Consequences of epilepsy in the developing brain: implications for surgical management

The developing brain is highly susceptible to seizures, as demonstrated by both human and animal studies. Until recently, the brain has been considered to be relatively resistant to damage induced by seizures early in life. Accumulating evidence in animal models now suggests that early seizures can cause structural and physiologic changes in developing neural circuits that result in permanent alterations in the balance between neuronal excitation and inhibition, deficits in cognitive function, and increased susceptibility to additional seizures. The disruption of normal neuronal activity by seizures can affect multiple developmental processes, resulting in these long-lasting changes. These data should be considered in the clinical approach to children with intractable epilepsy and suggest that early intervention may avoid some of these long-term neurologic deficits.     

Models of epilepsy in the developing and adult brain: implications for neuroprotection

Repeated seizures cause a sequence of molecular and cellular changes in both the developing and adult brain, which may lead to intractable epilepsy. This article reviews this sequence of neuronal alterations, with emphasis on the kindling model. At each step, the opportunity exists for strategic intervention to prevent or reduce the downstream consequences of epileptogenesis and seizure-induced adverse plasticity. The concept of seizure-induced brain damage must be expanded to include behavioral and cognitive deficits, as well as structural neuronal damage and increased predisposition to seizures.     

脑红蛋白与缺氧缺血性脑损伤

继血红蛋白和肌红蛋白之后，德国人Burmester等在2000年首次发现了另一类存在于人和小鼠脑内的携氧球蛋白：脑红蛋白（neuroglobin，Ngb）。作为球蛋白家族中的一员，Ngb在脑缺血缺氧状态下对神经元保护起着重要的作用。[第一段]     

Traumatic brain injury: Risks of epilepsy and implications for medicolegal assessment

Traumatic brain injury (TBI) is a potentially preventable cause of epilepsy. Increasing incidence among army personnel and the high incidence among children and young people raise concern. This article presents a review of selected studies dealing with the risks of TBI and the risk of posttraumatic epilepsy in humans. The incidence of persons admitted to hospital with TBI has decreased in developed countries in recent years. However, there is little change in TBI-associated deaths, and the decrease in hospitalization may merely reflect that more people with head injury are cared for on an outpatient basis. It is clear that epilepsy is a frequent consequence of brain injury, even many years after the injury. However, several well-controlled studies have been unable to identify therapies that prevent the development of epilepsy after TBI. Posttraumatic epilepsy has significant implications for the affected individuals, family, and society. Despite several interventions used to prevent posttraumatic epilepsy, the only proven "intervention" to date is to prevent TBI from occurring.     

Neurogenesis and epilepsy in the developing brain

Multiple studies have highlighted how seizures induce different molecular, cellular, and physiologic consequences in an immature brain as compared to a mature brain. In keeping with these studies, seizures early in life alter dentate granule cell birth in different, and even opposing, fashion to adult seizure models (see Table 1 ). During the first week of rodent postnatal life, seizures decrease cell birth in the postictal period, but do not alter the maturation of newborn cells. Seizures during the second week of life have varied effects on dentate granule cell birth, either causing no change or increasing birth, and may promote a mild increase in neuronal survival. During the third and fourth weeks of life, seizures begin to increase cell birth similar to that seen in adult seizure models. Interestingly, animals that experienced seizure during the first month of life have an increase in cell birth during adulthood, opposite to the reported decrease in chronic animals experiencing a prolonged seizure as an adult. Children have more ongoing cell birth in the dentate gyrus than adults, and markers of cell division are further increased in children with refractory temporal lobe epilepsy. There are clear age-dependent differences in how seizures alter cell birth in the dentate gyrus both acutely and chronically. Future studies need to focus on how these changes in neurogenesis influence dentate gyrus function and what they imply for epileptogenesis and learning and memory impairments, so commonly found in children with temporal lobe epilepsy.  

  Table 1.  Early seizures alter cell birth in rodent dentate gyrus     

6.

N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury     

Wang X  Svedin P  Nie C  Lapatto R  Zhu C  Gustavsson M  Sandberg M  Karlsson JO  Romero R  Hagberg H  Mallard C 《Annals of neurology》2007,61(3):263-271

OBJECTIVE: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model. METHODS: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI. RESULTS: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation. INTERPRETATION: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.     

7.

Plasticity and injury in the developing brain     

Johnston MV  Ishida A  Ishida WN  Matsushita HB  Nishimura A  Tsuji M 《Brain & development》2009,31(1):1-10

The child's brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity-dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders.     

8.

