Effects of neotrofin on neonatal hypoxic ischemic brain injury

Hypoxia-ischemia is a major cause of perinatal brain injury in the newborn. Neotrofin, a neurotrophin agonist, has been shown to provide neuroprotection in several in vivo and in vitro studies. The aim of this study is to investigate the neuroprotective and ameliorating effects of neotrofin treatment after hypoxic-ischemic-injury-induced neuronal cell death, apoptosis in a neonatal hypoxic-ischemic brain injury rat model. Twenty-one seven-day-old Wistar rat pups were used in this study. The groups were: (1) a neotrofin-treated hypoxic-ischemic-group, (2) a saline-treated hypoxic-ischemic-group, and (3) a sham-operated group. Rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. After the hypoxic exposure, group one received an intra-peritoneal injection of neotrofin at a dose of 60 mg/kg. Forty-eight hours after hypoxia, the animals were killed for histopathological evaluation to detect apoptosis and density of neurons. We found that neotrofin attenuates hypoxia-ischemia induced with neuronal density of the hippocampus, the prefrontal and the parietal cortex, and decreased apoptotic cell index in the same regions. Given our results, neotrofin may be useful in reducing brain injury; it possesses clinical relevance for the treatment of hypoxic-ischemic encephalopathy in the newborn.     

Alpha-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

Although white matter damage is a fundamental neuropathological feature of periventricular leukomalacia (PVL), the motor and cognitive deficits observed later in infants with PVL indicate the possible involvement of cerebral neuronal dysfunction. Using a previously developed rat model of white matter injury induced by cerebral lipopolysaccharide (LPS) injection, we investigated whether LPS exposure also results in neuronal injury in the neonatal brain and whether alpha-phenyl-n-tert-butyl-nitrone (PBN), an antioxidant, offers protection against LPS-induced neuronal injury. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in Sprague-Dawley rats (postnatal day 5) and control rats were injected with sterile saline. LPS exposure resulted in axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of beta-amyloid precursor protein, altered axonal length and width, and increased size of cortical neuronal nuclei. LPS exposure also caused loss of tyrosine hydroxylase positive neurons in the substantia nigra and the ventral tegmental areas of the rat brain. Treatments with PBN (100 mg/kg) significantly reduced LPS-induced neuronal and axonal damage. The protection of PBN was associated with an attenuation of oxidative stress induced by LPS as indicated by the reduced number of 4-hydroxynonenal, malondialdehyde or nitrotyrosine positive cells in the cortical area following LPS exposure, and with the reduction in microglial activation stimulated by LPS. The finding that an inflammatory environment may cause both white matter and neuronal injury in the neonatal brain supports the possible anatomical correlate for the intellectual deficits and the other cortical and deep gray neuronal dysfunctions associated with PVL. The protection of PBN may indicate the potential usefulness of antioxidants for treatment of these neuronal dysfunctions.     

Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain

Our previous studies have shown that intracerebral administration of endotoxin, lipopolysaccharide (LPS), induces selective white matter injury and hypomyelination in the neonatal rat brain and that the LPS-induced brain injury is associated with activation of microglia. To test the hypothesis that inhibition of microglial activation may protect against LPS-induced white matter injury, we examined roles of minocycline, a putative suppressor of microglial activation, on LPS-induced brain injury in the neonatal rat. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in postnatal day 5 Sprague-Dawley rats and control rats were injected with sterile saline. Minocycline (45 mg/kg) was administered intraperitoneally 12 h before and immediately after LPS injection and then every 24 h for 3 days. Inflammatory responses, activation of microglia and brain injury were examined 1 and 3 days after LPS injection. LPS injection resulted in brain injury in selective brain areas, including bilateral ventricular enlargement, cell death at the sub- and periventricular areas, loss of O4+ and O1+ oligodendrocyte (OL) immunoreactivity and hypomyelination, as indicated by decreased myelin basic protein immunostaining, in the neonatal rat brain. Minocycline administration significantly attenuated LPS-induced brain injury in these rat brains. The protective effect of minocycline was associated with suppressed microglial activation as indicated by the decreased number of activated microglial cells following LPS stimulation and with consequently decreased elevation of interleukin 1beta and tumor necrosis factor-alpha concentrations induced by LPS and a reduced number of inducible nitric oxide synthase expressing cells. Protection of minocycline was also linked with the reduction in LPS-induced oxidative stress, as indicated by 4-hydroxynonenal positive OLs. The overall results suggest that reduction in microglial activation may protect the neonatal brain from LPS-induced white matter injury and inhibition of microglial activation might be an effective approach for the therapeutic treatment of infection-induced white matter injury.     

