Hypothermia followed by rapid rewarming exacerbates ischemia-induced brain injury and augments inflammatory response in rats

Zhu, Shuchai; Gu, Yong; Wu, Zhou; Y, Hu; Pan, Suyue

doi:10.1016/j.bbrc.2016.04.095

Cited by 16 publications

(9 citation statements)

References 31 publications

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“…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]. In our study, we rewarmed at a rate of 0.5 °C/h, which is similar to clinical protocols of 0.5 °C over 1–2 h.…”

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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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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“…Before surgery, rats were trained with spontaneous locomotor activities and locomotor tests daily for 3 days. Then, rats underwent middle cerebral artery occlusion (MCAO) as we have described previously [ 19 ]. Animals were anesthetized with 5% isoflurane in 70% N 2 and 30% O 2 and maintained on 1.5% isoflurane anesthesia using a facemask.…”

Section: Methodsmentioning

confidence: 99%

“…The brain temperature was monitored using a cerebral thermometer probe (THERMOMETER, BAT7001H, Physitemp Instruments, Inc. Clifton, New Jersey, United States) that was inserted through a burr hole (3-mm posterior and 3-mm lateral to bregma and 4 mm below the skull surface) as we have described previously [ 20 ]. Bilateral burr holes (1 mm in diameter) were drilled 6 mm lateral and 1 mm posterior to bregma, and a laser Doppler flowmeter (Moor Instruments Ltd., Devon, UK) probe was positioned above the surface of the hemisphere to monitor the cerebral blood flow (CBF) [ 19 ]. Venous blood from the tails was collected to measure blood glucose with a commercially available glucose monitor (Freestyle Lite; Abbott, Abbott Park, IL).…”

Section: Methodsmentioning

confidence: 99%

Glibenclamide Enhances the Therapeutic Benefits of Early Hypothermia after Severe Stroke in Rats

Zhu¹,

Gao²,

Huang³

et al. 2018

Aging and disease

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Glibenclamide (GBC) is an antidiabetic drug that is in a class of medications known as sulfonylureas, which play critical roles in attenuating brain edema and reducing mortality in ischemic stroke patients. Therapeutic hypothermia (TH) is another robust neuroprotectant that prevents brain swelling and improves the neurological outcomes of stroke patients. However, whether the combination of GBC and TH can be used as a reliable neuroprotectant in ischemic stroke remains largely unknown. We used the middle cerebral artery occlusion (MCAO) rat model as well as oxygen and glucose deprivation-reoxygenation (OGD/R) endothelial cells as ischemic stroke models to investigate the efficacy and mechanisms of treating ischemic stroke with the combination of GBC and TH. The serum glucose, mortality rate, neurobehavioral functions, tight junctions, endothelial cells and inflammatory cytokines were evaluated in the stroke models after treatment with GBC, TH or the combination of them. After 5-hour occlusion and subsequent reperfusion, rats exhibited a large volume of hemispheric swelling and a high mortality rate. Stroke rats treated with the combined therapy did not exhibit hypoglycemia. The combination of GBC and TH exhibited synergistic neuroprotective effects in stroke rats that were associated with greater reductions in edema volume, better improvement in neurobehavioral functions, prevention of tight junction loss, and reduction of expression of the inflammatory cytokines COX-2 and iNOS. In OGD/R endothelia cells, the combination reduced endothelial cell death. This study demonstrated that both GBC and TH are neuroprotective after the severe stroke; however, combined therapy with GBC and TH enhanced the efficiency and efficacy of the effects of TH and GBC in the treatment of ischemia. This combined therapy may facilitate the clinical translation of TH management for severe stroke. The combination of GBC and TH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following severe stroke.

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“…All rats reached the target temperature within 15min. After that for 4 hours, the rats were rewarmed slowly to avoid intracranial hypertension [ 47 ]. The rectal temperature of the other groups was maintained at a constant 37°C.…”

Section: Methodsmentioning

confidence: 99%

Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke

Zhou

Wang

et al. 2017

Oncotarget

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We assessed neurological outcomes, infarct volume, and the expression of nestin and caspase-3 in the hippocampal dentate gyrus following middle cerebral artery occlusion (MCAO) followed by reperfusion, with mild hypothermia (MH) treatment at the onset of ischemia in a MCAO rat model. Reperfusion began 2 hours after the MCAO model was set-up. MH treatment began at the onset of ischemia and was maintained for 4 hours. We evaluated neurological deficit score, brain infarct volumes, along with the immunohistochemical staining of nestin and caspase-3 in the sub-granular zone of the injured hemisphere on the 1st, 3rd, 7th, and 14th day after the onset of ischemia. Correlations between the number of nestin-positive (nestin+) cells, caspase-3-positive (caspase-3+) cells with infarct volume, as well as neurological deficit scores, were evaluated by linear regression. MH significantly promoted survival, reduced mortality, improved neurological deficit score, reduced brain infarct volume, increased the number of neural stem/progenitor cells and inhibited neuronal apoptosis in the sub-granular zone of the injured hemisphere. The number of nestin+ cells correlated with neurological deficit score in the normothermic group, and with infarct volume in the hypothermia group except for the first day after the onset of ischemia. The number of caspase-3+ cells correlated with the neurological deficit score but not infarct volume. The neuroprotective effects of MH may be mediated by modulating neural stem/progenitor cells and neuronal apoptotic cells in the sub-granular zone of the injured hemisphere during cerebral ischemia/reperfusion injury.

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Hypothermia followed by rapid rewarming exacerbates ischemia-induced brain injury and augments inflammatory response in rats

Cited by 16 publications

References 31 publications

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

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

Glibenclamide Enhances the Therapeutic Benefits of Early Hypothermia after Severe Stroke in Rats

Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke

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