神经节苷脂GM1对缺血缺氧后脑中HSP70表达的影响

目的 研究神经节苷脂GM1对新生鼠缺血缺氧性脑损伤的保护作用及HSP70表达的影响。方法 建立新生鼠缺氧缺血性脑病动物模型,应用组织化学和免疫组织化学法观察缺血缺氧后3h、6h、1d、3d、7d、14d脑组织的病理变化及HSP70的表达,以及GM1给药后的变化。结果 单纯缺血缺氧组,在缺血缺氧后3h缺血侧皮层、海马CA3区、纹状体开始有少量HSP70表达,24h达高峰,14d未见HS70表达;GM1给药组,脑组织损伤明显减轻,6h才开始有少量HSP70表达,7d未见有表达。结论 GM1对新生鼠缺血缺氧性脑损伤具有明显的保护作用;HSP70的诱导表达是缺血缺氧性脑损伤敏感而可靠的指标,GM1可抑制这种表达。     

Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects

Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O(2) resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl-2-associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle-associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle-specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase-3, and caspase-12. When HI-treated P7 rats were resuscitated with 100% O(2) (HHI), there were increased lesion volumes as determined by T2-weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic-cleaved interleukin-1beta) and necrotic (increased nuclear 55-kDa-cleaved PARP-1 [poly-ADP-ribose 1] and decreased nuclear HMGB1 [nuclear high-mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O(2) resuscitation increases Bax-mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic-like cell death. In light of these findings, the use of 100% O(2) treatment for neonatal HI should be reevaluated.     

新生大鼠缺氧缺血脑损伤后bcl-x mRNA的表达

目的　探讨新生大鼠脑缺氧缺血后死亡相关基因 bcl- x m RNA表达的变化及其与脑缺氧缺血所致细胞凋亡的关系。方法　通过建立新生大鼠缺氧缺血性脑病动物模型 ,应用快速竞争性 RT- PCR技术对缺氧缺血后不同时间点的缺血侧大脑组织中 bcl- x m RNA的表达进行半定量分析 ,并在相同缺血基础上观察缺氧 1.5小时、2 .5小时和 3.5小时对 bcl- x m RNA表达的影响。结果　缺氧缺血后 ,新生大鼠脑 bcl- xs(bcl-x短型 ) m RNA的表达自缺氧结束后即刻即有明显增强 ,2 4小时达高峰 ,此后逐渐下降 ,7天时回复至正常基线水平。随着缺氧时间的延长即缺氧程度的加重 ,bcl- xs m RNA的表达有增强趋势 ,缺氧 1.5小时组、2 .5小时组及 3.5小时组之间 bcl- xs m RNA表达水平的差异均具显著性意义 (P<0 .0 1)。bcl- xs m RNA的表达高峰与缺氧缺血后脑细胞凋亡的高峰时相相吻合。缺氧缺血对 bcl- xl(bcl- x长型 ) m RNA的表达无影响。结论缺氧缺血可诱导新生大鼠脑 bcl- xs m RNA表达增强。在一定范围内 ,其表达强度与缺氧程度成正相关。 bcl-xs过表达在缺氧缺血后脑细胞凋亡的调控过程中起着一定的作用     

Transgenerational transmission of anxiety induced by neonatal exposure to lipopolysaccharide: implications for male and female germ lines

Neonatal lipopolysaccharide (LPS) exposure increases anxiety-like behaviour and alters neuroendocrine responses to stress in adult rats. The current study assessed whether this anxiety-related phenotype observed in rats neonatally exposed to LPS is transferable to subsequent generations. Wistar rats were exposed to LPS (0.05 mg/kg, Salmonella enteritidis) or non-pyrogenic saline (equivolume) on postnatal days 3 and 5. In adulthood, animals were subjected to restraint and isolation stress or no stress, and subsequently evaluated for anxiety-like behaviours on the elevated plus maze, acoustic startle response, and holeboard apparatus. Blood was collected to examine corticosterone responses to stress and behavioural testing in adulthood. Animals from both treatment groups which exhibited the anxiety-like phenotype were bred with untreated partners. Maternal care of the second generation (F2) was monitored over the first week of life. In adulthood, the F2 generation underwent identical testing procedures as the parental (F1) generation. The F2 offspring of females exposed to LPS as neonates exhibited an anxiety-like phenotype in adulthood and a potentiated corticosterone response to stress (p<.05). F2 offspring of males exposed to LPS as neonates also exhibited an anxiety-like phenotype (p<.05), however, no differences in corticosterone responses were observed. To determine the impact of maternal care on the anxiety-like phenotype, a cross-fostering study was conducted in which offspring of LPS-treated females were fostered to saline-treated mothers and vice versa, which was found to reverse the behavioural and endocrine phenotypes of the F2 generation. These data indicate that a neonatally bacterially induced anxiety phenotype is transferable across generations in both sexes. Maternal care is the mediating mechanism along the maternal line. We suggest that transmission may be dependent upon heritable epigenetic phenomena for the paternal line. The implications of this study apply to potential neuroimmune pathways through which psychopathology may be transmitted along filial lines.     

