Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: new categories to be enrolled

Gancia, Paolo; Pomero, Giulia

doi:10.3109/14767058.2012.715023

Cited by 46 publications

(29 citation statements)

References 9 publications

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“…The inhibition of hypothermic response to systemic LPS exposure may be associated with the inhibition of COX-induced hypotension (Steiner et al, 2009). Hypothermia is neuroprotective after hypoxia-ischemia in the neonatal rats (Xiong et al, 2012) and therapeutic hypothermia has been used to treat newborn with hypoxic ischemic encephalopathy (Gancia and Pomero, 2012). Other studies have indicated that low dose LPS preconditioning may provide potential therapies against hypoxic ischemic brain injury in neonatal rats (Lin et al, 2009, 2010).…”

Section: Discussionmentioning

confidence: 99%

Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats

et al. 2013

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Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. Cyclooxygenase-2 (COX-2) can be induced by inflammatory stimuli, such as cytokines and pro-inflammatory molecules, suggesting that COX-2 may be considered as the target for anti-inflammation. The objective of the present study was to examine whether celecoxib, a selective COX-2 inhibitor, can reduce systemic LPS-induced brain inflammation and brain damage. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in postnatal day 5 (P5) of Sprague-Dawley rat pups and celecoxib (20 mg/kg) or vehicle was administered i.p. 5 min after LPS injection. The body weight and wire hanging maneuver test were performed 24 hr after the LPS exposure, and brain injury was examined after these tests. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury, as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes, concentrations of IL-1β and TNFα, and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure, and the protective effects are associated with its anti-inflammatory properties.

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Section: Discussionmentioning

confidence: 99%

Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats

et al. 2013

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“…5 In addition, a recent meta-analysis advocated refinement of patient selection and TH duration whereas others have suggested that currently excluded neonates be considered in future trials. 6,7 Thus a need for further optimization of TH remains.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Oxygen Metabolism in Neonatal Hypoxic Ischemic Encephalopathy during and after Therapeutic Hypothermia

Dehaes

Aggarwal

Lin

et al. 2013

J Cereb Blood Flow Metab

108

121

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Pathophysiologic mechanisms involved in neonatal hypoxic ischemic encephalopathy (HIE) are associated with complex changes of blood flow and metabolism. Therapeutic hypothermia (TH) is effective in reducing the extent of brain injury, but it remains uncertain how TH affects cerebral blood flow (CBF) and metabolism. Ten neonates undergoing TH for HIE and seventeen healthy controls were recruited from the NICU and the well baby nursery, respectively. A combination of frequency domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) systems was used to non-invasively measure cerebral hemodynamic and metabolic variables at the bedside. Results showed that cerebral oxygen metabolism (CMRO 2i ) and CBF indices (CBF i ) in neonates with HIE during TH were significantly lower than post-TH and age-matched control values. Also, cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO 2 ) were significantly higher in neonates with HIE during TH compared with age-matched control neonates. Post-TH CBV was significantly decreased compared with values during TH whereas SO 2 remained unchanged after the therapy. Thus, FDNIRS-DCS can provide information complimentary to SO 2 and can assess individual cerebral metabolic responses to TH. Combined FDNIRS-DCS parameters improve the understanding of the underlying physiology and have the potential to serve as bedside biomarkers of treatment response and optimization. Keywords: cerebral blood circulation; cerebral hemoglobin oxygen saturation; cerebral metabolic rate of oxygen consumption; near infrared spectroscopy; neonatal hypoxic ischemic encephalopathy; therapeutic hypothermia INTRODUCTION Neonatal hypoxic ischemic encephalopathy (HIE) occurs in B2 to 3 per 1,000 live births in the USA, with devastating consequences including neurodevelopmental disabilities such as cerebral palsy, life-long cognitive impairment, and epilepsy.1 In HIE, there is a period of reduced blood flow (ischemia) and oxygen delivery (hypoxia) followed by reperfusion with transient energy recovery, and then a secondary energy failure.2 Treatment is aimed at preventing the cascade of events that begin with reperfusion and lead to secondary energy failure and inevitable cell death; this is the 'window of opportunity.' 3 Theories for injury mechanisms in this window suggest a central role for excitotoxicity and oxidative stress with the injury evolving over hours to weeks.2 Therapeutic hypothermia (TH) is the treatment of choice for HIE, as it is the only treatment with proven efficacy and acts through a variety of mechanisms, including those associated with decreased neuronal energy metabolism. 4 Although early studies showed that TH decreased rates of both mortality and disability, recently published long-term outcomes have demonstrated significance only for decreased mortality rates.5 In addition, a recent

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“…Therapeutic hypothermia (HT) is the standard treatment for term infants after perinatal HI injury [6], as it has been shown to significantly reduce mortality and neurodevelopmental disability in survivors [7]. However, around 50% of cooled asphyxiated newborns still suffer poor outcomes [7], some of which may have been exposed to perinatal infection [8]. …”

Section: Introductionmentioning

confidence: 99%

Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury

et al. 2015

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Introduction: Bacterial lipopolysaccharide (LPS) injection prior to hypoxia-ischaemia significantly increases hypoxia-ischaemic brain injury in 7-day-old (P7) rats. In addition, therapeutic hypothermia (HT) is not neuroprotective in this setting. However, the mechanistic aspects of this therapeutic failure have yet to be elucidated. This study was designed to investigate the underlying cellular mechanisms in this double-hit model of infection-sensitised hypoxia-ischaemic brain injury. Material and Methods: P7 rat pups were injected with either vehicle or LPS, and after a 4-hour delay were exposed to left carotid ligation followed by global hypoxia inducing a unilateral stroke-like hypoxia-ischaemic injury. Pups were randomised to the following treatments: (1) vehicle-treated pups receiving normothermia treatment (NT) (Veh-NT; n = 40), (2) LPS-treated pups receiving NT treatment (LPS-NT; n = 40), (3) vehicle-treated pups receiving HT treatment (Veh-HT; n = 38) and (4) LPS-treated pups receiving HT treatment (LPS-HT; n = 35). On postnatal day 8 or 14, Western blot analysis or immunohistochemistry was performed to examine neuronal death, apoptosis, astrogliosis and microglial activation. Results: LPS sensitisation prior to hypoxia-ischaemia significantly exacerbated apoptotic neuronal loss. NeuN, a neuronal biomarker, was significantly reduced in the LPS-NT and LPS-HT groups (p = 0.008). Caspase-3 activation was significantly increased in the LPS-sensitised groups (p < 0.001). Additionally, a significant increase in astrogliosis (glial fibrillary acidic expression, p < 0.001) was seen, as well as a trend towards increased microglial activation (Iba 1 expression, p = 0.051) in LPS-sensitised animals. Treatment with HT did not counteract these changes. Conclusion: LPS-sensitised hypoxia-ischaemic brain injury in newborn rats is mediated through neuronal death, apoptosis, astrogliosis and microglial activation. In this double-hit model, treatment with HT does not ameliorate these changes.

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Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: new categories to be enrolled

Cited by 46 publications

References 9 publications

Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats

Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats

Cerebral Oxygen Metabolism in Neonatal Hypoxic Ischemic Encephalopathy during and after Therapeutic Hypothermia

Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury

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