Neuroprotective effects of hypothermia in inflammatory‐sensitized hypoxic‐ischemic encephalopathy

Chevin, Mathilde; Guiraut, Clémence; Maurice-Gélinas, Caroline; Deslauriers, Jessica; Grignon, Sylvain; Sébire, Guillaume

doi:10.1016/j.ijdevneu.2016.09.002

Cited by 25 publications

(44 citation statements)

References 37 publications

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“…The severe injury seen in this region may be resistant to the benefits of TH in this model ( 20 , 21 ). These data are consistent with previous studies that demonstrated that TH-mediated attenuation of caspase-dependent pathway activation after HI in neonatal mice is region-specific ( 8 ) and that TH was neuroprotective in the HI-induced penumbra, but not in the core, and that protective effect was associated with a TH-induced increase of antioxidant enzymes SOD-1 and GPx, leaving several inflammatory mediators unchanged, including IL1β and MMP-9 ( 22 ). Another possibility is that the inflammatory response is strongest in the hippocampus, as evident from the Iba1 and GFAP coverage of microglia and astrocytes respectively, thus preferentially affecting oligodendrocytes in that region ( 23 ).…”

Section: Discussionsupporting

confidence: 93%

Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia–ischemia

et al. 2017

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BackgroundTherapeutic hypothermia (TH) is the standard of care for neonates with hypoxic-ischemic encephalopathy but is not fully protective in the clinical setting. Hypoxia-ischemia (HI) may cause white matter injury (WMI), leading to neurological and cognitive dysfunction.MethodsP9 mice were subjected to HI as previously described. Pups underwent 3.5 hours of systemic hypothermia or normothermia. Cresyl violet and Perl’s iron stain for histopathological scoring of brain sections was completed blindly on all brains. Immunocytochemical (ICC) staining for myelin basic protein (MBP), microglia (Iba1), and astrocytes (GFAP) was performed on adjacent sections. Volumetric measurements of MBP coverage were used for quantitative analysis of white matter.ResultsTH provided neuroprotection by injury scoring for the entire group (n=44) (p<0.0002). ICC analysis of a subset of brains showed that the lateral caudate was protected from WMI (p<0.05). Analysis revealed decreased GFAP and Iba1 staining in hippocampal regions, mostly CA2/CA3. GFAP and Iba1directly correlated with injury scores of normothermic brains.ConclusionsTH reduced injury and qualitative data suggest that hippocampus and lateral caudate are protected from HI. Mildly injured brains may better show the benefits of TH. Overall these data indicate regional differences in WMI susceptibility and inflammation in a P9 murine HI model.

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Section: Discussionsupporting

confidence: 93%

Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia–ischemia

et al. 2017

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“…An in vitro study on the effect of temperature on cytokine release from microglia showed that IL-10 was down-regulated by HT; this suggests a pro- rather than anti-inflammatory effect of HT [29]. In a rat, pre-clinical model of inflammatory sensitized HIE, neuroprotection from HT was independent of the interleukin-1 system and was dependent on an increase in antioxidant enzymes [30]. Rapid rewarming (by 3 °C over 20 min) has been associated with a pro-inflammatory state in a rodent model, with a robust increase in IL-6 and IL-1β [31].…”

Section: Discussionmentioning

confidence: 99%

Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model

Rocha‐Ferreira

Kelen

Faulkner

et al. 2017

J Neuroinflammation

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BackgroundInflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). The influence of hypothermia (HT) on cytokines after HI is unclear. Our aim was to assess in a piglet asphyxia model, under normothermic (NT) and HT conditions: (i) the evolution of serum cytokines over 48 h and (ii) cerebrospinal fluid (CSF) cytokine levels at 48 h; (iii) serum pro/anti-inflammatory cytokine profile over 48 h and (iv) relation between brain injury measured by magnetic resonance spectroscopy (MRS) and brain TUNEL positive cells with serum cytokines, serum pro/anti-inflammatory cytokines and CSF cytokines.MethodsNewborn piglets were randomized to NT (n = 5) or HT (n = 6) lasting 2–26 h after HI. Serum samples were obtained 4–6 h before, during and at 6–12 h intervals after HI; CSF was obtained at 48 h. Concentrations of interleukin (IL)-1β, −4, −6, −8, −10 and TNF-α were measured and pro/anti-inflammatory status compared between groups. White matter and thalamic voxel lactate/N-acetyl aspartate (Lac/NAA) (a measure of both oxidative metabolism and neuronal loss) were acquired at baseline, after HI and at 24 and 36 h.ResultsLac/NAA was reduced at 36 h with HT compared to NT (p = 0.013 basal ganglia and p = 0.033 white matter). HT showed lower serum TNF-α from baseline to 12 h (p < 0.05). Time-matched (acquired within 5 h of each other) serum cytokine and MRS showed correlations between Lac/NAA and serum IL-1β and IL-10 (all p < 0.01). The pro/anti-inflammatory ratios IL-1β/IL-10, IL-6/IL-10, IL-4/IL-10 and IL-8/IL-10 were similar in NT and HT groups until 36 h (24 h for IL-6/IL-10); after this, 36 h pro/anti-inflammatory cytokine ratios in the serum were higher in HT compared to NT (p < 0.05), indicating a pro-inflammatory cytokine surge after rewarming in the HT group. In the CSF at 48 h, IL-8 was lower in the HT group (p < 0.05). At 48 h, CSF TNF-α correlated with Lac/NAA (p = 0.02) and CSF IL-8 correlated with white matter TUNEL positive cell death (p = 0.04).ConclusionsFollowing cerebral HI, there was a systemic pro-inflammatory surge after rewarming in the HT group, which is counterintuitive to the putative neuroprotective effects of HT. While serum cytokines were variable, elevations in CSF inflammatory cytokines at 48 h were associated with MRS Lac/NAA and white matter cell death.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0821-x) contains supplementary material, which is available to authorized users.

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“…Only a few clinical or preclinical models address this question. However, a well-established anti-inflammatory effect of HT is the down regulation of oxidative stress within the brain ( 91 , 97 , 116 – 118 ). It has also been reported that HT is neuroprotective by limiting apoptotic cascades in human term newborns ( 110 , 119 – 121 ).…”

Section: New Hypotheses Bringing New Treatmentsmentioning

confidence: 99%

Role of Perinatal Inflammation in Neonatal Arterial Ischemic Stroke

et al. 2017

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Based on the review of the literature, perinatal inflammation often induced by infection is the only consistent independent risk factor of neonatal arterial ischemic stroke (NAIS). Preclinical studies show that acute inflammatory processes take place in placenta, cerebral arterial wall of NAIS-susceptible arteries and neonatal brain. A top research priority in NAIS is to further characterize the nature and spatiotemporal features of the inflammatory processes involved in multiple levels of the pathophysiology of NAIS, to adequately design randomized control trials using targeted anti-inflammatory vasculo- and neuroprotective agents.

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Neuroprotective effects of hypothermia in inflammatory‐sensitized hypoxic‐ischemic encephalopathy

Abstract: Hypothermia is neuroprotective against inflammatory-sensitized hypoxia-ischemia possibly through a hypothermia-induced increase of antioxidant enzymes. This neuroprotective effect seems to be independent of the interleukin-1 system.

Cited by 25 publications

References 37 publications

Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia–ischemia

Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia–ischemia

Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model

Role of Perinatal Inflammation in Neonatal Arterial Ischemic Stroke

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