Timing still key to treating hypoxic ischaemic brain injury

Gunn, Alistair J.

doi:10.1016/s1474-4422(15)00386-5

Cited by 16 publications

(12 citation statements)

References 10 publications

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“…One of the key translational considerations for potential neuroprotectants is when to treat [69]. In the present study, we gave the first dose of Etanercept immediately before LPS exposure.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Galinsky

Dhillon

Dean

et al. 2020

J Neuroinflammation

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Background: Increased circulating levels of tumor necrosis factor (TNF) are associated with greater risk of impaired neurodevelopment after preterm birth. In this study, we tested the hypothesis that systemic TNF inhibition, using the soluble TNF receptor Etanercept, would attenuate neuroinflammation in preterm fetal sheep exposed to lipopolysaccharide (LPS). Methods: Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive saline (control; n = 7), LPS infusion (100 ng/kg i.v. over 24 h then 250 ng/kg/24 h for 96 h plus 1 μg LPS boluses at 48, 72, and 96 h, to induce inflammation; n = 8) or LPS plus two i.v. infusions of Etanercept (2 doses, 5 mg/kg infused over 30 min, 48 h apart) started immediately before LPS-exposure (n = 8). Sheep were killed 10 days after starting infusions, for histology. Results: LPS boluses were associated with increased circulating TNF, interleukin (IL)-6 and IL-10, electroencephalogram (EEG) suppression, hypotension, tachycardia, and increased carotid artery perfusion (P < 0.05 vs. control). In the periventricular and intragyral white matter, LPS exposure increased gliosis, TNFpositive cells, total oligodendrocytes, and cell proliferation (P < 0.05 vs control), but did not affect myelin expression or numbers of neurons in the cortex and subcortical regions. Etanercept delayed the rise in circulating IL-6, prolonged the increase in IL-10 (P < 0.05 vs. LPS), and attenuated EEG suppression, hypotension, and tachycardia after LPS boluses. Histologically, Etanercept normalized LPS-induced gliosis, and increase in TNF-positive cells, proliferation, and total oligodendrocytes. Conclusion: TNF inhibition markedly attenuated white matter gliosis but did not affect mature oligodendrocytes after prolonged systemic inflammation in preterm fetal sheep. Further studies of long-term brain maturation are now needed.

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Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Galinsky

Dhillon

Dean

et al. 2020

J Neuroinflammation

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“…Clinically, because most HI occurs around birth, it is very difficult to identify fetuses who are likely to develop postnatal HIE in advance as the positive predictive value of heart rate monitoring in labor is exceedingly low [34] . It remains a formidable challenge to start any intervention even within the first 6 h after birth [35] . Thus, in most cases, it is very difficult to translate preclinical neuroprotective agents until the window of opportunity after HI is known.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, given that hypothermia is now standard clinical practice [35,36] , ultimately it is essential to also test the effectiveness of potential drug therapies as adjuvants to therapeutic hypothermia in order to improve current treatment protocols. In this analysis, just 9 out of the 61 papers surveyed (15%) assessed the effectiveness of hypothermia with adjuvant therapies.…”

Section: Discussionmentioning

confidence: 99%

In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature?

et al. 2016

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In the era of therapeutic hypothermia, reliable preclinical studies are integral to successfully identify neuroprotective strategies to further improve outcomes of encephalopathy at term. We reviewed preclinical neuroprotection studies reported between January 2014 and June 2016 to assess the use of effective temperature monitoring and control. As a secondary measure, we examined whether studies addressed other methodological issues such as stage of brain development, sex differences, the timing of the treatment relative to the insult, and the histological and functional endpoints used after hypoxia-ischemia. The extent and duration of temperature monitoring was highly inconsistent. Only a minority of papers monitored core (19/61; 31%) or brain temperature (3/61; 5%). Most (40/45) of the neuroprotectants either were likely to affect thermoregulation or their impact is unknown. In 85% of papers neonatal rodents were used (67% at P7); 51% of papers did not report the sex of the animals or tested the effect of potential neuroprotectants on just one sex. In 76% of studies, treatment was before or immediately after the insult (within the first 2 h), and few studies assessed long-term histological and behavioral outcomes. In conclusion, many recent preclinical neonatal studies cannot exclude the possibility that apparent neuroprotection might be related to drug-induced hypothermia or to other methodological choices. Close monitoring and control of brain temperature during, as well as for many days after, experimental hypoxia-ischemia are now critical to reliably develop new ways to improve neurodevelopmental outcomes after perinatal hypoxic-ischemic encephalopathy.

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“…While there is no exact consensus on the optimal degree of cooling, several studies have found cooling at 33°C to be most efective [7][8][9][10]. The vast majority of investigations on the topic feature a mild to moderate degree of cooling, with very few venturing into moderate-deep to deep hypothermia ( Table 1).…”

Section: Degrees Of Hypothermiamentioning

confidence: 99%

Hypothermia in Stroke Therapy: Systemic versus Local Application

Huber¹,

Duan²,

Chandra³

et al. 2017

Hypoxia and Human Diseases

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Presently, there are no efective, widely applicable therapies for ischemic stroke. There is strong clinical evidence for the neuroprotective beneits of hypothermia, and surfacecooling methods have been utilized for decades in the treatment of cerebral ischemia during cardiac arrest, but complications with hypothermia induction have hindered its clinical acceptance in ischemic stroke therapy. Recently, the microcatheter-based local endovascular infusion (LEVI) of cold saline directly to the infarct site has been proposed as a solution to the drawbacks of surface cooling. The safety and eicacy of LEVI in rat models have been established, and implementation in larger animals has been similarly encouraging. A recent pilot study even established the safety of LEVI in humans. This review seeks to outline the major research on LEVI, discusses the mechanisms that mediate its superior neuroprotection over surface and systemic cooling, and identiies areas that warrant further investigation. While LEVI features improvements on surface cooling, its core mechanisms of neuroprotection are still largely shared with therapeutic hypothermia in general. As such, the mechanisms of hypothermia-based neuroprotection are discussed as well.

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Timing still key to treating hypoxic ischaemic brain injury

Cited by 16 publications

References 10 publications

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature?

Hypothermia in Stroke Therapy: Systemic versus Local Application

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