Biopterin in the acute phase of hypoxia-ischemia in a neonatal pig model

To clarify the participation of inducible NOS (iNOS) in the hypoxia-ischemia, we examined iNOS and its tetrahydrobiopterin co-factor in the cerebral cortex and plasma in a newborn-piglet model. We also investigated the role of hypothermia in iNOS expression and biopterin production. Male newborn piglets were ventilated 6% oxygen for 45 min. Their common carotid arteries were clamped during hypoxia. Then they were resuscitated with 30% oxygen (HI group). Piglets of the hypothermia group were treated as the HI group and their body was cooled to 35.5 degrees C after hypoxic-ischemic insults. Sham-treated piglets were also reserved. In the HI group, iNOS was present in neurons and macrophages of the cerebral cortex 12h after the insult. The concentrations of nitrite and nitrate were elevated in the cerebral cortex 12h after hypoxic-ischemic insults but the biopterin level was unchanged. The plasma biopterin concentration after the insult (377.9+/-78.7 nM) was five times higher than before the insult (80.1+/-4.3 nM); this level peaked 4h after the insult (604.8+/-200.9 nM) and only slightly decreased after 12h (445.9+/-57.8 nM). In the hypothermia group, no iNOS expression was observed 12h after the insult. The plasma biopterin concentration after the insult (464.2+/-92.3 nM) was similar to that in the HI group, but was suppressed by 4h of hypothermia (229.3+/-106.8 nM). In this study, neuronal iNOS expression and increase of NO production were found in the acute phase of hypoxia-ischemia. Brain biopterin did not increase in hypoxia-ischemia although plasma biopterin was five-fold elevated. The discrepancy may also affect hypoxic-ischemic organ damage.     

Talampanel suppresses the acute and chronic effects of seizures in a rodent neonatal seizure model

Purpose: To test the efficacy of the novel candidate anticonvulsant talampanel (GYKI 53773) in a rodent model of hypoxic neonatal seizures. Talampanel is a noncompetitive antagonist of the alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid subtype of the glutamate receptor (AMPAR). We have previously shown that AMPARs play a critical role in the generation of acute seizures and later‐life seizure susceptibility in this model of neonatal seizures. Methods: Seizures were induced in postnatal day (P) 10 Long‐Evans rat pups by a 15 min exposure to global hypoxia. Acute seizure activity at P10 and subsequent susceptibility to seizure‐induced neuronal injury with a “second‐hit” kainate‐induced seizure at P30–31 were compared between animals receiving talampanel (1, 5, 7.5, or 10 mg/kg) intraperitoneally (i.p.) versus saline vehicle treatment. Results: Talampanel treatment suppressed seizures in a dose‐dependent manner, with maximal effect at 7.5 and 10 mg/kg. In addition, talampanel treatment 30 min before hypoxia prevented later‐life increases in seizure‐induced neuronal injury as assessed by in situ DNA nick end‐labeling (ISEL). Discussion: We have previously demonstrated efficacy of other AMPAR antagonists such as NBQX and topiramate in this model. The present finding shows that the novel agent talampanel, under evaluation as an antiepileptic drug in children and adults, may have clinical potential in the treatment of neonatal seizures, particularly those occurring in the context of hypoxic encephalopathy.     