Repeat traumatic brain injury in the developing brain     

M.L. Prins  C.C. Giza 《International journal of developmental neuroscience》2012

The Center for Disease Control estimates that there are 1.7 million brain injuries in the US each year with 51% of these injuries occurring during periods of cerebral development. Among this population there is a growing population of individuals with repeat traumatic brain injury (RTBI). While the exact incidence is unknown, estimates range from 5.6 to 36% of the TBI population. This review summarizes the clinical problems/challenges and experimental research models that currently exist. It is intended to reveal the critical areas that need to be addressed so that age-relevant clinical management guidelines can be established to protect this population.     

9.

Xuefuzhuyu decoction and astragalus prevent hypoxic-ischemic brain injury     

Ning Wang  Dongpi Wang  Zhong Lü  Xuan Chen  Long Lin  Zhiyong Hu Children''s Hospital of Zhejiang University School of Medicine  Hangzhou  Zhejiang Province  China Huqingyu Hall Traditional Chinese Medicine Museum  Hangzhou  China Red Cross Hospital  China 《中国神经再生研究》2011,6(21)

Hypoxic-ischemic brain injury models were generated by bilateral carotid artery ligation in Sprague-Dawley rats. Successful models were treated with a combination of Xuefuzhuyu decoction and 10g of astragalus. The experimental results showed that neuronal morphology and structure recovered, nerve growth factor mRNA expression increased in brain tissues, and neurological function signifi-cantly improved. There was no significant difference in these measures compared with rats treated with Xuefuzhuyu decoctio...     

10.

Quantitative EEG reactivity and machine learning for prognostication in hypoxic-ischemic brain injury     

《Clinical neurophysiology》2019,130(10):1908-1916

ObjectiveElectroencephalogram (EEG) reactivity is a robust predictor of neurological recovery after cardiac arrest, however interrater-agreement among electroencephalographers is limited. We sought to evaluate the performance of machine learning methods using EEG reactivity data to predict good long-term outcomes in hypoxic-ischemic brain injury.MethodsWe retrospectively reviewed clinical and EEG data of comatose cardiac arrest subjects. Electroencephalogram reactivity was tested within 72 h from cardiac arrest using sound and pain stimuli. A Quantitative EEG (QEEG) reactivity method evaluated changes in QEEG features (EEG spectra, entropy, and frequency features) during the 10 s before and after each stimulation. Good outcome was defined as Cerebral Performance Category of 1–2 at six months. Performance of a random forest classifier was compared against a penalized general linear model (GLM) and expert electroencephalographer review.ResultsFifty subjects were included and sixteen (32%) had good outcome. Both QEEG reactivity methods had comparable performance to expert EEG reactivity assessment for good outcome prediction (mean AUC 0.8 for random forest vs. 0.69 for GLM vs. 0.69 for expert review, respectively; p non-significant).ConclusionsMachine-learning models utilizing quantitative EEG reactivity data can predict long-term outcome after cardiac arrest.SignificanceA quantitative approach to EEG reactivity assessment may support prognostication in cardiac arrest.     

11.

Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury     

Juan Rodriguez  Tao Li  Yiran Xu  Yanyan Sun  Changlian Zhu 《中国神经再生研究》2021,16(2):205

Perinatal complications, such as asphyxia, can cause brain injuries that are often associated with subsequent neurological deficits, such as cerebral palsy or mental retardation. The mechanisms of perinatal brain injury are not fully understood, but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion. Among these proteins, apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia, but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury. In this review, we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy, specifically on the importance of apoptosis-inducing factor. The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality, especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress, acting as a free radical scavenger. We also discuss all the different apoptosis-inducing factor isoforms discovered, focusing especially on apoptosis-inducing factor 2, which is only expressed in the brain and the functions of which are starting now to be clarified. Finally, we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions(prosurvival and pro-apoptotic) and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.     

12.

Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury   总被引：17，自引：0，他引：17  

Arvin KL  Han BH  Du Y  Lin SZ  Paul SM  Holtzman DM 《Annals of neurology》2002,52(1):54-61

Hypoxic-ischemic brain injury in the perinatal period is a major cause of morbidity and mortality. Presently, there are no proven effective therapies with which to safeguard the human neonatal brain against this type of injury. Minocycline, a semisynthetic tetracycline, has been shown to be neuroprotective in certain adult ischemic injury/stroke and neurodegenerative disease models. However, minocycline's neuroprotective effects have not been assessed after insults to the neonatal brain. We now report that minocycline administered either immediately before or immediately after a hypoxic-ischemic insult substantially blocks tissue damage in a rodent model of neonatal hypoxic-ischemic brain injury. Minocycline treatment prevents the formation of activated caspase-3, a known effector of apoptosis, as well as the appearance of a calpain cleaved substrate, a marker of excitotoxic/necrotic cell death. To our knowledge, this is the first report of a systemic treatment that can be administered after a hypoxic-ischemic insult, which provides robust, nearly complete neuroprotection to the developing brain. Our data suggest that minocycline or a related neuroprotective tetracycline may be a candidate to consider in human clinical trials to protect the developing brain against hypoxic-ischemic-induced damage.     

