Potential neuroprotective strategies for perinatal infection and inflammation

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Contents lists available at ScienceDirect

International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu

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Potential neuroprotective strategies for perinatal infection and inflammation S.M. Ranchhod a , K.C. Gunn a , T.M. Fowke a , J.O. Davidson a , C.A. Lear a , J. Bai a , L. Bennet a , C. Mallard b , A.J. Gunn a , J.M. Dean a,∗ a

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Department of Physiology, University of Auckland, Auckland, New Zealand Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Article history: Received 30 January 2015 Received in revised form 16 February 2015 Accepted 16 February 2015 Available online xxx

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Keywords: Perinatal Infection Inflammation Cytokines Brain injury White matter Lipopolysaccharide

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1. Introduction

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Preterm born infants have high rates of brain injury, leading to motor and neurocognitive problems in later life. Infection and resulting inflammation of the fetus and newborn are highly associated with these disabilities. However, there are no established neuroprotective therapies. Microglial activation and expression of many cytokines play a key role in normal brain function and development, as well as being deleterious. Thus, treatment must achieve a delicate balance between possible beneficial and harmful effects. In this review, we discuss potential neuroprotective strategies targeting systemic infection or the resulting systemic and central inflammatory responses. We highlight the central importance of timing of treatment and the critical lack of studies of delayed treatment of infection/inflammation. © 2015 Published by Elsevier Ltd. on behalf of ISDN.

Worldwide, 6–15% of all live-born infants are born prematurely. Modern neonatal intensive care has dramatically improved the survival of these infants, but more modestly reduced brain injury and disability, particularly in very preterm infants (<32 weeks gestation) (Blencowe et al., 2012). In addition to severe disabilities such as cerebral palsy, which affects 5–10% of surviving preterm infants (Keogh and Badawi, 2006), up to 50% develop more subtle adverse neurodevelopmental outcomes, including impaired learning, memory, cognition, visuospatial integration, and deficits in attention and socialization throughout childhood and later life (Woodward et al., 2009). Although the etiology of these disorders

∗ Corresponding author at: Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1023, New Zealand. Tel.: +64 9 373 7599; fax: +64 9 923 1111. E-mail addresses: [email protected] (S.M. Ranchhod), [email protected] (K.C. Gunn), [email protected] (T.M. Fowke), [email protected] (J.O. Davidson), [email protected] (C.A. Lear), [email protected] (J. Bai), [email protected] (L. Bennet), [email protected] (C. Mallard), [email protected] (A.J. Gunn), [email protected] (J.M. Dean).

is complex and likely multifactorial, there is strong evidence for a role of fetal and postnatal infection and resulting inflammation. The incidence of invasive bacterial infection is several-fold higher in preterm born infants compared to that at term, and 60% or more of very preterm infants will experience at least one postnatal infection during neonatal care (Stoll et al., 2010). Worldwide, gram-negative bacteria including Escherichia coli (E. coli) are the most common cause of severe neonatal infection, although in developed countries, late-onset neonatal sepsis with gram positive organisms, including less pathogenic species such as coagulase negative staphylococci (CoNS), is now prevalent and is also associated with poor neurodevelopmental outcomes (Shane and Stoll, 2014). However, at present there are no effective treatments for infection/inflammation-mediated brain injury in the preterm neonate. Indeed, use of prophylactic antibiotics may increase the risk of death and disability, as discussed in detail later in this review (Flenady et al., 2013). Inflammation is an essential response by which the organism acts to remove the infection and then direct the repair of damaged tissues. Without the ability to trigger inflammation, the host would die. However, this beneficial response can itself cause or exaggerate tissue damage, particularly if the stimulus cannot be cleared (Mueller, 2013). Even in the absence of primary brain infection, peripheral inflammation can trigger secondary inflammation and

http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006 0736-5748/© 2015 Published by Elsevier Ltd. on behalf of ISDN.

Please cite this article in press as: Ranchhod, S.M., et al., Potential neuroprotective strategies for perinatal infection and inflammation. Int. J. Dev. Neurosci. (2015), http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006