Differential activation of c-fos and caspase-3 in hippocampal neuron subpopulations following neonatal hypoxia-ischemia

Neonatal hypoxia-ischemia (HI) induces immediate early gene (IEG) c-fos expression as well as neuron death. The precise role of IEGs in neonatal HI is unclear. We investigated the temporal and spatial patterns of c-Fos expression in postnatal day 7 mice after unilateral carotid ligation and exposure to 8% oxygen. mRNA levels of c-fos quantitated by real-time polymerase chain reaction (PCR) increased nearly 40-fold (log 1.2 +/- 0.4) in the ipsilateral hippocampus 3 hr following neonatal HI, then returned to basal levels within 12 hr, although no change was observed in c-jun mRNA. Frozen coronal brain sections were stained with cresyl violet or used for immunohistochemical detection of c-Fos, cleaved caspase-3, glial fibrillary acidic protein (GFAP), and the mature neuron marker NeuN. c-Fos immunoreactivity increased throughout the injured hippocampus 3 hr after HI but became restricted to the CA2-3 subregion and the dentate gyrus (DG) at 6-12 hr and declined by 24 hr. In contrast, cleaved (activated) caspase-3 immunoreactivity was most abundant in the ipsilateral CA1 region at 3-6 hr after neonatal HI, then became more prominent in CA2-3 and DG. Double-labeling experiments showed c-Fos and cleaved caspase-3 immunoreactivity localized in spatially distinct neuron subpopulations. Prominent c-Fos immunoreactivity was observed in surviving CA2-3 and external granular DG neurons, and robust cleaved caspase-3 immunoreactivity was observed in pyknotic CA1, CA2-3, and subgranular DG neurons. The differential expression of c-Fos in HI-resistant hippocampal subpopulations vs. cleaved caspase-3 in dying neurons suggests a neuroprotective role for c-Fos expression in neonatal HI.     

Post-ischemic hypothermia-induced tissue protection and diminished apoptosis after neonatal cerebral hypoxia-ischemia

Hypothermia is possibly the single most effective method of neuroprotection developed to date. However, the mechanisms are not completely understood. The aim of this study was to investigate the effects of post-ischemic hypothermia on brain injury and apoptotic neuronal cell death as well as related biochemical changes after neonatal hypoxia-ischemia (HI). Seven-day-old rats were subjected to left common carotid artery ligation and hypoxia (7.8%) for 1 h. Systemic hypothermia was induced immediately after hypoxia-ischemia, and body temperature was maintained at 30 degrees C for 10 h. The normothermic group was kept at 36 degrees C. Brain infarct volumes and neuronal loss in the CA1 area of the hippocampus were significantly reduced at 72 h post-HI in the hypothermia group. Cytochrome c release and activation of caspase-3 and -2 at 24 h post-HI were significantly diminished by hypothermia. The numbers of cytochrome c- and TUNEL-positive cells in the cortex and dentate gyrus of the hippocampus were significantly reduced in the hypothermia group compared with the normothermia group at 72 h post-HI. These results indicate that hypothermia may, at least partially, act through inhibition of the intrinsic pathway of caspase activation in the neonatal brain, thereby preventing apoptotic cell death.     

不同途径应用胰岛素样生长因子1对新生大鼠缺氧缺血性脑损伤的影响

目的 研究不同途径应用胰岛素样生长因子1（IGF-1）对新生大鼠缺氧缺血性脑损伤（HIBD）的影响。方法 40只新生大鼠分为4组：HIBD模型对照组（对照组）、静脉注射组、经鼻腔滴入组和假手术组：给药组于缺氧后分别给予尾静脉注射和经鼻腔滴入IGF-1 2．5μg（溶于生理盐水0．1ml中）;对照组于HIBD后给予等量的生理盐水尾静脉注射;假手术组仅分离颈总动脉,不结扎不缺氧。24h后处死取脑组织,免疫组化法观察脑组织caspase-3的表达,组织学方法观察脑组织病理改变情况。结果 与对照组相比,给药各组caspase-3表达减少（均P〈0．01）,神经细胞总数增加（均P〈0．01）,变性／坏死神经细胞数减少（均P〈0．01）,结论 静脉注射和鼻腔滴入IGF-1均可能通过降低HIBD脑组织中caspase-3表达,从而对HIBD脑组织损伤产生保护作用。     

Hemispheric side of damage influences sex-related differences in smoking cessation in neurological patients