13.

Mechanisms of injury in hypoxic-ischemic encephalopathy: implications to therapy   总被引：4，自引：0，他引：4  

Greer DM 《Seminars in neurology》2006,26(4):373-379

Cardiac arrest survivors commonly suffer ischemic brain injury, and understanding the mechanisms of injury is essential to providing insight for effective therapies for brain protection. Injury can occur at the time of the cardiac arrest and is dependent not only on the duration but also the degree of impaired circulation. Injury can be ongoing even after the return of spontaneous circulation, giving the clinician an additional window of opportunity to treat and protect the injured brain. This section will review the molecular basis of injury with cardiac arrest and will elucidate the different mechanisms of injury between cardiac arrest, pure respiratory arrest, and arrest secondary to toxins (e.g., carbon monoxide). The rationale for multiple postarrest therapies, such as hypothermia and induced hypertension, will also be reviewed.     

14.

Progesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature rats     

Tsuji M  Taguchi A  Ohshima M  Kasahara Y  Ikeda T 《Experimental neurology》2012,233(1):214-220

Progesterone and its metabolite, allopregnanolone, are neurosteroids that are present at high concentrations in fetal brains that decrease right after birth. Allopregnanolone is a potent positive modulator of γ-aminobutyric acid A (GABA(A)) receptor function. We examined the effect of exogenous administration of these steroids on hypoxic-ischemic encephalopathy in immature rats. Progesterone (10mg/kg), allopregnanolone (10mg/kg), or vehicle alone was intraperitoneally administered immediately before and then subcutaneously 6h and 24h after hypoxia-ischemia to postnatal day 7 (P7), day 14 (P14), and day 21 (P21) rats. The effects of the treatments were evaluated using histological analyses (hemispheric volumes and semi-quantitative scoring for neuropathologic injury). Both progesterone and allopregnanolone significantly exacerbated brain injury in P7 and P14 rats, but not in P21 rats. This detrimental effect was similar across the examined brain regions (the cortex, striatum, hippocampus, and thalamus) and showed no sex differences. Co-administration of the GABA(A) receptor antagonist, bicuculline, partially mitigated the exacerbating effect of allopregnanolone. Based on the similarity of the effects of these neurosteroids, we speculate that progesterone accentuates neuronal injury mainly via the activity of allopregnanolone. The present study indicates that the detrimental effects of allopregnanolone were, at least in part, mediated via GABAergic neuroexcitability. This is in line with the notion that GABA is excitatory for immature neurons, while it is inhibitory for mature neurons.     

15.

Phenobarbital modifies seizure-related brain injury in the developing brain     

Mohamad A. Mikati  Gregory L. Holmes  Antonia Chronopoulos  Pamela Hyde  Samuel Thurber  Arkadi Gatt  Zhao Liu  Suzanne Werner  Carl E. Stafstrom 《Annals of neurology》1994,36(3):425-433

To investigate the potential role of drug therapy in preventing or exacerbating seizure-related brain injury in the prepubescent brain, we administered kainic acid to rats at postnatal day 35. Therapy with daily phenobarbital was started directly before or 1 day after kainic acid was administered, and was continued through postnatal day 153. Rats receiving phenobarbital had therapeutic concentrations during most of the 24-hour dosing period, but also experienced supratherapeutic peak concentrations. The animals were subsequently tested using the water maze (a measure of visuospatial memory), open field (a measure of activity level), and handling tests (a measure of emotionality). The frequency of spontaneous recurrent seizures was monitored during and after phenobarbital therapy. Kainic acid resulted in status epilepticus on postnatal day 35 in all the rats that received it but those receiving phenobarbital first manifested a shorter and less severe status epilepticus as compared to the rats given kainic acid alone. Rats starting phenobarbital immediately before kainic acid was administered did not differ from control rats on behavioral testing and had no subsequent spontaneous recurrent seizures and no histological lesions. Rats receiving kainic acid alone performed significantly poorer than did control rats in the water maze, were more aggressive, had histological lesions, and manifested spontaneous recurrent seizures. As compared to the group treated only with kainic acid, rats receiving kainic acid followed by phenobarbital at postnatal days 36 to 153 manifested similar aggressiveness and histological lesions, similar frequency of spontaneous recurrent seizures after phenobarbital taper, and even greater disturbances in memory, learning, and activity level. These results demonstrate that kainic acid–related injury can be prevented by a medication working through inhibitory mechanisms; that structural and functional damage in the prepubescent brain can be prevented through strategically timed pharmacotherapy; and that treatment of spontaneous recurrent seizures alone with daily exposure to phenobarbital does not decrease, and may actually exacerbate, damage in the kainic acid model.     

16.

