Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro

Su, Fang; Guo, Anchen; Li, Weiwei; Zhao, Yilong; Qu, Zhengyi; Wang, Yongjun; Wang, Qun; Zhu, Yulan

doi:10.1007/s12264-016-0080-3

Cited by 33 publications

(18 citation statements)

References 53 publications

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“…As melatonin is sparingly soluble, solubility enhancers, such as ethanol, are used. Ethanol could confound previous studies of melatonin protection 13,[15][16][17][18][19] , as low-dose ethanol ~4 h after HI is protective in adult models of stroke [20][21][22] . In a previous piglet study, we observed augmentation of HT protection with 30 mg/kg/24 h melatonin with ethanol excipient when started 10 mins after hypoxia-ischemia (HI), reaching blood levels >15 mg/l within 1 h 13 .…”

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confidence: 99%

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Robertson

Lingam

Meehan

et al. 2020

Sci Rep

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With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (Ht+V; n = 7); (iii) HT + Melatonin (Ht+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after Hi. comparing Ht+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/ exchangeable phosphate were higher at 48 h in HT+M versus Ht (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in Ht+M (47.1 cells/mm 2 ) compared to HT (123.8 cells/mm 2 ) (p = 0.0003) and HT+V (97.5 cells/mm 2 ) compared to Ht (p = 0.012). Localized protection was seen in white matter for HT+M versus Ht (p = 0.036) and internal capsule for HT+M compared to Ht (p = 0.001) and HT+V versus Ht (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.Intrapartum-related neonatal encephalopathy (NE) is a major healthcare problem. Worldwide in 2010, NE accounted for 287,000 deaths and 400,000 survivors with impairment 1 . NE cannot be prevented in most cases and therapies are limited. The incidence of NE in Western Europe is 1-3/1000 term births and in low-and mid-resource settings the incidence is ~10 times higher 1,2 . Over the last 2 decades, in settings with neonatal intensive care facilities, therapeutic hypothermia (HT) is routinely used for moderate-to-severe NE, improving survival and reducing disability 3 . However, although the severity of cerebral palsy has reduced with HT 4 , survivors have significantly lower cognitive scores which are on average 14 IQ points lower than matched peers even in the absence of cerebral palsy at school-age 5 . Further adjustments to HT protocols do not improve outcome 6,7 , therefore adjunct therapies to augment HT protection are urgently needed.Pre-clinical studies suggest that melatonin (N-acetyl-5-methoxytryptamine) in pharmacologic levels is safe and neuroprotective for hypoxic-ischemic injury in the adult 8 and neonatal 9 brain, mediated by anti-oxidant, anti-apoptotic and anti-inflammatory properties 10,11 . Ex...

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confidence: 99%

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Robertson

Lingam

Meehan

et al. 2020

Sci Rep

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“…Many researches (Chi et al, 2010;Gribkoff et al, 2001;Hewawasam et al, 2003;Li et al, 2014;Su et al, 2017) have shown that BK Ca channel is one of the molecular targets of the ischemic stroke. Therefore, we tested whether vitamin C could activate the BK Ca channel.…”

Section: Vitamin C Activates Bk Ca Channelsmentioning

confidence: 99%

BK_Cachannel is a molecular target of vitamin C to protect against ischemic brain stroke

et al. 2019

Molecular Membrane Biology

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“…Activation of BK Ca channel can cause hyperpolarization of membrane potential, which participates in regulation of neurons functions . The pharmacological application has demonstrated a protective role of BK Ca channel against ischaemic injury, such as that low dose ethanol preconditioning protects primary rat cortical neurons from anoxia/reoxygenation (A/R)‐induced injury by activating BK Ca channel . Although TFR could activate the K Ca channel in cerebral artery VSMCs, whether it has a direct effect on nerve cell to produce neuroprotection, especially its action on neuronal K Ca channel, is unclear.…”

Section: Introductionmentioning

confidence: 99%

“…[15] The pharmacological application has demonstrated a protective role of BK Ca channel against ischaemic injury, such as that low dose ethanol preconditioning protects primary rat cortical neurons from anoxia/ reoxygenation (A/R)-induced injury by activating BK Ca channel. [16] Although TFR could activate the K Ca channel in cerebral artery VSMCs, whether it has a direct effect on nerve cell to produce neuroprotection, especially its action on neuronal K Ca channel, is unclear. The present study was therefore designed to investigate the effect of TFR against H/R injury in rat hippocampal neurons and its mechanism related to BK Ca channel.…”

Section: Introductionmentioning

confidence: 99%

Total flavones of Rhododendron simsii Planch flower protect rat hippocampal neuron from hypoxia-reoxygenation injury via activation of BKCa channel

Guo

Chen

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives To study the effects of total flavones of Rhododendra simsii Planch flower (TFR) on hypoxia/reoxygenation (H/R) injury in rat hippocampal neurons and its underlying mechanism. Method Model of H/R was established in newborn rat primary cultured hippocampal neuron. Lactate dehydrogenase (LDH) and neuron‐specific enolase (NSE) activity as well as malondialdehyde (MDA) content in cultured supernatants of the neurons were examined. Methyl thiazolyl tetrazolium assay and Hoechst33258 staining were, respectively, used to detect cell viability and apoptosis of neurons. Protein expression and current of BKCa channel were assessed by using Western blotting and whole‐cell patch‐clamp methods, respectively. Key findings In the ranges of 3.7–300 mg/l, TFR significantly inhibited H/R‐induced decrease of neuronal viability and increases of LDH, NSE and MDA in the supernatants as well as apoptosis; TFR 33.3, 100 and 300 mg/l markedly increased current of BKCa channel rather than the BKCa channel protein expression in the neurons. Conclusions Total flavones of R. simsii Planch flower had a protective effect against H/R injury in rat hippocampal neuron, and activation of BKCa channel may contribute to the neuroprotection.

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Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro

Cited by 33 publications

References 53 publications

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

BK_Cachannel is a molecular target of vitamin C to protect against ischemic brain stroke

Total flavones of Rhododendron simsii Planch flower protect rat hippocampal neuron from hypoxia-reoxygenation injury via activation of BKCa channel

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Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro

Cited by 33 publications

References 53 publications

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

BKCachannel is a molecular target of vitamin C to protect against ischemic brain stroke

Total flavones of Rhododendron simsii Planch flower protect rat hippocampal neuron from hypoxia-reoxygenation injury via activation of BKCa channel

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BK_Cachannel is a molecular target of vitamin C to protect against ischemic brain stroke