Patterns of smoking behavior vary between the sexes. There is evidence that decision making, which is one of the key “executive functions” necessary for making life-style modifications such as smoking cessation, is relatively lateralized to the right hemisphere in males and left hemisphere in females. In the current study, we examined whether the side of brain lesion has a differential effect on smoking behavior between the sexes. We hypothesized sex differences in smoking cessation based on lesion side. Participants were 49 males and 50 females who were smoking at the time of lesion onset. The outcome variable was abstinence from smoking (quit rate) at least one year post lesion. We found that in patients with left-hemisphere damage, quit rates were significantly higher in males than in females; however, in patients with right-hemisphere damage, quit rates were not statistically different. The findings support previous cognitive neuroscience literature showing that components of behavior responsible for maintaining addiction tend to be more strongly lateralized in males, whereas in females there is a more bilateral distribution. Our study provides further evidence for differences in lateralization of complex behavior between the sexes, which has significant implications for differences in treatment strategies between the sexes.     

Sex differences in brain MRI abnormalities and neurodevelopmental outcomes in a rat model of neonatal hypoxia-ischemia

Purpose/aim of the study: Hypoxic-ischemic brain injury (HIBI) is associated with high mortality and neurodevelopmental deficits. We explored gender influence in a HIBI rat model. Materials and methods: Sprague–Dawley rats underwent HIBI on postnatal day (P) 7. Nervous reflexes, footprints, Morris water maze performances and magnetic resonance imaging (MRI) were analyzed. Results: Mortality rate was higher in HIBI males (20%) than in females (12.5%). Growth rate was slower in the HIBI group (p < 0.05), but was similar between HIBI males and females. HIBI rats showed impaired performances in the cliff aversion reflex, negative geotaxis reflex and gait tests at P14 (p < 0.05), but not at P9 or P11. There were no significant differences for the cliff aversion reflex and gait tests between genders. Negative geotaxis reflex impairment at P14 was more severe in HIBI males (p < 0.05). Step length and toe distance contralateral (but not ipsilateral) to the cerebral damage were shorter in HIBI rats, and were shorter in HIBI males than females (p < 0.05). Morris water maze latency time and swimming distance were longer in the HI group than in controls, and prolonged in HIBI males compared with females (p < 0.05). In the HIBI group, MRI showed more severe injury at P10 and P67 in males than in females (p < 0.05). Conclusions: Male rats are more vulnerable to the detrimental consequences of HIBI, with more severe nervous reflex deficits, brain injury, memory impairment and hemiplegic paralysis than female rats. Serial neurobehavioral follow-up is still executed on the HIBI infants who is absent of detectable abnormalities in early children.     

Neuroprotective effects of L-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats.

Kynurenic acid is the only known endogenous excitatory amino acid receptor antagonist in the central nervous system. In the present study, we examined whether increasing brain concentrations of kynurenic acid by loading with its precursor L-kynurenine, or blocking its excretion with probenecid, could exert neuroprotective effects. Neuroprotective effects were examined in a neonatal model of hypoxia-ischemia, and following intrastriatal injection of N-methyl-D-aspartate (NMDA). Seven-day-old rats underwent unilateral ligation of the carotid artery, followed by exposure to 8% oxygen for 1.5 h. L-kynurenine administered 1 h before the hypoxia-ischemia showed a dose-dependent significant neuroprotective effect, with complete protection at a dose of 300 mg kg-1. The induction of c-fos immunoreactivity in cerebral cortex was also blocked by this dose of L-kynurenine. Probenecid alone had moderate neuroprotective effects, while a combination of a low dose of probenecid with doses of 50-200 mg kg-1 of L-kynurenine showed significant dose-dependent neuroprotection. Kynurenine dose-dependently protected against NMDA neurotoxicity in 7-day-old rats. Neurochemical analysis confirmed that L-kynurenine with or without probenecid markedly increased concentrations of kynurenic acid in cerebral cortex of 7-day-old rats. These results show for the first time that pharmacologic manipulation of endogenous concentrations of kynurenic acid can exert neuroprotective effects.     