Seizures,hypoxic-ischemic brain injury,and intraventricular hemorrhage in the newborn     

Alan Hill  Joseph J. Volpe 《Annals of neurology》1981,10(2):109-121

This review deals with neonatal seizures, perinatal hypoxic-ischemic brain injury, and neonatal intraventricular hemorrhage. Neonatal seizures are the most prominent signals of the largest number of neonatal neurological disorders. The convulsive phenomena may be subtle. The predominant etiological process is hypoxic-ischemic encephalopathy. Prognosis is related primarily to the neurological disease responsible for the seizures. Treatment may be specific for the underlying disorder (e.g., glucose or calcium) or less specific (i.e., therapy with anticonvulsant drugs). Prompt control of the seizures is important to avoid brain injury secondary to the effects of the seizures on ventilation, perfusion, and brain metabolism. Hypoxic-ischemic encephalopathy in the newborn most often is a consequece of intrauterine asphyxia. Diagnosis depends primarily on recognition of the clinical syndrome but also on a variety of neurodiagnostic techniques, including radionuclide and CT brain scans. Prognosis is estimated best by a combination of clinical analysis and specialized neurodiagnostic studies. Management is based principally on vigorous support, particularly of ventilation and perfusion, maintenance of adequate glucose influx, and control of seizures. Intraventricular hemorrhage is the most common type of neonatal intracranial hemorrhage. The neuropathology is characterized by bleeding from capillaries of the subependymal germinal matrix. Secondary rupture of the ependymal lining then causes intraventricular hemorrhage. Pathogenesis relates to the anatomy of the germinal matrix, the distribution and regulation of cerebral blood flow, and the structure and vulnerability of periventricular capilaries. Precise diagnosis requires a brain imaging procedure; portable, real-time ultrasound is the preferred approach for critically ill infants. Prognosis relates to the severity of the hemorrhage as well as any preceding hypoxic-ischemic insults and the subsequent occurrence of hydrocephalus. Choice of therapy for posthemorrhagic ventricular dilation depends upon severity and rapidity of progression and ranges from close observation only to ventriculoperitoneal shunting.     

17.

Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury     

West T  Atzeva M  Holtzman DM 《Developmental neuroscience》2007,29(4-5):363-372

A previous study from our lab has shown that the polyphenol-rich pomegranate juice can protect the neonatal mouse brain against hypoxic-ischemic (H-I) injury when given to mothers in their drinking water. To test the hypothesis that this protection is due to the polyphenols in the juice, we studied the effects of the pomegranate polyphenol extract in the same neonatal H-I model. To further explore the role of a specific polyphenol in neonatal H-I we investigated the effects of resveratrol. The neuroprotective effects of resveratrol have been demonstrated in adult models of stroke, but had not previously been examined in neonates. We show that pomegranate polyphenols and resveratrol reduce caspase-3 activation following neonatal H-I. Resveratrol reduced caspase-3 activation when given before the injury but not when given 3 h after the injury. In addition to preventing caspase-3 activation, resveratrol also reduced calpain activation. Finally, we show that resveratrol can protect against tissue loss measured at 7 days after the injury. These and other recent findings suggest that polyphenols should be further investigated as a potential treatment to decrease brain injury due to neonatal H-I.     

18.

神经干细胞移植治疗缺氧缺血性脑损伤的实验研究   总被引：23，自引：4，他引：19  

刘相名  杨立业  惠国桢  郭礼和 《中华神经外科杂志》2002,18(5):294-297

目的 研究神经干细胞移植治疗缺氧缺血性脑损伤的可行性。方法 取孕龄为12－16天的母鼠，从胎脑中分离神经细胞，进行培养、鉴定。用出生7天的SD大鼠的新生鼠制作缺氧缺血性脑损伤的动物模型，7天后接受神经干细胞移植（移植组，n＝16只），同时设置对照组，只注射磷酸缓冲液（对照组，n=8只），8－10周后，作Y迷宫实验检测大鼠的学习能力和记忆能力。取脑组织作免疫组织化学检查。结果 从大鼠胎脑中成功培养出神经干细胞，培养条件下呈悬浮状态生长，形成神经球，绝大多数的细胞表达神经干细胞的标志物神经巢蛋白（nestin）。接爱神经干细胞移植组大鼠的学习能力、记忆能力和对照组相比，有明显提高，差异具有显著性（P＜0.05）。接受神经干细胞移植大鼠组织中可见存活的移植细胞，并和宿主脑组织融合在一起。结论 在体外培养条件下，可从胎脑组织中培养出神经干细胞，移植到缺氧缺血性脑损伤大鼠脑内后，细胞与宿主的脑组织融合在一起，动物的学习、记忆能力有改善。移植神经干细胞是治疗缺氧缺知性脑损伤的有效方法之一。     

19.

