived from astrocytes, microglia and neurons. Myelin is particularly susceptible to inflammatory molecular cascades triggered by oxidative stress-associated with HI (Ferriero, 2001; Volpe, 2001). Much of oligodendroglial derived myelination occurs in the third trimester in humans and early neonatal developmental stages in rodents validating the use of day six rodents in much of HI research (Rice and Barone 2000; Paus et al., 2000). Kaur et al review the literature that supports the hypothesis that a major contributor to the myelination deficits associated with HI (Volpe, 2001) are due in part to deficits in the levels of the signaling molecules originating in surrounding astrocytes, microglia and neurons (Bercury and Macklin, 2015, Baur et al., 2005). Kaur et al then provide a general review of different therapeutic agents in the treatment of HI. Snyder et al., attempt to develop a ferret model of HI with features common to those reported for preterm infants with infection complication and a focus on myelination. Myelination in the ferret has features that make it a likely mimic of the human condition. Snyder et al (see this issue) correlate white matter development with motor skill performance and relate these to toll like receptor expression, a marker of inflammation associated with bacterial and viral infection in animals exposed to HI followed by hyperoxia pretreated with Lipopolysaccharide in a variation of the Vannucci model (Rice et al., 1981). Their results would suggest that the ferret is a good platform for mechanistic studies of preterm infant infection. These two different animal models of HI offer different perspectives and thus provide two useful animal models that make complementary contributions to our knowledge of developmental responses to HI and consider confounding elements present in subpopulations of the affected cohort populations. Netto et al (see this issue) provide a thorough review of neuroprotective drug efficacy in the treatment of HI mostly acting as modulators of oxidative stress molecular action. A second aspect covered in the review are the effects of dietary elements central to protein, fatty acids and energy metabolism (Franz et al., 2009) known to also be important contributors to burn therapy (De-Souza and Greene, 1998). Other general aspects covered are conditioning and exercise protection. Proper myelination during brain development is essential for motor, cognitive and sensory functions (Volpe, 2011). The focus of Kamei’s contribution (ref) to this special issue is in the interplay between neurons and microglia and the role of norepinephrine (NE) in HI (Blennow et al., 1995) relying on the Vannucci model (Rice et al., 1981). Kamei describes how blockade of NE reuptake with atomoxetine inhibitor results in beneficial effects on HI when HI-induced NE increases are reduced with a subsequent decreased cell death and microglia/neuronal deleterious effects, a promising finding. Potter et al., (ref) also take advantage of the Vannucci model of HI to test the efficacy of two neuroprotective agents, hypothermia and caffeine, based on their present use on full term infants. Evaluations of efficacy relied on behavioral tests and histological measures of cortical and hippocampal volumes and showed significant improvement for caffeine treatment but not hypothermia. Whereas Hagberg et al., (ref) provide data on preconditioning protection (Meller and Simon, 2013) induced by MgSO4 (Koning et al., 2017) in both the rat Vannucci model and an adaptation of the model in mice. This provides a useful comparison based on injury assessment by immunohistochemistry in grey and white matter. Control measurements of circulating levels of magnesium confirm that the treatments significantly increased magnesium circulation. In summary, this collection of papers serve two functions; they