Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic–ischemic brain injury

Osredkar, Damjan; Thoresen, Marianne; Maes, Elke; Flatebø, Torun; Elstad, Maja; Sabir, Hemmen

doi:10.1016/j.resuscitation.2013.12.006

Cited by 116 publications

(148 citation statements)

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“…Hypothermia has been shown to be only effective when started within 6 h after HI in term neonates [85,86]. Recently, Osredkar et al [87] showed that hypothermia has no neuroprotective effect after LPS-sensitized HI brain injury. Furthermore, Wintermark et al [9] suggested that chorioamnionitis with fetal vasculitis may limit the effectiveness of therapeutic hypothermia following HI in human full-term neonates.…”

Section: Discussionmentioning

confidence: 99%

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

Bonestroo¹,

Heijnen²,

Groenendaal

et al. 2015

Dev Neurosci

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Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

Bonestroo¹,

Heijnen²,

Groenendaal

et al. 2015

Dev Neurosci

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“…All experiments were performed as previously described [5]. Briefly, at the start of each experiment, animals were injected according to randomisation with a single intraperitoneal dose of either vehicle (0.9% NaCl) or LPS solution ( Escherichia coli O55:B5, Sigma; 0.1 mg/kg), given in a volume of 10 µl/g of body weight.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, at the start of each experiment, animals were injected according to randomisation with a single intraperitoneal dose of either vehicle (0.9% NaCl) or LPS solution ( Escherichia coli O55:B5, Sigma; 0.1 mg/kg), given in a volume of 10 µl/g of body weight. At this dose, LPS does not induce area loss unless combined with hypoxia-ischaemia [5]. After a 4-hour delay with their dams, pups were exposed to a mild HI insult (ligation of left carotid artery under isoflurane anaesthesia followed by exposure to 8% O 2 for 50 min).…”

Section: Methodsmentioning

confidence: 99%

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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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“…Метод внедрен в клиническую практику ряда стран, в частности Великобритании [83], где уже подведены первые экономические результаты, согласно которым внедрение признано эффективным, исходы ГИП в целом улучшаются примерно на 15% [84]. Подтверждений эффективности гипотермии при перина-тальных поражениях другого генеза, например инфекци-онного, в экспериментах пока не получено [85].…”

Section: обзор литературыunclassified

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

Каркашадзе¹,

Аникин²,

Зимина³

et al. 2016

Pediatr. farmakol.

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ВВЕДЕНИЕ Общемировой научно-технический прогресс в отно-шении исследовательских технологий за последние де-сятилетия привел к качественному и количественно-му скачку нейронаук. Наиболее активно наполняется новыми данными поле фундаментальных представлений о развитии головного мозга, что обусловливает интересы ученых к таким областям медицины, как перинатальная неврология и неврология раннего возраста. Несмотря на расширение представлений о вкладе генетической составляющей, по-прежнему большое внимание уделяет-ся изучению прямых патофизиологических механизмов гипоксически-ишемических поражений (ГИП) головного мозга у новорожденных. К настоящему моменту накоплен массив новых данных в этой области, что подталкивает медицину к внедрению передовых лечебных технологий.Цель работы -провести литературный обзор совре-менных научных данных о механизмах гипоксически-ише-мических повреждений мозга у новорожденных и разра-батываемых на их основании новых методов лечения. ПАТОФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ГИПОКСИЧЕСКИ-ИШЕМИЧЕСКИХ ПОРАЖЕНИЙТрадиционно основные лечебные тактики в острый период гипоксически-ишемических перинатальных поражений головного мозга (ГИППГМ) предусма-тривают медикаментозное поддержание сердечно-легочных функций и противосудорожную защиту [1]. Послед ние достижения в раскрытии патофизиологи-ческих механизмов непосредственно ГИП дают опору для поиска и внедрения новых лечебных технологий. У доношенных детей основным прямым механизмом ГИП является внутриутробная асфиксия, вызванная проблемами кровообращения, в том числе в области плацентарных артерий, отслойкой плаценты или вос-палительным процессом. За этим следуют снижение объема кислорода и углекислого газа в крови и тяже-лый лактат-ацидоз. Выраженное снижение сердечного выброса в условиях гипоксии, называемое гипоксией-ишемией, в течение 12-36 ч приводит к поражению головного мозга [2].

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Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic–ischemic brain injury

Cited by 116 publications

References 32 publications

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

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

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

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