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injury in the brain, at least in part through saturable transport of cytokines across the blood brain barrier (Threlkeld et al., 2010). Further, microglia (the mediators of intrinsic immunity in the brain) can both initiate and amplify inflammation, but also help to clear damaged cells and promote tissue repair (Mallard et al., 2014). Therefore, for any therapy targeting the inflammatory response, the delicate balance between the beneficial and potentially deleterious effects of suppressing this key process must be considered. In this review, we will briefly summarize the current understanding of the pathology of preterm brain injury, its association with perinatal infection and resulting inflammatory responses, the potential causative mechanisms, and neonatal animal models of infection/inflammation-induced brain injury (for more detail see: (Back and Rosenberg, 2014; Dean et al., 2015; Strunk et al., 2014)). On this background, we will then critically discuss potential therapeutic strategies for infection/inflammation-induced brain injury in the preterm infant. 2. Pathology of preterm brain injury Periventricular cerebral white matter damage is the most common pattern of brain injury observed in surviving preterm infants, and may be accompanied by neuronal and axonal damage (Volpe, 2009). As recently reviewed (Dean et al., 2014), the incidence of severe focal white matter lesions has progressively fallen over time. Indeed, in modern cohorts, milder, diffuse injury is now the predominant pattern (Billiards et al., 2008; Buser et al., 2012). The age of maximum vulnerability to preterm white matter injury in human babies at 23–32 weeks gestation corresponds closely with the rapid proliferation and differentiation of precursors of oligodendrocytes, the myelinating cells of the brain (Kinney and Back, 1998). Diffuse white matter injury is characterized by arrested maturation of premyelinating oligodendrocyte precursors, associated with local reactive astrogliosis and microgliosis, without major primary axonal injury (Billiards et al., 2008; Buser et al., 2012). Animal studies also show that following acute oligodendrocyte cell death after hypoxia–ischemia, the total oligodendrocyte pool is rapidly restored by extensive oligodendrocyte progenitor cell (OPC) proliferation, although these cells may fail to mature and produce myelin (Riddle et al., 2011; Segovia et al., 2008). Of particular interest, proliferation and impaired maturation of OPCs may also occur after exposure to inflammation in the absence of acute oligodendrocyte cell death (Favrais et al., 2011a; Nobuta et al., 2012). In turn, injury to the white matter is associated with reduced brain growth and complexity, including gray matter structures such as the cerebral cortex (Dean et al., 2014). Although there is evidence for neuronal loss in human cases with severe cystic white matter injury (Pierson et al., 2007; Volpe, 2009), minimal neuronal loss was observed in cases with diffuse white matter injury. Brain growth in the second half of gestation is largely related to expansion of the neuronal dendritic arbor and synaptogenesis (de Graaf-Peters and Hadders-Algra, 2006). There is now compelling experimental evidence that hypoxia–ischemia can impair these events in the thalamus and cerebral cortex, even in the absence of neuronal cell death (Dean et al., 2013; McClendon et al., 2014). This is consistent with human studies showing impaired cerebral connectivity after premature birth (Ball et al., 2013; Vinall et al., 2013). 3. In utero infection and inflammation There is increasing clinical evidence that white matter injury and cerebral palsy are associated with elevated levels of proinflammatory cytokines around the time of birth in umbilical cord blood, amniotic fluid, plasma, and cerebrospinal fluid (ArmstrongWells et al., 2014; Ellison et al., 2005; Silveira et al., 2008; Yoon

et al., 2003). Further, postmortem studies have shown increased cytokine expression by immunohistochemistry in areas of necrotic white matter injury, including tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6) (associated with microglial activation) (Deguchi et al., 1996), and interferon- (IFN-) (associated with reactive astrocytes, markers of oxidative stress, and oligodendrocyte cell death), consistent with the hypothesis that cytokines contributed to injury (Folkerth et al., 2004). Intrauterine infection of the chorioamniotic membranes (i.e., chorioamnionitis) is highly associated with preterm delivery and, in turn, with white matter injury (Strunk et al., 2014; Thomas and Speer, 2010). The source of microorganisms in the amniotic cavity is likely ascending infection from the vagina and cervix. Microorganisms detected by culture or polymerase chain reaction include ureaplasmas, mycoplasma, fusobacterium, streptococcus, bacteriocies, and prevotella, and culture resistant anaerobes such as fusobacterium, sneathia, and leptotrichia species (Gardella et al., 2004; Romero et al., 2014). These microorganisms can initiate an inflammatory response that propagates from the chorioamniotic membranes to the amniotic fluid, and then the fetus (Romero et al., 2007). This fetal involvement, as shown by the so-called ‘fetal inflammatory response syndrome’, is most clearly associated with adverse neurodevelopmental outcomes such as a very low Bayley Q5 mental developmental index at 2 years of age (Kaukola et al., 2006; Korzeniewski et al., 2014; Leviton et al., 2010; Soraisham et al., 2013).

4. Postnatal infection and inflammation Postnatal inflammation is also associated with adverse outcomes. This may reflect ongoing inflammation, as shown by the association of elevated levels of cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins in the first postnatal days after birth with subsequent white matter injury and adverse neurodevelopmental outcomes, including measures of impaired early cognitive functioning and cerebral palsy at two years of age (Kuban et al., 2015; O’Shea et al., 2013). In part, postnatal inflammation may result from serious infections such as culture-positive bacteremia and necrotizing enterocolitis (O’Shea et al., 2013), although critically, may also be related to non-infectious stimuli such as mechanical ventilation (Bose et al., 2013). Moreover, recurrent or persistent elevations in inflammation-related proteins are more strongly associated with white matter injury and a severely reduced Bayley mental development index at 2 years of age (O’Shea et al., 2013). The majority of preterm infants also experience at least one postnatal infection during neonatal intensive care, and this risk is greatest in the most immature infants (Stoll et al., 2004). Gramnegative bacteria such as E. coli and Klebsiella species are the most common cause of ‘severe’ postnatal infection and sepsis worldwide, and are highly associated with MRI-defined white matter injury and cognitive and motor impairments at 2 years of age (Shah et al., 2014). A wide range of other micro-organisms also contribute to postnatal infection, including gram-negative organisms (e.g., Enterobacter species), group B Streptococcus (GBS), Staphylococcus aureus, ureaplasma, mycoplasma species, yeast infections (e.g., Candida) (Hecht et al., 2008; Hentges et al., 2014; Stoll et al., 2004), and many viruses including herpes group B and cytomegalovirus (Nijman et al., 2013). In developed countries, low-level infections with less pathogenic CoNS (e.g., Staphylococcus epidermidis) are now the most common postnatal infection. CoNS is associated with over 50% of all late onset infections in preterm infants (Marchant et al., 2013; Venkatesh et al., 2006). Even these less severe infections are associated with adverse outcomes, including cerebral palsy (Stoll et al.,

Please cite this article in press as: Ranchhod, S.M., et al., Potential neuroprotective strategies for perinatal infection and inflammation. Int. J. Dev. Neurosci. (2015), http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006