alpha-Phenyl-n-tert-butyl-nitrone attenuates hypoxic-ischemic white matter injury in the neonatal rat brain   总被引：4，自引：0，他引：4  

Lin S  Rhodes PG  Lei M  Zhang F  Cai Z 《Brain research》2004,1007(1-2):132-141

White matter of the neonatal brain is highly sensitive to hypoxic-ischemic insult. The susceptibility of premature oligodendrocytes (OLs) to free radicals (FRs) produced during hypoxia-ischemia (HI) has been proposed as one of the mechanisms involved. To test this hypothesis, and to further investigate if the FR scavenger alpha-phenyl-N-tert-butyl-nitrone (PBN) attenuates hypoxic-ischemic white matter damage (WMD), postnatal day 4 (P4) SD rats were subjected to bilateral common carotid artery ligation (BCAL), followed by 8% oxygen exposure for 20 min. Pathological changes were evaluated on P6 and P9, 2 and 5 days after the HI insult. HI caused severe WMD including rarefaction, necrosis and cavity formation in the corpus callosum, external and internal capsule areas. OL injury was evidenced by degeneration of O4 positive OLs on P6. Disrupted myelination was verified by decreased immunostaining of myelin basic protein (MBP) on P9. Axonal injury was demonstrated by increased amyloid precursor protein (APP) immunostaining on both P6 and P9. Two lipid peroxidation end products, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), showed a one-fold elevation within 1-24 h following HI. 4-HNE immunostaining was found to specifically localize in the white matter area. Furthermore, pyknotic O4+ OLs were double-labeled with 4-HNE. These findings suggest that FRs are involved in the pathogenesis of neonatal WMD. PBN (100 mg/kg, i.p.) treatment alleviated the pathological changes of WMD following HI. It improved the survival of O4 positive OLs, attenuated hypomyelination and reduced axonal damage. PBN treatment also decreased the brain concentration of MDA/4-HNE and positive 4-HNE staining in the white matter area. These findings indicate that in the current WMD model, PBN protects both OLs and axons, the two main components in the white matter, from neonatal HI insult. FR scavenging appears to be the primary mechanism underlying its neuroprotective effect.     

20.

Neurotransmitter alterations in a model of perinatal hypoxic-ischemic brain injury   总被引：11，自引：0，他引：11  

M V Johnston 《Annals of neurology》1983,13(5):511-518

Vulnerability of neurotransmitter-specific neurons to hypoxia-ischemia was examined in the immature rat corpus striatum. Carotid artery ligation plus 2 hours of 8% oxygen atmosphere at 1 week of age produced ipsilateral striatal injury and reduced hemisphere mass 2 and 6 weeks later. Striatal injury was always more severe than damage to overlying cortex. Over half the animals had status marmoratus, a neuropathological change seen in the basal ganglia and thalamus after hypoxic-ischemic injury in full-term human infants. Two weeks after the insult, markers for cholinergic, dopaminergic, and gamma-aminobutyric acid-containing neurons were all reduced, but the reduction in cholinergic markers was greater than that for the other two transmitters. Muscarinic cholinergic receptors were relatively preserved, but their distribution was disrupted. In adult animals specific activity of cholinergic neuronal markers was normal, suggesting that the balance of neurotransmitters was restored after the early insult.     

N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury

OBJECTIVE: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model. METHODS: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI. RESULTS: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation. INTERPRETATION: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.     

Plasticity and injury in the developing brain

The child's brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity-dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders.     

Repeat traumatic brain injury in the developing brain

The Center for Disease Control estimates that there are 1.7 million brain injuries in the US each year with 51% of these injuries occurring during periods of cerebral development. Among this population there is a growing population of individuals with repeat traumatic brain injury (RTBI). While the exact incidence is unknown, estimates range from 5.6 to 36% of the TBI population. This review summarizes the clinical problems/challenges and experimental research models that currently exist. It is intended to reveal the critical areas that need to be addressed so that age-relevant clinical management guidelines can be established to protect this population.     

Xuefuzhuyu decoction and astragalus prevent hypoxic-ischemic brain injury

Hypoxic-ischemic brain injury models were generated by bilateral carotid artery ligation in Sprague-Dawley rats. Successful models were treated with a combination of Xuefuzhuyu decoction and 10g of astragalus. The experimental results showed that neuronal morphology and structure recovered, nerve growth factor mRNA expression increased in brain tissues, and neurological function signifi-cantly improved. There was no significant difference in these measures compared with rats treated with Xuefuzhuyu decoctio...     

