Farrerol (FA) is a traditional Chinese herbal medicine known for its anti-inflammatory and anti-oxidative properties in various diseases. Ferroptosis is an iron-dependent oxidative stress-induced cell death. It is characterized by lipid peroxidation and glutathione depletion and is involved in neuronal injury. However, the role of FA in inhibiting ferroptosis in hypoxic-ischemic encephalopathy (HIE) and its underlying mechanisms are not yet completely elucidated. This study aimed to investigate whether FA could mediate ferroptosis and explore its function and molecular mechanism in HIE. A neonatal rat model of HIE was used, and rats were treated with FA, ML385 (a specific inhibitor of nuclear factor erythroid 2-related factor 2 [Nrf2]), or a combination of both. Neurological deficits, infarction volume, brain water content, pathological changes, and iron ion accumulation in the brain tissues were measured using the Zea-Longa scoring system and triphenyl tetrazolium chloride (TTC), hematoxylin-eosin (HE), and Perls' staining. The expression levels of GSH-Px, MDA, SOD, and ROS in brain tissues were also evaluated. Western blot analysis was performed to analyze the expression of the Nrf2 pathway and ferroptosis-related proteins. The results showed that FA administration significantly reduced neuronal damage, infarct volume, cerebral edema, and iron ion accumulation and inhibited MDA and ROS levels while promoting GSH-Px and SOD levels. FA also increased the expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Moreover, the combination of ML385 and FA in HIE abolished the FA protective effects. Therefore, the study concludes that FA exerts a neuroprotective effect after HIE by inhibiting oxidative stress and ferroptosis via the Nrf2 signaling pathway.
- MeSH
- faktor 2 související s NF-E2 MeSH
- ferroptóza * MeSH
- glutathion MeSH
- krysa rodu rattus MeSH
- mozková hypoxie a ischemie * farmakoterapie MeSH
- novorozená zvířata MeSH
- reaktivní formy kyslíku MeSH
- superoxiddismutasa MeSH
- železo MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
V ostatnej dobe stúpa počet dôkazov o tom, že novorodenci s miernou hypoxicko-ischemickou encefalopatiou (HIE) majú významné riziko úmrtnosti, poškodenia mozgu a nepriaznivého neurologického vývoja. Abnormálne krátkodobé následky pozorované u novorodencov s miernou HIE zahŕňajú kŕče, abnormálny neurologický nález pri prepustení, poruchy príjmu potravy a abnormálne nálezy na mozgu pri zobrazovaní magnetickou rezonanciou. Vo veku 2 až 3 rokov je mierna HIE spojená so zvýšeným rizikom autizmu, jazykovým a kognitívnym deficitom. Novorodenci po perinatálnej asfyxii sú zvyčajne diagnostikovaný do 6 hodín po narodení. Toto časové okno zodpovedá možnosti liečby stredne ťažkej až ťažkej HIE. Neexistujú žiadne presne stanovené liečebné stratégie pre skupinu novorodencov s miernou HIE, pretože títo neboli zahrnutí do počiatočných randomizovaných kontrolovaných štúdií terapeutickej hypotermie. V súčasnosti mnohé centrá, napriek obmedzeným dôkazom o jej bezpečnosti a účinnosti, využívajú terapeutickú hypotermiu (TH) v liečbe miernej HIE. Na stanovenie bezpečnosti, účinnosti a optimálneho trvania liečby miernej HIE pomocou TH sú potrebné randomizované kontrolované štúdie. Práca sa zaoberá hľadaním definície miernej HIE a jej incidenciou, sumarizuje dôkazy o nepriaznivých následkoch miernej HIE a zároveň hľadaním ďalších diagnostických pomôcok pre vytváranie terapeutických stratégií pre miernu HIE.
Recently, there is increasing evidence that neonates with mild hypoxic-ischemic encephalopathy (HIE) are at significant risk of mortality, brain damage, and adverse neurodevelopment. Abnormal short-term outcomes seen in neonates with mild HIE include convulsions, abnormal neurologic findings at discharge, feeding disorders, and abnormal brain findings on magnetic resonance imaging. At 2 to 3 years of age, mild HIE is associated with an increased risk of autism, language, and cognitive deficits. Newborns after perinatal asphyxia are usually diagnosed within 6 hours after birth. This time window corresponds to the possibility of treating moderate to severe HIE. There are no well-established treatment strategies for the group of neonates with mild HIE, as these were not included in the initial randomized controlled trials of therapeutic hypothermia. Currently, many centers are using therapeutic hypothermia (TH) in the treatment of mild HIE, despite limited evidence of its safety and efficacy. Randomized controlled trials are needed to establish the safety, efficacy, and optimal duration of treatment of mild HIE with TH. The work deals with the search for the definition of mild HIE and its incidence, summarizes the evidence on the adverse consequences of mild HIE, and at the same time with the search for additional diagnostic aids for the creation of therapeutic strategies for mild HIE.