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2004) and adverse neurodevelopmental outcomes at 2–3 years of age (Alshaikh et al., 2014; O’Shea et al., 2013), and motor problems in school aged children (Mitha et al., 2013). In summary, there is now compelling evidence that both severe and subacute prenatal and postnatal infections, and non-specific sterile inflammation, are highly associated with adverse neurodevelopmental outcomes. It is important to note that nearly all the clinical evidence linking infection with adverse outcomes comes from large epidemiological cohorts, which do not lend themselves to clinico-pathological correlations. Further, to our knowledge there is no evidence for specific patterns of preterm brain injury associated with specific patterns of infection or inflammation, other than the well-known neuropathologies associated with meningitis and with congenital viral infections such as Rubella virus and Cytomegalovirus, which are outside the scope of this review. The overwhelming majority of the literature simply shows associations between evidence of infection or inflammation with the typical patterns of white matter injury, gray matter injury, and neurological deficits observed in preterm infants; i.e., the consequences of antenatal and neonatal infections merge in with the range of outcomes of prematurity. It is also striking that experimental animal models show that exposure to peripheral infection or inflammation results in a remarkably similar pattern of brain injury, irrespective of the agent used, suggesting that brain injury may be the result of activation of a common peripheral immune response pathway (Dean et al., 2015).

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By contrast, large animal models are relatively expensive, but valuable as they exhibit a larger gyrencephalic brain, and allow cardiovascular and neural responses to infection and treatments to be studied continuously both in utero and postnatally (Mathai et al., 2013). The most commonly used species is the sheep, which is relatively precocial, and is most similar to the 26–32 week human at 95–102 days gestation (term is 147 days) (Back et al., 2012). These models are useful for testing potential neuroprotective agents. 6. Neuroprotective strategies for perinatal infection/inflammation At present, there are no established therapies to reduce infection-related preterm brain injury. The timing of the infection, subsequent peripheral and central inflammatory events, and the timing of brain injury are key considerations for any treatment. Potential treatment strategies include antibiotics, antiinflammatory agents, inhibition of cell death pathways, promotion of cellular maturation and development, and cellular regeneration/replacement. When assessing the evidence for different strategies, it is important to consider that pragmatically it would be difficult to institute any treatment before infection or inflammation was confirmed. Further, given the current evidence that prophylactic antibiotic therapy does not improve neurological outcomes in preterm infants, neuroprotective strategies should focus on targeting the inflammatory responses to infection.

5. Animal models of infection/inflammation

7. Antibiotics

Animal studies suggest that the association of infection/inflammation with neonatal brain injury is causal (Van Steenwinckel et al., 2014). As recently reviewed (Dean et al., 2015), conceptually these models broadly try to replicate in utero versus postnatal exposure to infection/inflammation. The majority of studies have used agents that mimic the inflammatory component of bacterial and viral infections, such as bacterial/viral fragments or specific components, toll-like receptor agonists, and cytokines. The single most common agent is lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria that initiates a broad systemic and central inflammatory response. However, exposure to LPS or specific cytokines may not reflect the full complexity of bacterial/viral infections. Thus, models utilizing live bacteria or viruses have also been developed. The use of live replicating E. coli, GBS, and Staphylococcus aureus bacteria typically represent relatively severe clinical infections, while models involving exposure to less pathogenic bacteria including Staphylococcus epidermidis may be representative of the more common low-level ‘subclinical’ infections (Kronforst et al., 2012). Rodents are the most widely used animal paradigm of infection/inflammation. Compared to humans, rats and mice are relatively immature at birth. Rodents at postnatal days (P)1–3 predominantly express oligodendrocyte progenitors in the white matter (Craig et al., 2003; Dean et al., 2011), without evidence of myelination, consistent with the 23–32 weeks gestation human. By P5 and later, the oligodendrocyte progenitor population has rapidly matured into immature oligodendrocytes capable of myelination, which is more equivalent to the late preterm/near-term human. Consistent with this, peak brain growth occurs at term in humans and from P7–10 in rodents (Dobbing and Sands, 1979). This stage of brain development corresponds with the rapid expansion of the dendritic arbor of cortical neurons (Koenderink and Uylings, 1995). Although perinatal rodents have a small white matter volume size relative to total brain size and lack cortical gyri, they provide rapid and cost-effective access to address questions related to cellular and molecular mechanisms of brain injury.

In large clinical trials, antibiotic treatment actually increased the risk of death and disability in preterm infants (Brocklehurst et al., 2013). For example, use of erythromycin or amoxicillin–clauvanate in pregnant women with spontaneous preterm labor with intact membranes was associated with an increase in functional impairment and cerebral palsy in children at 7 years of age (Kenyon et al., 2008). In another study, antibiotic treatment was associated with no change in overall infant outcomes, but an increase in neonatal deaths (Flenady et al., 2013). These adverse effects suggest that killing live bacteria with antibiotics may increase inflammation due to release of bacterial fragments, and thus increase brain injury (Peng et al., 2012). 7.1. Prenatal tetracycline therapy No studies available. 7.2. Postnatal tetracycline therapy Tetracyclines such as minocycline and doxycycline are a class of broad-spectrum antibiotics that also exhibit intrinsic anti-inflammatory, anti-apoptotic, and antioxidant properties independent of their antibacterial actions (Dalhoff and Shalit, 2003). Treatment with minocycline (45 mg/kg i.p.) given −12 h plus immediately before intracerebral LPS injection (10 ␮g) in P5 rats, and then every 24 h for 3 days, was associated with decreased neural microglial activation and IL-1␤ and TNF-␣ expression, with moderate protection against oligodendrocyte cell death and ventriculomegaly, and improved myelination (Fan et al., 2005a,b). These histological improvements were associated with better neurobehavioral recovery as measured by attenuation of deficits in latency times in the wire hanging maneuver, latency in cliff avoidance, gait, learning and memory deficits, and induced hypostress in the elevated plus-maze test. Further, in co-cultures of neurons and microglia from human fetal brains, microglial activation and