Quantitative EEG reactivity and machine learning for prognostication in hypoxic-ischemic brain injury

ObjectiveElectroencephalogram (EEG) reactivity is a robust predictor of neurological recovery after cardiac arrest, however interrater-agreement among electroencephalographers is limited. We sought to evaluate the performance of machine learning methods using EEG reactivity data to predict good long-term outcomes in hypoxic-ischemic brain injury.MethodsWe retrospectively reviewed clinical and EEG data of comatose cardiac arrest subjects. Electroencephalogram reactivity was tested within 72 h from cardiac arrest using sound and pain stimuli. A Quantitative EEG (QEEG) reactivity method evaluated changes in QEEG features (EEG spectra, entropy, and frequency features) during the 10 s before and after each stimulation. Good outcome was defined as Cerebral Performance Category of 1–2 at six months. Performance of a random forest classifier was compared against a penalized general linear model (GLM) and expert electroencephalographer review.ResultsFifty subjects were included and sixteen (32%) had good outcome. Both QEEG reactivity methods had comparable performance to expert EEG reactivity assessment for good outcome prediction (mean AUC 0.8 for random forest vs. 0.69 for GLM vs. 0.69 for expert review, respectively; p non-significant).ConclusionsMachine-learning models utilizing quantitative EEG reactivity data can predict long-term outcome after cardiac arrest.SignificanceA quantitative approach to EEG reactivity assessment may support prognostication in cardiac arrest.     

Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury

Perinatal complications, such as asphyxia, can cause brain injuries that are often associated with subsequent neurological deficits, such as cerebral palsy or mental retardation. The mechanisms of perinatal brain injury are not fully understood, but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion. Among these proteins, apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia, but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury. In this review, we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy, specifically on the importance of apoptosis-inducing factor. The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality, especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress, acting as a free radical scavenger. We also discuss all the different apoptosis-inducing factor isoforms discovered, focusing especially on apoptosis-inducing factor 2, which is only expressed in the brain and the functions of which are starting now to be clarified. Finally, we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions(prosurvival and pro-apoptotic) and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.     

Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury

Hypoxic-ischemic brain injury in the perinatal period is a major cause of morbidity and mortality. Presently, there are no proven effective therapies with which to safeguard the human neonatal brain against this type of injury. Minocycline, a semisynthetic tetracycline, has been shown to be neuroprotective in certain adult ischemic injury/stroke and neurodegenerative disease models. However, minocycline's neuroprotective effects have not been assessed after insults to the neonatal brain. We now report that minocycline administered either immediately before or immediately after a hypoxic-ischemic insult substantially blocks tissue damage in a rodent model of neonatal hypoxic-ischemic brain injury. Minocycline treatment prevents the formation of activated caspase-3, a known effector of apoptosis, as well as the appearance of a calpain cleaved substrate, a marker of excitotoxic/necrotic cell death. To our knowledge, this is the first report of a systemic treatment that can be administered after a hypoxic-ischemic insult, which provides robust, nearly complete neuroprotection to the developing brain. Our data suggest that minocycline or a related neuroprotective tetracycline may be a candidate to consider in human clinical trials to protect the developing brain against hypoxic-ischemic-induced damage.     

Mechanisms of injury in hypoxic-ischemic encephalopathy: implications to therapy

Cardiac arrest survivors commonly suffer ischemic brain injury, and understanding the mechanisms of injury is essential to providing insight for effective therapies for brain protection. Injury can occur at the time of the cardiac arrest and is dependent not only on the duration but also the degree of impaired circulation. Injury can be ongoing even after the return of spontaneous circulation, giving the clinician an additional window of opportunity to treat and protect the injured brain. This section will review the molecular basis of injury with cardiac arrest and will elucidate the different mechanisms of injury between cardiac arrest, pure respiratory arrest, and arrest secondary to toxins (e.g., carbon monoxide). The rationale for multiple postarrest therapies, such as hypothermia and induced hypertension, will also be reviewed.     

Progesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature rats

Progesterone and its metabolite, allopregnanolone, are neurosteroids that are present at high concentrations in fetal brains that decrease right after birth. Allopregnanolone is a potent positive modulator of γ-aminobutyric acid A (GABA(A)) receptor function. We examined the effect of exogenous administration of these steroids on hypoxic-ischemic encephalopathy in immature rats. Progesterone (10mg/kg), allopregnanolone (10mg/kg), or vehicle alone was intraperitoneally administered immediately before and then subcutaneously 6h and 24h after hypoxia-ischemia to postnatal day 7 (P7), day 14 (P14), and day 21 (P21) rats. The effects of the treatments were evaluated using histological analyses (hemispheric volumes and semi-quantitative scoring for neuropathologic injury). Both progesterone and allopregnanolone significantly exacerbated brain injury in P7 and P14 rats, but not in P21 rats. This detrimental effect was similar across the examined brain regions (the cortex, striatum, hippocampus, and thalamus) and showed no sex differences. Co-administration of the GABA(A) receptor antagonist, bicuculline, partially mitigated the exacerbating effect of allopregnanolone. Based on the similarity of the effects of these neurosteroids, we speculate that progesterone accentuates neuronal injury mainly via the activity of allopregnanolone. The present study indicates that the detrimental effects of allopregnanolone were, at least in part, mediated via GABAergic neuroexcitability. This is in line with the notion that GABA is excitatory for immature neurons, while it is inhibitory for mature neurons.     