BACKGROUND: The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia. METHODS: Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM® version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h. RESULTS: Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital. CONCLUSIONS: Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.
- MeSH
- asfyxie novorozenců * komplikace farmakoterapie MeSH
- asfyxie komplikace farmakoterapie MeSH
- dospělí MeSH
- fenobarbital farmakokinetika terapeutické užití MeSH
- lidé MeSH
- mozková hypoxie a ischemie * terapie MeSH
- novorozenec MeSH
- terapeutická hypotermie * metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
Perinatal hypoxic-ischemic insult (HII) is one of the main devastating causes of morbidity and mortality in newborns. HII induces brain injury which evolves to neurological sequelae later in life. Hypothermia is the only therapeutic approach available capable of diminishing brain impairment after HII. Finding a novel therapeutic method to reduce the severity of brain injury and its consequences is critical in neonatology. The present paper aimed to evaluate the effect of sulforaphane (SFN) pre-treatment on glucose metabolism, neurodegeneration, and functional outcome at the acute, sub-acute, and sub-chronic time intervals in the experimental model of perinatal hypoxic-ischemic insult in rats. To estimate the effect of SFN on brain glucose uptake we have performed 18F-deoxyglucose (FDG) microCT/PET. The activity of FDG was determined in the hippocampus and sensorimotor cortex. Neurodegeneration was assessed by histological analysis of Nissl-stained brain sections. To investigate functional outcomes a battery of behavioral tests was employed. We have shown that although SFN possesses a protective effect on glucose uptake in the ischemic hippocampus 24 h and 1 week after HII, no effect has been observed in the motor cortex. We have further shown that the ischemic hippocampal formation tends to be thinner in HIE and SFN treatment tends to reverse this pattern. We have observed subtle chronic movement deficit after HII detected by ladder rung walking test with no protective effect of SFN. SFN should be thus considered as a potent neuroprotective drug with the capability to interfere with pathophysiological processes triggered by perinatal hypoxic-ischemic insult.
- MeSH
- fluorodeoxyglukosa F18 terapeutické užití MeSH
- glukosa MeSH
- hypoxie komplikace MeSH
- isothiokyanatany MeSH
- krysa rodu rattus MeSH
- mozek diagnostické zobrazování patologie MeSH
- mozková hypoxie a ischemie * diagnostické zobrazování farmakoterapie MeSH
- novorozená zvířata MeSH
- poranění mozku * MeSH
- sulfoxidy MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Neonatal hypoxic-ischemic encephalopathy is a disorder with heterogeneous manifestation due to asphyxia during perinatal period. It affects approximately 3-12 children per 1000 live births and cause death of 1 million neonates worldwide per year. Besides, motor disabilities, seizures, impaired muscle tone and epilepsy are few of the consequences of hypoxic-ischemic encephalopathy. Despite an extensive research effort regarding various treatment strategies, therapeutic hypothermia with intensive care unit supportive treatment remains the only approved method for neonates who have suffered from moderate to severe hypoxic-ischemic encephalopathy. However, these protocols are only partially effective given that many infants still suffer from severe brain damage. Thus, further research to systematically test promising neuroprotective treatments in combination with hypothermia is essential. In this review, we discussed the pathophysiology of hypoxic-ischemic encephalopathy and delved into different promising treatment modalities, such as melatonin and erythropoietin. However, preclinical studies and clinical trials are still needed to further elucidate the mechanisms of action of these modalities.