Please cite this article in press as: Ranchhod, S.M., et al., Potential neuroprotective strategies for perinatal infection and inflammation. Int. J. Dev. Neurosci. (2015), http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006

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neuronal cell death induced by LPS was prevented by co-treatment with minocycline (Filipovic and Zecevic, 2008). In two studies of delayed treatment after either maternal injection of the viral mimic polyriboinosinic–polyribocytidilic acid (20 mg/kg i.p.) in E9 mice or bilateral LPS injection (0.3 ␮g) into the ventral hippocampus in P7 rats, daily administration of minocycline (40 mg/kg intragastric) from (P)42–55 improved behavioral problems, as shown by attenuated deficits in social interaction, novel object recognition and prepulse inhibition, and reduced microglia activation at P56–65 (Zhu et al., 2014). Of interest, the widely used fluoroquinolone antibiotics also show independent anti-inflammatory actions. Repeated administration of the fluoroquinolone ciprofloxacin (50 mg/kg/injection subcutaneously (s.c.)) at 7.5 and 24 h after E. coli inoculation (5000 colony-forming unit (CFU)) in P5 rat pups reduced microglia activation and inducible nitric oxide synthase (iNOS) expression, and reduced oligodendrocyte cell death and myelin deficits, while the cephalosporin antibiotic cefotaxime had no effect (Loron et al., 2011). 7.3. Limitations of tetracycline treatment

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Experimental studies have shown a species-specific effect of minocycline, such that treatment initiated before hypoxia–ischemia reduced brain injury in rats, but increased brain injury in mice (Tsuji et al., 2004). Critically, the use of tetracycline antibiotics can also result in disruption of normal bone and tooth enamel formation, and therefore, tetracyclines are highly contraindicated in this setting (Mozaffar and Gordon, 2006).

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The anti-inflammatory synthetic glucocorticoids such as dexamethasone and betamethasone are routinely given to mothers at risk of preterm delivery to reduce lung disease and acute neonatal morbidity and mortality after preterm birth (Roberts and Dalziel, 2006). There is some evidence that antenatal steroids may also reduce the risk for cystic white matter injury (Whitelaw and Thoresen, 2000). By contrast, postnatal administration of steroids to preterm infants is unequivocally associated with impaired neurodevelopmental outcomes, including cerebral palsy (Bennet et al., 2012a; Tam et al., 2011). Consistent with this, as previously reviewed, numerous studies in neonatal rodents and large fetal animals have reported adverse effects of glucocorticoids on normal brain function and development (Bennet et al., 2012a). 8.1. Prenatal synthetic glucocorticoid therapy

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Experimentally, in preterm fetal sheep, maternal betamethasone (0.5 mg/kg intramuscular (i.m.)) given seven days before intra-amniotic LPS injection (10 mg; at 113 d gestation) suppressed neural microglial activation and loss of synaptophysin, whereas betamethasone given seven days after intra-amniotic LPS (at 106 d gestation) exacerbated injury, as shown by increased microglial infiltration and apoptosis (Kuypers et al., 2013). Taken together, these data show that the timing of treatment is critical, and suggest that glucocorticoid therapy may not be beneficial for established infection/inflammation.

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In P5 rat pups exposed to intracerebral injection of LPS (10 ␮g), pretreatment with single dose dexamethasone or betamethasone (5 mg/kg i.p. at 1 h before LPS) suppressed neural microglial activation and iNOS expression in response to LPS, and prevented

oligodendrocyte cell death and myelin deficits in the white matter (Pang et al., 2012). Glucocorticoid therapy was also associated with significant improvements in rearing, vibrissa-elicited forelimb placing, beam walking, and learning, with evidence of reduced anxiety-like behavior. In a model of LPS-induced sensitization (1 mg/kg i.p.) to cerebral hypoxia–ischemia in P7 rats, a single dose of dexamethasone (0.5 mg/kg i.p.) given at the same time as LPS (4 h before hypoxia–ischemia) also reduced gross brain injury and learning and memory deficits (Ikeda et al., 2005). 9. Nonsteroidal anti-inflammatory drugs The nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and ibuprofen, which inhibit cyclooxygenase (COX) activity, are widely used to treat patent ductus arteriosus in preterm infants (Antonucci et al., 2012). Infection is associated with upregulation of COX-2 and prostaglandin synthesis, while in vitro, LPS-mediated upregulation of COX-2 activity can contribute to oligodendrocyte death (Weaver-Mikaere et al., 2013). Clinically, prolonged exposure to indomethacin in infants born before 28 weeks gestation was associated with a reduced risk of white matter injury (Miller et al., 2006). By contrast, prophylaxis with indomethacin in extremely low birth weight infants did not improve the rate of survival without neurosensory impairment at 18 months, despite reducing the frequency of severe periventricular and intraventricular hemorrhage (Schmidt et al., 2001). Further, in a large cohort of preterm born infants, NSAIDs during pregnancy was associated with renal side effects (Pacifici, 2014) and an increased risk of quadriparetic and diparetic cerebral palsy (Tyler et al., 2012).