Phenobarbital modifies seizure-related brain injury in the developing brain

To investigate the potential role of drug therapy in preventing or exacerbating seizure-related brain injury in the prepubescent brain, we administered kainic acid to rats at postnatal day 35. Therapy with daily phenobarbital was started directly before or 1 day after kainic acid was administered, and was continued through postnatal day 153. Rats receiving phenobarbital had therapeutic concentrations during most of the 24-hour dosing period, but also experienced supratherapeutic peak concentrations. The animals were subsequently tested using the water maze (a measure of visuospatial memory), open field (a measure of activity level), and handling tests (a measure of emotionality). The frequency of spontaneous recurrent seizures was monitored during and after phenobarbital therapy. Kainic acid resulted in status epilepticus on postnatal day 35 in all the rats that received it but those receiving phenobarbital first manifested a shorter and less severe status epilepticus as compared to the rats given kainic acid alone. Rats starting phenobarbital immediately before kainic acid was administered did not differ from control rats on behavioral testing and had no subsequent spontaneous recurrent seizures and no histological lesions. Rats receiving kainic acid alone performed significantly poorer than did control rats in the water maze, were more aggressive, had histological lesions, and manifested spontaneous recurrent seizures. As compared to the group treated only with kainic acid, rats receiving kainic acid followed by phenobarbital at postnatal days 36 to 153 manifested similar aggressiveness and histological lesions, similar frequency of spontaneous recurrent seizures after phenobarbital taper, and even greater disturbances in memory, learning, and activity level. These results demonstrate that kainic acid–related injury can be prevented by a medication working through inhibitory mechanisms; that structural and functional damage in the prepubescent brain can be prevented through strategically timed pharmacotherapy; and that treatment of spontaneous recurrent seizures alone with daily exposure to phenobarbital does not decrease, and may actually exacerbate, damage in the kainic acid model.     

Seizures,hypoxic-ischemic brain injury,and intraventricular hemorrhage in the newborn

This review deals with neonatal seizures, perinatal hypoxic-ischemic brain injury, and neonatal intraventricular hemorrhage. Neonatal seizures are the most prominent signals of the largest number of neonatal neurological disorders. The convulsive phenomena may be subtle. The predominant etiological process is hypoxic-ischemic encephalopathy. Prognosis is related primarily to the neurological disease responsible for the seizures. Treatment may be specific for the underlying disorder (e.g., glucose or calcium) or less specific (i.e., therapy with anticonvulsant drugs). Prompt control of the seizures is important to avoid brain injury secondary to the effects of the seizures on ventilation, perfusion, and brain metabolism. Hypoxic-ischemic encephalopathy in the newborn most often is a consequece of intrauterine asphyxia. Diagnosis depends primarily on recognition of the clinical syndrome but also on a variety of neurodiagnostic techniques, including radionuclide and CT brain scans. Prognosis is estimated best by a combination of clinical analysis and specialized neurodiagnostic studies. Management is based principally on vigorous support, particularly of ventilation and perfusion, maintenance of adequate glucose influx, and control of seizures. Intraventricular hemorrhage is the most common type of neonatal intracranial hemorrhage. The neuropathology is characterized by bleeding from capillaries of the subependymal germinal matrix. Secondary rupture of the ependymal lining then causes intraventricular hemorrhage. Pathogenesis relates to the anatomy of the germinal matrix, the distribution and regulation of cerebral blood flow, and the structure and vulnerability of periventricular capilaries. Precise diagnosis requires a brain imaging procedure; portable, real-time ultrasound is the preferred approach for critically ill infants. Prognosis relates to the severity of the hemorrhage as well as any preceding hypoxic-ischemic insults and the subsequent occurrence of hydrocephalus. Choice of therapy for posthemorrhagic ventricular dilation depends upon severity and rapidity of progression and ranges from close observation only to ventriculoperitoneal shunting.     

Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury

A previous study from our lab has shown that the polyphenol-rich pomegranate juice can protect the neonatal mouse brain against hypoxic-ischemic (H-I) injury when given to mothers in their drinking water. To test the hypothesis that this protection is due to the polyphenols in the juice, we studied the effects of the pomegranate polyphenol extract in the same neonatal H-I model. To further explore the role of a specific polyphenol in neonatal H-I we investigated the effects of resveratrol. The neuroprotective effects of resveratrol have been demonstrated in adult models of stroke, but had not previously been examined in neonates. We show that pomegranate polyphenols and resveratrol reduce caspase-3 activation following neonatal H-I. Resveratrol reduced caspase-3 activation when given before the injury but not when given 3 h after the injury. In addition to preventing caspase-3 activation, resveratrol also reduced calpain activation. Finally, we show that resveratrol can protect against tissue loss measured at 7 days after the injury. These and other recent findings suggest that polyphenols should be further investigated as a potential treatment to decrease brain injury due to neonatal H-I.     

