Mechanisms of hypothermic neuroprotection

Drury, Paul P.; Bennet, Laura; Gunn, Alistair J.

doi:10.1016/j.siny.2010.05.005

Cited by 103 publications

(93 citation statements)

References 82 publications

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“…Although the mechanisms of white (and gray) matter protection with delayed hypothermia induced after hypoxia-ischemia are not fully understood, suppression of secondary apoptosis and inflammation after ischemia appear to be major contributors [21,22]. In the present study, caspase 3 expression in the white matter tracts 5 days after ischemia colocalized with CNPase, consistent with ongoing apoptotic cell death in oligodendrocytes [13].…”

Section: Discussionsupporting

confidence: 50%

White Matter Protection with Insulin-Like Growth Factor 1 and Hypothermia Is Not Additive after Severe Reversible Cerebral Ischemia in Term Fetal Sheep

George

Weaver-Mikaere²,

Fraser³

et al. 2011

Dev Neurosci

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Moderate cerebral hypothermia significantly improves survival without disability from perinatal hypoxia-ischemia. However, protection is partial. Insulin-like growth factor 1 (IGF-1) plays a key role in oligodendrocyte survival and myelination. The purpose of this study was to test the hypothesis that the combination of IGF-1 plus hypothermia could reduce postischemic white matter damage compared with hypothermia alone. Unanesthetized near-term fetal sheep received 30 min of cerebral ischemia, followed by either an infusion of 3 µg of IGF-1 intracerebroventricularly from 4.5 to 5.5 h plus cooling from 5.5 to 72 h (IGF-1 + hypothermia; n = 8), vehicle infusion plus cooling from 5.5 to 72 h (vehicle + hypothermia; n = 12), sham cooling plus sham infusion (ischemia control; n = 12) or sham ischemia (n = 5). The fetal extradural temperature was reduced from 39.4 ± 0.1°C to between 30 and 33°C. White matter was assessed after 5 days. Ischemia was associated with severe loss of CNPase-positive oligodendrocytes in white matter compared with sham ischemia (380 ± 138 vs. 1,180 ± 152 cells/field; mean ± SD; p < 0.001). Delayed hypothermia reduced cell loss (847 ± 297 cells/field, p < 0.01, vs. ischemia control), but there was no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (1,015 ± 211 cells/field; NS). Ischemia was associated with increased caspase 3 expression in white matter (216 ± 41 vs. 19 ± 18 cells/field; p < 0.001). Hypothermia reduced numbers of activated caspase 3-positive cells (116 ± 81 cells/field; p < 0.05), with no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (91 ± 27 cells/field; NS). In conclusion, delayed cotreatment with IGF-1 plus hypothermia after ischemia was associated with an improvement in white matter damage similar to that achieved by hypothermia alone.

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Section: Discussionsupporting

confidence: 50%

White Matter Protection with Insulin-Like Growth Factor 1 and Hypothermia Is Not Additive after Severe Reversible Cerebral Ischemia in Term Fetal Sheep

George

Weaver-Mikaere²,

Fraser³

et al. 2011

Dev Neurosci

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“…Hypothermia is currently the main therapy applied to infants who have suffered a perinatal brain injury, but its efficacy depends on the severity of the damage and how quickly hypothermia can be applied after the initial brain injury [6]. The neuroprotective effect of hypothermia is believed to occur via reduced cellular metabolism, suppression of the inflammatory cascade, decreased glutamate excitotoxicity and apoptotic cell death [7].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Benefits of Delayed Lithium Administration in the Neonatal Rat after Cerebral Hypoxia-Ischemia

et al. 2014

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AimWe have previously shown that lithium treatment immediately after hypoxia-ischemia (HI) in neonatal rats affords both short- and long-term neuroprotection. The aim of this study was to evaluate possible therapeutic benefits when lithium treatment was delayed 5 days, a time point when most cell death is over.MethodsEight-day-old male rats were subjected to unilateral HI and 2 mmol/kg lithium chloride was injected intraperitoneally 5 days after the insult. Additional lithium injections of 1 mmol/kg were administered at 24 h intervals for the next 14 days. Brain injury was evaluated 12 weeks after HI. Serum cytokine measurements and behavioral analysis were performed before sacrificing the animals.ResultsBrain injury, as indicated by tissue loss, was reduced by 38.7%, from 276.5±27.4 mm3 in the vehicle-treated group to 169.3±25.9 mm3 in the lithium-treated group 12 weeks after HI (p<0.01). Motor hyperactivity and anxiety-like behavior after HI were normalized by lithium treatment. Lithium treatment increased neurogenesis in the dentate gyrus as indicated by doublecortin labeling. Serum cytokine levels, including IL-1α, IL-1β, and IL-6, were still elevated as late as 5 weeks after HI, but lithium treatment normalized these cytokine levels.ConclusionsDelayed lithium treatment conferred long-term neuroprotection in neonatal rats after HI, and this opens a new avenue for future development of treatment strategies for neonatal brain injury that can be administered after the acute injury phase.

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“…Although the mechanism of cerebral injury resulting from DHCA has not been fully elucidated, the neuroinflammatory theory is a novel mechanism involved in this process [7,8]. It is well documented that Toll-like receptors (TLRs) are the first-line molecules activating innate immune and neuroinflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

Selective Antegrade Cerebral Perfusion Attenuating the TLR4/NF-κB Pathway during Deep Hypothermia Circulatory Arrest in a Pig Model

Tang

Chen²,

Liang³

et al. 2014

Cardiology

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Objectives: The alteration of the Toll-like receptor/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway during deep hypothermia circulatory arrest (DHCA) has not yet been defined. The aim of this study was to explore the expression of the TLR4/NF-κB pathway cytokine in cerebral injury resulting from DHCA as well as the effect of selective antegrade cerebral perfusion (SACP) on TLR4/NF-κB pathway expression. Methods: Twelve pigs were randomly assigned to DHCA alone (n = 6) or DHCA with SACP (n = 6) at 18°C for 80 min. Serum interleukin (IL)-6 was assayed by ELISA. Apoptosis and NF-κB proteins were detected by fluorescence TUNEL and Western blot, respectively. The level of TLR4 mRNA and protein were determined through qRT-PCR and Western blot. Results: The serum IL-6 level of the SACP group was significantly lower than that of the DHCA group at the end of circulation arrest and experimentation. Apoptotic index and NF-κB protein were apparently lower in SACP animals (p < 0.05). Compared to the DHCA group, the levels of TLR4 protein and mRNA in the SACP group were lower with significance (p < 0.05). Conclusions: The TLR4/NF-κB signaling pathway plays a critical role in the pathogenesis of DHCA cerebral injury. Attenuation of the TLR4/NF-κB inflammatory cytokines probably contributes to the neuroprotective effect of SACP. The TLR4/NF-κB inflammatory signaling pathway may be a novel therapeutic target for developing a new strategy for neuroprotection in DHCA.

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Mechanisms of hypothermic neuroprotection

Cited by 103 publications

References 82 publications

White Matter Protection with Insulin-Like Growth Factor 1 and Hypothermia Is Not Additive after Severe Reversible Cerebral Ischemia in Term Fetal Sheep

White Matter Protection with Insulin-Like Growth Factor 1 and Hypothermia Is Not Additive after Severe Reversible Cerebral Ischemia in Term Fetal Sheep

Therapeutic Benefits of Delayed Lithium Administration in the Neonatal Rat after Cerebral Hypoxia-Ischemia

Selective Antegrade Cerebral Perfusion Attenuating the TLR4/NF-κB Pathway during Deep Hypothermia Circulatory Arrest in a Pig Model

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