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9.2. Postnatal NSAID therapy There are few experimental studies examining the effects of NSAIDs on perinatal infection/inflammation. Repeated pretreatment with indomethacin (0.125 mg/kg i.p. twice daily) in P1–4 mice pups blocked the sensitizing effect of IL-1␤ on excitotoxic brain lesions induced at P5 (Favrais et al., 2007). Further, administration of the selective COX-2 inhibitor celecoxib (20 mg/kg i.p.) immediately after injection of LPS (2 mg/kg i.p.) in P5 rat pups reduced CNS inflammation, oligodendrocyte cell death, neuronal dysfunction, and neurobehavioral problems, including attenuation of sensorimotor deficits and improved latency on a wire-hanging test (Fan et al., 2013; Kaizaki et al., 2013). 10. Specific cytokine inhibitors Exposure to perinatal infection can trigger a cascade of inflammatory events in the brain, including activation of microglia and release of pro-inflammatory cytokines such as TNF-␣ and IL-1␤. TNF-␣ activation after infection is associated with cognitive impairment in preterm infants (O’Shea et al., 2013; Stoll et al., 2004) and cognitive decline in adulthood (Terrando et al., 2010). Experimentally, TNF-␣ is also toxic to oligodendrocytes (Kim et al., Q6 2011) and can impair maturation of neuronal dendrites (Gilmore et al., 2004). Similarly, the pro-inflammatory cytokine IL-1␤ is commonly elevated systemically and centrally following infection, and there is increasing evidence that IL-1␤ signaling can contribute to brain injury (Girard et al., 2010a; Rosenzweig et al., 2014). Experimentally, peripheral injection of IL-1␤ was reported to generate

Please cite this article in press as: Ranchhod, S.M., et al., Potential neuroprotective strategies for perinatal infection and inflammation. Int. J. Dev. Neurosci. (2015), http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006

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a pattern of white matter injury similar to that observed in the preterm infant (Favrais et al., 2011b). 10.1. Prenatal cytokine inhibitor therapy

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Blockade of IL-1␤ signaling by recombinant human (rh) IL-1Ra (2, 10, or 20 mg/kg i.p.; an FDA-approved class B drug in pregnancy (Braddock and Quinn, 2004)), administered 30 min before LPS injection (200 ␮g/kg i.p. repeated twice daily) in E18–20 pregnant rats, reduced CNS inflammation (including microglia activation) and chronic motor dysfunctions (Girard et al., 2010b). In an E15 mouse model of intrauterine LPS injection (250 ␮g/kg), pretreatment with rhIL-1Ra (10 mg/kg i.p. at 30 prior to LPS) also blocked the impaired dendritic growth of cortical neurons observed in vitro (Leitner et al., 2014). Interleukin-10 (IL-10) is an anti-inflammatory cytokine known to inhibit the expression of other pro-inflammatory cytokines including those involved in developmental brain injury. Interestingly, administration of IL-10 (1 ␮g/kg i.v. every 12 h) to E18–21 rat pups at 24 h following intrauterine E. coli (1 × 107 CFU) at E17, markedly reduced white matter injury, including microgliosis, astrogliosis, oligodendrocyte cell death, and myelin deficits, in surviving pups at P8–15 (Pang et al., 2005; Rodts-Palenik et al., 2004).

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Etanercept is a fusion protein consisting of the ligand-binding portion of the human p75 TNF receptor that effectively neutralizes the action of soluble TNF-␣. It is currently used clinically to treat various inflammatory diseases, with case series evidence of safety in pregnant women (Berthelot et al., 2009; Yurttutan et al., 2014). In a model of IL-1␤-induced sensitization to ibotenateinduced brain injury in P5 mice, post-insult injection of Etanercept (20 mg/kg i.p., once daily from P5–P7, started 1 h after ibotenate) reduced neural injury (Aden et al., 2010). Further, in a rat model of repeated twice-daily maternal LPS injection (200 ␮g/kg i.p.) from E20–22/23, blockade of IL-1␤ with twice daily administration of rhIL-1Ra (10 mg/kg i.p.) from P1–P9 prevented white and gray matter injury, and was associated with improved motor function and exploratory behavior (Girard et al., 2012).

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11. Inhibitors of nuclear factor-kappa B

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Nuclear factor-kappa B (NF-k␤) plays a key role in regulating the immune response to infection, including production of cytokines, chemokines, and adhesion molecules (Lawrence, 2009). Thus, pharmacological inhibition of NF-k␤ transcriptional activity is a key target used to reduce inflammation.

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11.1. Prenatal sulfasalazine therapy

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Sulfasalazine is a potent, specific inhibitor of NF-k␤ transcription that has been widely used clinically to treat inflammatory bowel disease. Importantly, sulfasalazine can be safely given to pregnant women without adverse maternal/neonatal outcomes (Moskovitz et al., 2004). Experimentally, injection of sulfasalazine (150 mg/kg daily s.c.) to pregnant mice reduced the rate of preterm birth induced by exposure to E. coli (104 CFU) (Nath et al., 2010). However, it is unknown whether sulfasalazine is neuroprotective against perinatal infection/inflammation.