神经干细胞移植治疗缺氧缺血性脑损伤的实验研究

目的 研究神经干细胞移植治疗缺氧缺血性脑损伤的可行性。方法 取孕龄为12－16天的母鼠，从胎脑中分离神经细胞，进行培养、鉴定。用出生7天的SD大鼠的新生鼠制作缺氧缺血性脑损伤的动物模型，7天后接受神经干细胞移植（移植组，n＝16只），同时设置对照组，只注射磷酸缓冲液（对照组，n=8只），8－10周后，作Y迷宫实验检测大鼠的学习能力和记忆能力。取脑组织作免疫组织化学检查。结果 从大鼠胎脑中成功培养出神经干细胞，培养条件下呈悬浮状态生长，形成神经球，绝大多数的细胞表达神经干细胞的标志物神经巢蛋白（nestin）。接爱神经干细胞移植组大鼠的学习能力、记忆能力和对照组相比，有明显提高，差异具有显著性（P＜0.05）。接受神经干细胞移植大鼠组织中可见存活的移植细胞，并和宿主脑组织融合在一起。结论 在体外培养条件下，可从胎脑组织中培养出神经干细胞，移植到缺氧缺血性脑损伤大鼠脑内后，细胞与宿主的脑组织融合在一起，动物的学习、记忆能力有改善。移植神经干细胞是治疗缺氧缺知性脑损伤的有效方法之一。     

alpha-Phenyl-n-tert-butyl-nitrone attenuates hypoxic-ischemic white matter injury in the neonatal rat brain

White matter of the neonatal brain is highly sensitive to hypoxic-ischemic insult. The susceptibility of premature oligodendrocytes (OLs) to free radicals (FRs) produced during hypoxia-ischemia (HI) has been proposed as one of the mechanisms involved. To test this hypothesis, and to further investigate if the FR scavenger alpha-phenyl-N-tert-butyl-nitrone (PBN) attenuates hypoxic-ischemic white matter damage (WMD), postnatal day 4 (P4) SD rats were subjected to bilateral common carotid artery ligation (BCAL), followed by 8% oxygen exposure for 20 min. Pathological changes were evaluated on P6 and P9, 2 and 5 days after the HI insult. HI caused severe WMD including rarefaction, necrosis and cavity formation in the corpus callosum, external and internal capsule areas. OL injury was evidenced by degeneration of O4 positive OLs on P6. Disrupted myelination was verified by decreased immunostaining of myelin basic protein (MBP) on P9. Axonal injury was demonstrated by increased amyloid precursor protein (APP) immunostaining on both P6 and P9. Two lipid peroxidation end products, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), showed a one-fold elevation within 1-24 h following HI. 4-HNE immunostaining was found to specifically localize in the white matter area. Furthermore, pyknotic O4+ OLs were double-labeled with 4-HNE. These findings suggest that FRs are involved in the pathogenesis of neonatal WMD. PBN (100 mg/kg, i.p.) treatment alleviated the pathological changes of WMD following HI. It improved the survival of O4 positive OLs, attenuated hypomyelination and reduced axonal damage. PBN treatment also decreased the brain concentration of MDA/4-HNE and positive 4-HNE staining in the white matter area. These findings indicate that in the current WMD model, PBN protects both OLs and axons, the two main components in the white matter, from neonatal HI insult. FR scavenging appears to be the primary mechanism underlying its neuroprotective effect.     

Neurotransmitter alterations in a model of perinatal hypoxic-ischemic brain injury

Vulnerability of neurotransmitter-specific neurons to hypoxia-ischemia was examined in the immature rat corpus striatum. Carotid artery ligation plus 2 hours of 8% oxygen atmosphere at 1 week of age produced ipsilateral striatal injury and reduced hemisphere mass 2 and 6 weeks later. Striatal injury was always more severe than damage to overlying cortex. Over half the animals had status marmoratus, a neuropathological change seen in the basal ganglia and thalamus after hypoxic-ischemic injury in full-term human infants. Two weeks after the insult, markers for cholinergic, dopaminergic, and gamma-aminobutyric acid-containing neurons were all reduced, but the reduction in cholinergic markers was greater than that for the other two transmitters. Muscarinic cholinergic receptors were relatively preserved, but their distribution was disrupted. In adult animals specific activity of cholinergic neuronal markers was normal, suggesting that the balance of neurotransmitters was restored after the early insult.