Huperzine A attenuates cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia

The protective effects of huperzine A, a novel acetylcholinesterase inhibitor, on hypoxic-ischemic (HI) brain injury were investigated in neonatal rats. A unilateral HI brain injury was produced by the ligation of left common carotid artery followed by 1 h hypoxia with 7.7% oxygen in 7-day-old rat pups. After 5 weeks, HI brain injury in rat pups resulted in working memory impairments shown by increased escape latency in a water maze and reduced time spent in the target quadrant. The combination of common carotid artery ligation and exposure to a hypoxic environment caused the damage in the striatum, cortex, and hippocampus in the ipsilateral hemisphere, and the neuronal loss in the CA1 region. Huperzine A was administrated daily at the dose of 0.05 or 0.1 mg/kg i.p. for 5 weeks after HI injury. The significant protection against HI injury on behavior and neuropathology was produced by huperzine A at the dose of 0.1 mg/kg. These findings suggest that huperzine A might be beneficial in the treatment of hypoxic-ischemic encephalopathy in neonates.     

Selective sparing of NADPH-diaphorase neurons in neonatal hypoxia-ischemia

Excitatory amino acids have been implicated in ischemic neuronal injury. To test this hypothesis in neonatal hypoxia-ischemia, lesions of the cortex and striatum were induced in 7-day-old rats by unilaterally ligating their carotid arteries and subjecting them to hypoxic conditions for 2 hours. Brains examined 1 week later demonstrated, within the regions of ischemic damage, a striking preservation of neurons that stained histochemically for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity. Concentrations of the neuropeptides somatostatin and neuropeptide Y, which colocalize in neurons containing NADPH-d, were unaffected in the areas of ischemic damage. The same pattern of injury with sparing of NADPH-d-reactive neurons was reproduced by focal microinfusion of the excitotoxin quinolinic acid, an endogenous N-methyl-d-aspartate (NMDA) agonist, into the striatum. These results support the hypothesis that neonatal hypoxic-ischemic injury is mediated through excitatory transmitters acting at the NMDA receptor and that the NADPH-d-reactive neurons in the neonate are resistant to excitotoxic damage. This pattern of cell vulnerability is unique to the developing striatum and may relate to the distinct pathological appearance of the basal ganglia that follows neonatal asphyxia.     

Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats. Alterations in the biogenic amine contents of the adult brain

Biogenic amines (norepinephrine, dopamine, homovanillic acid, serotonin and 5-hyroxyindole acetic acid) were measured by HPLC method in adult F1 generation rats’ brain regions (brainstem, hypothalamus, hippocampus, striatum and frontal cortex), whose mothers (P generation) were treated with vitamin A or vitamin D neonatally (hormonal imprinting). Many significant differences were found, related to the maternally untreated controls. In the earlier studied P generation females, vitamin A consistently influenced the serotonerg system (5HIAA), while vitamin D the dopaminerg system (DA or HVA). Vitamin A imprinting always resulted in reduced, while that by vitamin D always in increased tissue levels. In the present case (directly untreated F1 generation) the transgenerational effect was not unidirectional, however biogenic amine tissue levels were strongly disturbed and brain-area dependent. The results call attention to the transgenerational effect of hormonal imprinting in the case of receptor level acting vitamins which are frequently used in the most imprinting-sensitive period (perinatally) of human life and suggests that caution is warranted.     

Determinants of quality of life in people with epilepsy and their gender differences

Improving the patient's quality of life (QOL) is the most important goal of epilepsy management. We performed this study to determine the factors associated with QOL in people with epilepsy and to assess whether there are gender differences in these determinants. Patients were interviewed using the Quality of Life in Epilepsy Inventory-31(QOLIE-31), the Adverse Event Profile (AEP), the Self-Rating Anxiety Scale (SAS), and the Hamilton Depression Rating Scale (HAMD). Two hundred forty-seven patients (152 men, 95 women) were included in the analysis. Among all patients, regressive analyses showed that AEP score was the strongest predictor of the QOLIE-31 overall score, accounting for 10.4% of the variance. The next strongest predictors were the number of currently used antiepileptic drugs (AEDs) (3.6%), the HAMD score (2.5%), and the SAS score (1.2%). Importantly, there were gender differences in these predictors of QOL. The strongest predictors of the QOLIE-31 overall score in women were the AEP score and the number of AEDs. In contrast, the strongest predictors in men were the SAS score, the AEP score and the frequency of seizures. These results indicate that perceived adverse effects of treatments and number of AEDs exerted greater effects on QOL in women, whereas anxiety and seizure-related variables had a stronger impact on QOL among men. Accordingly, it may be necessary to individualize interventions to improve the QOL of people with epilepsy.     