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11.3. Prenatal melatonin therapy Melatonin is a naturally occurring circadian hormone that exhibits anti-inflammatory actions via NF-k␤ inhibition (Reiter et al., 2000). Melatonin is widely used clinically (Chen et al., 2012; Gitto et al., 2001), and was suggested to be ready for use in preterm infants as a neuroprotectant (Biran et al., 2014; Robertson et al., 2013). In pregnant mice given LPS (500 ␮g/kg i.p.) on E17, maternal pretreatment with melatonin (5.0 mg/kg i.p.) 30 min before LPS significantly attenuated the peripheral and central pro-inflammatory cytokine responses, including TNF-␣ and IL-6, at 1.5 h after LPS (Xu et al., 2007). 11.4. Postnatal melatonin therapy In P5 rat pups injected with LPS (2 mg/kg i.p.), administration of melatonin (20 mg/kg i.p.) at 5 min after LPS prevented oligodendrocyte cell death and axonal injury in the white matter, reduced neural microglial activation and markers of oxidative stress, and improved sensorimotor performance at P6, as measured by the latency of the righting reflex and time that the rats could hang onto a wire (Wong et al., 2014). 11.5. Curcumin therapy Curcumin (diferuloylmethane) is a naturally occurring diarylheptanoid (predominantly found in turmeric) with anti-NFk␤ transcription and anti-oxidant activities (Gupta et al., 2013). Experimentally, treatment with curcumin protected preoligodendrocytes from injury by activated microglia in vitro and in vivo (He et al., 2010). 12. Antioxidants Human preterm white matter lesions have been reported to exhibit signs of oxidative damage (Back et al., 2005; Haynes et al., 2003). Experimental studies in neonatal animal models also suggest that systemic infection/inflammation can induce oxygen free radical accumulation and oxidative stress in the brain (Fan et al., 2008), potentially via activation of microglia (Baburamani et al., 2014; Wilms et al., 2010). 12.1. Prenatal n-acetylcysteine therapy A number of studies of neonatal infection/inflammation have shown that administration of antioxidants such as n-acetylcysteine (NAC) (as well as melatonin, curcumin, and erythropoietin; see described) can be neuroprotective. For example, in a model of intrauterine administration of LPS (0.1 mg/kg) in E15–20 pregnant mice, pre-treatment with NAC (0.1 mg) attenuated the fetal neuroinflammatory response, including reduced TNF-␣, IL-1␤, and IL-6 levels, and reduced myelin deficit in the white matter (Chang et al., 2011). Combined maternal pre- and post-treatment with NAC (−30 min and 150 min; 300 mg/kg i.v. per dose) in pregnant rats exposed to LPS (500 ␮g/kg i.p.) at E18 also reduced brain inflammatory response at E18–20 (Beloosesky et al., 2012) and MRI-defined white and gray matter injury at P25 (Beloosesky et al., 2013). Further, maternal pre-treatment with NAC (50 mg/kg i.p.) given 2 h before LPS (1 mg/kg) in rats at E18, attenuated LPS-induced expression of pro-inflammatory cytokines in the fetal brains, and reduced hypomyelination at P16–30 (Paintlia et al., 2004). However, it is of concern that in preterm fetal sheep (95 d gestation), although NAC treatment (50–200 mg/5 h i.v.) alone had no adverse effects, NAC initiated immediately after LPS (1 ␮g/kg i.v.) was associated with exacerbation of the fetal hypoxemia and hypotension during LPS exposure and with greater polycythemia

Please cite this article in press as: Ranchhod, S.M., et al., Potential neuroprotective strategies for perinatal infection and inflammation. Int. J. Dev. Neurosci. (2015), http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006

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(Probyn et al., 2010). Thus, NAC may not be suitable for antenatal therapy, and further large animal studies are essential to understand the mechanisms of this major apparent adverse effect.

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studies suggesting a neuroprotective role of MgSO4 in infectionrelated brain injury. 14.1. Prenatal MgSO4 therapy

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Although we were unable to identify any studies of postnatal treatment of infection-induced brain injury using NAC, combined pre- and post-insult treatment with NAC (200 mg/kg i.p.) markedly reduced LPS-sensitized hypoxic–ischemic brain injury in P8 rats when evaluated at P15 (Wang et al., 2007). Further, in P6 mice injected with LPS (25 mg/kg i.p.), pretreatment with NAC (50 mg/kg) attenuated the increases in TNF-␣ and IL-6 levels, but augmented IL-10 levels, at 2 h post-LPS (Mukherjee et al., 2010), supporting potential for NAC to protect against the acute inflammatory response to infection.

Treatment with MgSO4 (270 mg/kg s.c. bolus started at −4 h, plus 27 mg/kg every 20 min for 8 h) prior to LPS (1 mg/kg i.p.) in E19 rats reduced LPS-induced pro-inflammatory cytokine expression in maternal serum, amniotic fluid, fetal serum, and the fetal brain at 4 h after LPS; no effects were observed with only pre- or post-insult treatments (Tam Tam et al., 2011). Further, in pregnant mice exposed to intrauterine LPS (250 ␮g) at E15, maternal MgSO4 (270 mg/kg i.p. bolus, 27 mg/kg every 20 min for 4 h, and 270 mg/kg bolus at 4 h) started immediately after LPS attenuated the deficits in dendritic development observed in neurons cultured from fetal brains collected at 4–6 h after LPS (Burd et al., 2010; Cho et al., 2014).

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Erythropoietin (EPO) is a hematopoietic cytokine that regulates red blood cell production, and has been shown to exhibit antiinflammatory, anti-oxidative, anti-apoptotic, and neurotrophic actions (McPherson and Juul, 2010; Robertson et al., 2012). EPO is widely used clinically for anemia of prematurity, while evidence from pilot studies in term infants suggests that EPO may reduce death and disability at 18 months after hypoxic–ischemic encephalopathy (Zhu et al., 2009). Two retrospective studies also suggest that EPO may improve neurodevelopmental outcome in preterm infants (Bierer et al., 2006; Brown et al., 2009), although another study reported no effect (Ohls et al., 2004). There is increasing evidence that EPO may be neuroprotective against infection/inflammation-mediated brain injury (Merelli et al., 2015). 13.1. Prenatal EPO therapy

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In preterm fetal sheep (107 d gestation), concurrent rhEPO treatment (5000 international units (IU)/kg/day i.v.) in animals exposed to repeated LPS bolus (0.9 ␮g/kg/day i.v.) reduced oligodendrocyte cell death and myelination deficits after 10 days recovery (Rees et al., 2010). In maternal rats exposed to intrauterine E. coli (∼1 – 1.6 × 108 CFU) at E15, single treatment with rhEPO (5000 IU/kg i.p.) immediately after birth attenuated neural proinflammatory cytokine release and white matter damage, including astrogliosis and deficits in myelin at P7 (Shen et al., 2009); a similar effect was found with rhEPO (5000 IU/kg i.p.) administered immediately following repeated maternal LPS (500 ␮g/kg i.p.) on E18–19 (Kumral et al., 2007).