- MeSH
- erythropoetin terapeutické užití MeSH
- hypoxie komplikace farmakoterapie patofyziologie MeSH
- látky tlumící činnost CNS terapeutické užití MeSH
- lidé MeSH
- melatonin terapeutické užití MeSH
- mozková hypoxie a ischemie farmakoterapie etiologie patofyziologie MeSH
- novorozenec MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The study examined the morphological and long-term behavioral impacts of neonatal hypoxic-ischemic brain injury in a mouse model. We investigated the modification of different behavioral domains, such as spontaneous climbing, which represents fine motor skills. We also focused on sex-dependent differences during hypoxic-ischemic encephalopathy. The Rice-Vannucci model of hypoxia-ischemia was used, adjusted and adapted to 7-day-old C57BL/6NTac mice. The effects of induced hypoxia and ischemia were also studied separately. At postnatal day 60, mice underwent behavioral testing using the LABORAS apparatus. The perfusion for histological evaluation was performed one day after the behavioral analyses. In groups with separately induced hypoxia or ischemia, the observed alterations in behavior were not accompanied by morphological changes in the cortex or hippocampal formation. Female mice naturally climbed significantly more and hypoxic females reared less than hypoxic males (p<0.05). Male mice postnatally exposed to hypoxia-ischemia exhibited significantly lower vertical activity and higher horizontal activity (p<0.05). Mild hypoxic damage may not be morphologically detectable but may induce substantial behavioral changes in adult mice. There were significant differences between horizontal and vertical activity in reaction to hypoxia-ischemia. Our study indicates that the importance of behavioral testing is irreplaceable and may be reflected in neonatal medicine.
- MeSH
- biomechanika MeSH
- chov zvířat metody MeSH
- chování zvířat * MeSH
- mozková hypoxie a ischemie patofyziologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- novorozená zvířata MeSH
- poranění mozku patofyziologie MeSH
- sociální izolace * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- první rok života dítěte, první kontakt, převzetí do péče, ambulantní porod, adaptace novorozence, zralost, indikace,
- MeSH
- asfyxie novorozenců MeSH
- chromozomální poruchy klasifikace MeSH
- Downův syndrom diagnóza MeSH
- exantém etiologie MeSH
- fyziologie kůže MeSH
- gestační stáří MeSH
- hemangiom klasifikace MeSH
- hospitalizace MeSH
- kojení metody MeSH
- kontinuita péče o pacienty MeSH
- kožní nemoci klasifikace MeSH
- lidé MeSH
- místo porodu MeSH
- mozková hypoxie a ischemie MeSH
- neprospívání etiologie MeSH
- novorozenec nedonošený MeSH
- novorozenec * MeSH
- novorozenecká hyperbilirubinemie MeSH
- porodní hmotnost MeSH
- postnatální péče organizace a řízení MeSH
- puerperální infekce diagnóza etiologie MeSH
- riziko MeSH
- rizikové faktory MeSH
- rodiče výchova MeSH
- stupeň závažnosti nemoci MeSH
- vrozené vady diagnóza etiologie klasifikace MeSH
- Check Tag
- lidé MeSH
- novorozenec * MeSH
- Publikační typ
- přehledy MeSH
Hypoxic-ischemic encephalopathy (HIE) is a neonatal condition that occurs as a consequence of perinatal asphyxia, which is caused by a number of factors, commonly via compression of the umbilical cord, placental abruption, severe meconium aspiration, congenital cardiac or pulmonary anomalies and birth trauma. Experimental studies have confirmed that male rat pups show a higher resistance to HIE treatment. Moreover, the long-term consequences of hypoxia in male are more severe in comparison to female rat pups. These sex differences can be attributed to the pathophysiology of hypoxia-ischemia, whereby studies are beginning to establish such gender-specific distinctions. The current and sole treatment for HIE is hypothermia, in which a reduction in temperature prevents long-term effects, such as cerebral palsy or seizures. However, in most cases hypothermia is not a sufficient treatment as indicated by a high mortality rate. In the present review, we discuss the gender differences within the pathophysiology of hypoxia-ischemia and delve into the role of gender in the incidence, progression and severity of the disease. Furthermore, this may result in the development of potential novel treatment approaches for targeting and preventing the long-term consequences of HIE.
- MeSH
- apoptóza MeSH
- asfyxie novorozenců komplikace MeSH
- lidé MeSH
- mozek metabolismus MeSH
- mozková hypoxie a ischemie etiologie metabolismus terapie MeSH
- novorozenec MeSH
- oxidační stres MeSH
- pohlavní dimorfismus * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- dítě MeSH
- informovaný souhlas pacienta MeSH
- lidé MeSH
- mozková hypoxie a ischemie terapie MeSH
- novorozenec MeSH
- terapeutická hypotermie * metody MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
