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Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed “encephalopathy of prematurity”. The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.

The authors outline the three major forms of brain injury in very preterm infants and the role of injury in subsequent brain development, noting mediating factors and their neurodevelopmental consequences.

Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.

Reactive microglia in the CNS have been implicated in the pathogenesis of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, the mechanism by which activated microglia kill oligodendrocytes (OLs) remains elusive. Here we show that lipopolysaccharide (LPS)-induced death of developing OLs is caused by microglia-derived peroxynitrite, the reaction product of nitric oxide (NO) and superoxide anion. Blocking peroxynitrite formation with nitric oxide synthase inhibitors, superoxide dismutase mimics, or a decomposition catalyst abrogated the cytotoxicity. Only microglia, but not OLs, expressed inducible NO synthase (iNOS) after LPS challenge; microglia from iNOS knockout mice were not cytotoxic upon activation. The molecular source for superoxide was identified as the superoxide-generating enzyme NADPH oxidase. The oxidase was activated upon LPS exposure, and its inhibition prevented microglial toxicity toward OLs. Furthermore, microglia isolated from mice deficient in the catalytic component of the oxidase, gp91 phox, failed to induce cell death. Our results reveal a role for NADPH oxidase in LPS-induced OL death and suggest that peroxynitrite produced by iNOS and NADPH oxidase in activated microglia may play an important role in the pathogenesis of white matter disorders.

Despite the key role of γ-aminobutyric acid (GABA) neurons in the modulation of cerebral cortical output, little is known about their development in the human cortex. We analyzed several GABAergic parameters in standardized regions of the cerebral cortex and white matter in a total of 38 human fetuses and infants from 19 gestational weeks to 2.7 postnatal years using immunocytochemistry, Western blotting, tissue autoradiography, and computer-based cellular quantitation. At least 20% of GABAergic neurons in the white matter migrated toward the cortex over late gestation. After term, migration declined and ended within 6 postnatal months. In parallel, the GABAergic neuronal density increased in the cortex over late gestation, also with a peak at term. From midgestation to infancy, the pattern of GABAA receptor binding changed from uniformly low across all cortical layers to high levels concentrated in the middle laminae; glutamic acid decarboxylase (GAD65 and GAD67) levels differentially increased. Thus, the second half of gestation is a period of rapid development of the cortical GABAergic system that continues into early infancy. This period corresponds to the peak window of vulnerability to perinatal hypoxia-ischemia in which GABAergic neurons are potentially developmentally susceptible, including in the preterm infant.

Periventricular leukomalacia (PVL), the major substrate of cerebral palsy in survivors of prematurity, is defined as focal periventricular necrosis and diffuse gliosis in immature cerebral white matter. We propose that nitrosative and/or oxidative stress to premyelinating oligodendrocytes complicating cerebral ischemia in the sick premature infant is a key mechanism of injury interfering with maturation of these cells to myelin-producing oligodendrocytes and subsequent myelination. Using immunocytochemical markers in autopsy brain tissue from 17 PVL cases and 28 non-PVL controls, we found in the PVL cases1) selective regionalization of white matter injury, including preferential involvement of the deep compared to intragyral white matter; 2) prominent activation of microglia diffusely throughout the white matter; 3) protein nitration and lipid peroxidation in premyelinating oligodendrocytes in the diffuse component; 4) preferential death of premyelinating oligodendrocytes diffusely; and 5) virtual sparing of the overlying cerebral cortex, as demonstrated by markers of activated astrocytes and microglia. These data establish that PVL is primarily a white matter disease that involves injury to premyelinating oligodendrocytes, potentially through activation of microglia and release of reactive oxygen and nitrogen species. Agents that prevent nitrosative and oxidative stress may play a key role in ameliorating PVL in premature infants in the intensive care nursery.

Developing oligodendrocytes (OLs) are highly vulnerable to excitotoxicity and oxidative stress, both of which are important in the pathogenesis of many brain disorders. OL excitotoxicity is mediated by ionotropic glutamate receptors (iGluRs) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate type on these cells. Here we report that metabotropic GluRs (mGluRs) are highly expressed in OL precursors but are down-regulated in mature OLs. Activation of group 1 mGluRs attenuates OL excitotoxicity by controlling downstream oxidative stress after iGluR overactivation and also prevents nonexcitotoxic forms of oxidative stress by inhibiting reactive oxygen species accumulation and intracellular glutathione loss. The modulating effect of group 1 mGluRs on hypoxic-ischemic OL injury is not due to iGluR endocytosis that occurs in neurons in response to mGluR activation but requires activation of PKCα after G protein coupling to phospholipase C. Our results reveal a previously undescribed role for mGluRs in limiting OL injury and suggest that targeting group 1 mGluRs may be a useful therapeutic strategy for treating disorders that involve excitotoxic injury and/or oxidative stress to OLs.

Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing. Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and –0·19 (–1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group). Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2–25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam. F Hoffmann-La Roche.

Hypoxic-ischemic brain injury in premature infants results in cerebral white matter lesions with prominent oligodendroglial injury and loss, a disorder termed periventricular leukomalacia (PVL). We have previously shown that glutamate receptors mediate hypoxic-ischemic injury to oligodendroglial precursor cells (OPCs) in a model of PVL in the developing rodent brain. We used primary OPC cultures to examine the mechanism of cellular toxicity induced by oxygen-glucose deprivation (OGD) to simulate brain ischemia. OPCs were more sensitive to OGD-induced toxicity than mature oligodendrocytes, and OPC toxicity was attenuated by nonselective [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), 6-cyano-7-nitroquinoxaline-2,3-dione], α-amino-3-hydroxy-5-methyl -4-isoxazolepropionic acid (AMPA)-preferring (GYKI 52466), kainate-preferring (γ- D-glutamylaminomethanesulfonic acid), or Ca2+-permeable AMPA/kainate receptor antagonists (joro spider toxin, JSTx) administered either during or after OGD. Furthermore, NBQX or JSTx blocked OGD-induced Ca2+influx. Relevant to recurrent hypoxic-ischemic insults in developing white matter, we examined the effects of sublethal OGD preconditioning. A prior exposure of OPCs to sublethal OGD resulted in enhanced vulnerability to subsequent excitotoxic or OGD-induced injury associated with an increased Ca2+influx. AMPA/kainate receptor blockade with NBQX or JSTx either during or after sublethal OGD prevented its priming effect. Furthermore, OGD preconditioning resulted in a down-regulation of the AMPA receptor subunit GluR2 on cell surface that increased Ca2+permeability of the receptors. Overall, these data suggest that aberrantly enhanced activation of Ca2+-permeable AMPA/kainate receptors may be a major mechanism in acute and repeated hypoxic-ischemic injury to OPCs in disorders of developing cerebral white matter, such as PVL.

Periventricular leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29–51 postconceptional (PC) weeks] and 16 control cases (20–144 PC weeks). Using a standardization score of 0–3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 ± 0.3) cases compared to controls (score of 0.7 ± 0.3) ( P  = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL’s pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.