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By contrast, there is concerning evidence that treatment of adult mice with EPO during systemic Salmonella infection reduced survival with impaired pathogen clearance, although EPO reduced inflammation in a model of sterile colitis (Nairz et al., 2011). Thus, further studies of the safety of EPO during or after overt infection in neonatal animals are essential.

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Meta-analysis of large randomized controlled trials suggests that antenatal administration of magnesium sulphate (MgSO4 ) may slightly reduce the risk of cerebral palsy in early childhood after preterm birth (Doyle et al., 2009), although it remains highly unclear whether post-insult treatment with MgSO4 is neuroprotective (Galinsky et al., 2014). Experimentally, there are only limited

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Novel innate defense regulator (IDR) peptides are synthetic derivatives of endogenous cationic host defense peptides that can selectively suppress inflammation, but augment protective immunity against pathogens (Nijnik et al., 2010; Scott et al., 2007; Wieczorek et al., 2010). Interestingly, in a model of LPS-sensitized hypoxic–ischemic brain injury in P9 mice, a single postnatal injection of IDR-1018 (8 mg/kg i.p.) at 3 h after LPS-hypoxia–ischemia markedly reduced white and gray matter injury after seven days recovery, potentially by suppressing microglia-induced inflammatory responses (Bolouri et al., 2014). 15.2. Pentoxifylline Pentoxifylline is a synthetic xanthine-derived phosphodiesterase inhibitor that increases intracellular cAMP, resulting in reduced production of key inflammatory mediators. Clinically, pentoxifylline has been used to treat bronchopulmonary dysplasia in preterm infants (Schulzke et al., 2014) and reduced mortality in preterm infants with sepsis (Haque et al., 2003; Harris et al., 2010; Lauterbach et al., 1999). However, it is unknown at present whether pentoxifylline is neuroprotective against perinatal infection/inflammation. 15.3. Stem cells

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Multipotent (stem or progenitor) cells have shown promise in decreasing neurological impairment after a variety of insults in animal studies. Of particular relevance, there is evidence that cellbased therapy can reduce damage associated with post-ischemic inflammation and lack of environmental stimulation, as previously reviewed (Bennet et al., 2012b). Thus, although we were unable to identify any postnatal studies of stem cell therapy for neonatal infection or inflammatory brain injury, this is likely to be a promising approach. Supporting this concept, maternal administration of human adipose tissue-derived mesenchymal stem cells at 15 h before intrauterine LPS (50 ␮g) at E17 reduced neural microglia reactivity and IL-6 expression and attenuation of deficits in the cliff aversion test at P5, suggesting a modulatory role on fetal immune responses (Lei et al., 2014). Consistent with an anti-inflammatory effect, human amnion epithelial cells given intravenously to late-preterm

Please cite this article in press as: Ranchhod, S.M., et al., Potential neuroprotective strategies for perinatal infection and inflammation. Int. J. Dev. Neurosci. (2015), http://dx.doi.org/10.1016/j.ijdevneu.2015.02.006

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fetal sheep (117 days) starting at the same time as an intra-amniotic injection of LPS (20 mg) was associated with reduced microglial induction in white and gray matter regions and reduced cell death after seven days recovery (Yawno et al., 2013).

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cytokines and their deleterious effects during excessive inflammation, there is potential for clinical translation of agents targeting pro-inflammatory cytokine signaling. Nevertheless, it may be that modulation of specific components of the inflammatory response would be a safer therapeutic strategy than global suppression.

16. Considerations for animal models of infection/inflammation and neuroprotection

18. Inflammation can be protective

Prenatal events such as chorioamnionitis may be present for many weeks or months before preterm birth. Moreover, there may be considerable delays even before postnatal infections are diagnosed. For example, in preterm infants, infection was typically diagnosed at two days after plasma cytokine levels were first increased (Kuster et al., 1998). Thus, in practice, treatment will almost always be delayed in the majority of cases, sometimes substantially. It is of critical concern that in the majority of animal studies described above, treatment was started before or shortly after exposure to infection. Moreover, most models do not reflect the chronic nature of perinatal inflammation. The results of such early treatment may not be translatable to the inevitably delayed therapy in the clinic. In some studies, discussed above, treatment was started antenatally. In that setting, for example of Etanercept administration to mother, it is unlikely that such a large molecule crossed the placenta, and so the effect is likely mediated by altering maternal inflammation, or even by altering the immune balance of the placenta itself (Jerzak et al., 2010; Renaud et al., 2011).

Studies in multiple species show that low-dose exposure to LPS can lead to self-tolerance to subsequent high dose LPS (Mathai et al., 2013). Indeed, a recent study in preterm fetal sheep (102 d gestation) showed that the combination of acute-on-chronic LPS with subsequent asphyxia reduced neuroinflammation and white matter injury compared with either intervention alone after 10 days recovery (van den Heuij et al., 2014). Similarly, postnatal injection of a non-injurious dose of LPS in rat pups at 24 h before severe hypoxia–ischemia can reduce subsequent damage (Eklind et al., 2005), albeit the precise effect of low level infection varies considerably with maturation and over time. Speculatively, this raises the interesting possibility that in the context of the multiple insults and very high risks of subsequent neurodevelopmental impairment to which very preterm infants are exposed, a low level of inflammation may be beneficial. Thus, the net effect of even a very effective and safe anti-inflammatory treatment is highly likely to change with the severity of inflammation, evolution of microglial phenotypes, stage of brain maturation, and timing of treatment.