Dexamethasone effects on cerebral protein synthesis prior to and following hypoxia-ischemia in immature rat

We hypothesized that the neuroprotection against cerebral hypoxic-ischemic damage observed with dexamethasone treatment in immature rats is related to a change in cerebral protein synthesis. Six-day-old Wistar rats were injected with either vehicle (10 ml/kg) or dexamethasone (0.1 mg/kg) 24 h prior to cerebral hypoxia-ischemia. Local cerebral protein synthesis (incorporation of 14C-leucine into proteins) was measured in 7-day-old rats during normoxia, during hypoxia-ischemia, and after hypoxia-ischemia which was produced with right carotid artery ligation and 2-h exposure to 8% O2. In normoxic controls, cerebral protein synthesis was similar in dexamethasone and vehicle-treated animals. During hypoxia-ischemia, local cerebral protein synthesis decreased markedly (p < 0.0001) in ischemic regions ipsilateral to the occlusion, irrespective of treatment. After hypoxia-ischemia, protein synthesis declined even further in vehicle-treated animals. Reductions in protein synthesis were substantially more severe in vehicle- than dexamethasone-treated animals, particularly after hypoxia-ischemia (p < 0.0001). Thus, neuroprotection with dexamethasone is not related to a reduction in basal levels of cerebral protein synthesis, but is associated with an improved protein synthesis during and following hypoxia-ischemia.     

Glial cell line-derived neurotrophic factor protects against ischemia/hypoxia-induced brain injury in neonatal rat

Ischemic/hypoxic brain damage induced in 7-day-old rats was significantly attenuated in a dose-dependent manner by intracerebral injection of glial cell line-derived neurotrophic factor (GDNF; 2 or 4 μg) within 30 min after the insult. Whereas the great majority of the vehicle-treated animals showed massive infarction involving more than 75% of the affected cerebral hemisphere, GDNF injection resulted in a remarkable reduction in both the incidence and severity of the brain damage (incidence ranging from 76% to 93% in controls to 34% to 64% in the 2.0-μg group and 7% to 29% in 4.0-μg group). The induction of immunoreactive 70-kDa heat shock protein (HSP70) in cerebral cortical neurons was also significantly reduced in GDNF-treated animals as compared to controls. The mechanisms responsible for the neuroprotective effects of GDNF remain unknown, although it has been speculated that these may be endogeneous. The higher expression of GDNF and its mRNA in developing brains may be one of the factors responsible for the relative resistance to ischemia of fetal and neonatal as opposed to adult brains. GDNF may possibly act by protecting against oxidative stress or by scavenging free radicals generated during ischemia. The results of our study strongly suggest that GDNF may prove to be an effective and potent protective agent against perinatal ischemic/hypoxic encephalopathy. Received: 13 July 1999 / Revised: 6 October 1999 / Accepted: 25 October 1999     

Adenosine deaminase activity,lipid peroxidation and astrocyte responses in the cerebral cortex of rats after neonatal hypoxia ischemia

Hypoxia ischemia (HI) is a common cause of damage in the fetal and neonatal brain. Lifelong disabilities such as cerebral palsy, epilepsy, behavioral and learning disorders are some of the consequences of brain injury acquired in the perinatal periods. Inflammation and formation of free radicals appear to play key roles in neonatal HI. The aim of this study was to describe the chronological sequence of adenosine deaminase (ADA) activity, the oxidative damage changes and astrocyte response using the classic model of neonatal HI. We observed an increase in the activity of ADA and lipid peroxidation in the cerebral cortex 8 days after neonatal HI. This was accompanied by a GFAP-positive, and the degree of brain damage was determined histochemically by hematoxylin–eosin (HE). Taking into account the important anti-inflammatory role of adenosine, ADA may provide an efficient means for scavenging cell-surrounding adenosine and play an important part in subsequent events of neonatal HI in association with GFAP reactive gliosis. The present investigation showed that neonatal HI causes the increase of free radicals and significant damage in the cerebral cortex. The increase in ADA activity may reflect the activation of the immune system caused by HI because the morphological analysis exhibited a lymphocytic infiltration.