17. Microglia and cytokines during normal brain development It is now well established that microglial activation and the expression of many cytokines play a key role in normal physiology as well as being potentially deleterious in excess. For example, macrophages can exhibit both damaging and protective phenotypes (Mosser and Edwards, 2008), and similar characteristics have been suggested for microglia (Chhor et al., 2013). Activated microglia initially express a so-called ‘M1’ phenotype that is believed to cause brain injury by producing multiple proinflammatory mediators (Svedin et al., 2007), while they can then transition over hours to days toward a protective or ‘M2’ phenotype that mediates restorative and neuroprotective activity (Imai et al., 2007). Consistent with the dual role of microglia, administration of exogenous microglia can be neuroprotective (Imai et al., 2007), while the net effect of depletion of microglia was worsening of injury after hypoxia–ischemia in neonatal rodents (Faustino et al., 2011). In the healthy developing rat, suppression of microglial activation with minocycline from P2 to P5 was associated with reduced levels of the cytokines IL-1␤, IL-6, TNF-␣, and IFN- ␥, and suppression of neurogenesis and oligodendrogenesis in the subventricular zone (Shigemoto-Mogami et al., 2014). Conversely, activated microglia and exposure to these cytokines enhanced neurogenesis and oligodendrogenesis in vitro. Over-expression of IFN-␥ in the developing mouse brain also impaired development of the external granule neuron layer of the cerebellum via sonic hedgehog-related mechanisms (Wang et al., 2004). Thus, blocking normal inflammatory pathways may lead to abnormal brain development. It is somewhat reassuring that a recent large cohort study reported no fetal malformations after Etanercept treatment in pregnancy (Viktil et al., 2012), and case studies suggest that it is generally safe in pregnancy (Scioscia et al., 2011). Indeed, studies in rats and case reports in humans have found that Etanercept safely reduces pregnancy loss associated with inflammation (Jerzak et al., 2010; Renaud et al., 2011). Thus, although it is essential to remain mindful of the balance between the normal role of

19. Conclusions Experimentally, a wide range of neuroprotective strategies have been tested for treatment of infection/inflammation-mediated brain injury. However, development of more clinically relevant models of low-level infection utilizing live bacteria is important to model the human condition. Any treatment must take into account the potential for evolution of microglial phenotypes over time and for protective adaptations to develop. This review has highlighted a critical need for studies of post-insult treatment in preclinical animal models. Funding This work was supported by grants from the Health Research Q7 Council of New Zealand (HRC), the Auckland Medical Research Foundation, The Lottery Grants board of New Zealand, and the Marsden Foundation. References Aden, U., Favrais, G., Plaisant, F., Winerdal, M., Felderhoff-Mueser, U., Lampa, J., Lelievre, V., Gressens, P., 2010. Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: key role of TNFalpha pathway and protection by etanercept. Brain Behav. Immun. 24, 747–758. Alshaikh, B., Yee, W., Lodha, A., Henderson, E., Yusuf, K., Sauve, R., 2014. Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome. J. Perinatol. 34, 125–129. Antonucci, R., Zaffanello, M., Puxeddu, E., Porcella, A., Cuzzolin, L., Pilloni, M.D., Fanos, V., 2012. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr. Drug Metab. 13, 474–490. Armstrong-Wells, J., Donnelly, M., Post, M.D., Manco-Johnson, M.J., Winn, V.D., Sebire, G., 2014. Inflammatory predictors of neurologic disability after preterm Q8 premature rupture of membranes. Am. J. Obstetrics Gynecol. Baburamani, A.A., Supramaniam, V.G., Hagberg, H., Mallard, C., 2014. Microglia toxicity in preterm brain injury. Reprod. Toxicol. 48, 106–112. Back, S.A., Luo, N.L., Mallinson, R.A., O’Malley, J.P., Wallen, L.D., Frei, B., Morrow, J.D., Petito, C.K., Roberts Jr., C.T., Murdoch, G.H., Montine, T.J., 2005. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann. Neurol. 58, 108–120. Back, S.A., Riddle, A., Dean, J., Hohimer, A.R., 2012. The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurother. J. Am. Soc. Exp. NeuroTher. 9, 359–370.

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C.D., Back, S.A., 2013. Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci. Trans. Med. 5, 168ra167. Dean, J.M., Moravec, M.D., Grafe, M., Abend, N., Ren, J., Gong, X., Volpe, J.J., Jensen, F.E., Hohimer, A.R., Back, S.A., 2011. Strain-specific differences in perinatal rodent oligodendrocyte lineage progression and its correlation with human. Dev. Neurosci. 33, 251–260. Dean, J.M., Shi, Z., Fleiss, B., Gunn, K.C., Groenendaal, F., van Bel, F., Derrick, M., Juul, S., Tan, S., Gressens, P., Mallard, C., Bennet, L., Gunn, A.J., 2015. A critical review of models of perinatal infection. Dev. Neurosci., EPUB AHEAD OF PRINT. Deguchi, K., Mizuguchi, M., Takashima, S., 1996. Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia. Pediatr. Neurol. 14, 13–16. Dobbing, J., Sands, J., 1979. Comparative aspects of the brain growth spurt. Early Human Dev. 3, 79–83. 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