Prenatal LPS exposure reduces olfactory perception in neonatal and adult rats

Prenatal lipopolysaccharide (LPS) exposure causes reproductive, behavioral and neurochemical defects in both dams and pups. The present study evaluated male rats prenatally treated with LPS for behavioral and neurological effects related to the olfactory system, which is the main sensorial path in rodents. Pregnant Wistar rats received 100 μg/kg of LPS intraperitoneally (i.p.) on gestational day (GD) 9.5, and maternal behavior was evaluated. Pups were evaluated for (1) maternal odor preference, (2) aversion to cat odor, (3) monoamine levels and turnover in the olfactory bulb (OB) and (4) protein expression (via immunoblotting) within the OB dopaminergic system and glial cells. Results showed that prenatal LPS exposure impaired maternal preference and cat odor aversion and decreased dopamine (DA) levels in the OB. This dopaminergic impairment may have been due to defects in another brain area given that protein expression of the first enzyme in the DA biosynthetic pathway was unchanged in the OB. Moreover, there was no change in the protein expression of the DA receptors. The fact that the number of astrocytes and microglia was not increased suggests that prenatal LPS did not induce neuroinflammation in the OB. Furthermore, given that maternal care was not impaired, abnormalities in the offspring were not the result of reduced maternal care.     

Prenatal stress produces sex differences in nest odor preference

Prenatal stress (PS) and early postnatal environment may alter maternal care. Infant rats learn to identify their mother through the association between maternal care and familiar odors. Female Wistar rats were exposed to restraint stress for 30 min, 4 sessions per day, in the last 7 days of pregnancy. At birth, pups were cross-fostered and assigned to the following groups: prenatal non-stressed mothers raising non-stressed pups (NS:NS), prenatal stressed mothers raising non-stressed pups (S:NS), prenatal non-stressed mothers raising stressed pups (NS:S), prenatal stressed mothers raising stressed pups (S:S). Maternal behaviors were assessed during 6 postpartum days. On postnatal day (PND) 7, the behavior of male and female pups was analyzed in the odor preference test; and noradrenaline (NA) activity in olfactory bulb (OB) was measured. The results showed that restraint stress increased plasma levels of corticosterone on gestational day 15. After parturition, PS reduced maternal care, decreasing licking the pups and increasing frequency outside the nest. Female pups from the NS:S, S:NS, S:S groups and male pups from the S:S group showed no nest odor preference. Thus, at day 7, female pups that were submitted to perinatal interventions showed more impairment in the nest odor preference test than male pups. No changes were detected in the NA activity in the OB. In conclusion, repeated restraint stress during the last week of gestation reduces maternal care and reduces preference for a familiar odor in rat pups in a sex-specific manner.     

丙酮酸乙酯对LPS致急性肺损伤大鼠肺组织NF-κB p65及TNF-α和IL-lβ的影响

目的:观察丙酮酸乙酯(EP)对内毒素性急性肺损伤(ALI)大鼠肺组织核转录因子-κB(NF-κB)p65表达及肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)含量的影响,探讨EP可能的肺保护机制。方法:雄性SD大鼠30只随机分为三组(n均=10):正常对照组,静脉注射与其它二组等量生理盐水;LPS组,静脉注射脂多糖(LPS)5mg/kg复制大鼠ALI模型;EP+LPS组,于静脉注射LPS前1h腹腔内注射EP(40mg/kg)。所有动物于注射LPS或生理盐水后4h颈动脉放血处死,取肺组织用Westernblot测定其NF-κBp65的表达,用ELISA测定其TNF-α和IL-1β的含量。结果:与对照组相比,LPS组、EP+LPS组肺组织NF-κBp65表达增加,肺组织TNF-α和IL-lβ含量升高(P0.05);与LPS组相比,EP+LPS组肺组织NF-κBp65表达降低,肺组织TNF-α和IL-lβ含量降低(P0.05)。结论:EP通过下调大鼠LPS诱导的肺组织NF-κBp65表达,降低了TNF-α和IL-lβ的释放。EP可减轻ALI大鼠肺的炎症反应。     

Hyperthermia amplifies brain cytokine and reactive oxygen species response in a model of perinatal inflammation

Chorioamnionitis, a perinatal infection of the fetal membranes, and maternal fever, which often accompanies infection are both risk factors for cerebral palsy (CP). Inflammation is a typical reaction to infection. Thus the aim of this study was to determine if hyperthermia alters newborn rat brain inflammatory response and oxidant stress after a maternal rat lipopolysaccaharide (LPS) injection. Since chorioamnionitis can predispose the fetus to perinatal hypoxia, we also explored the interaction with postnatal hypoxia. Exposure of newborn pups to brief hypoxia alone significantly increased brain tumor necrosis factor-alpha (TNF-alpha) and slightly increased levels of nitrite/nitrate. When maternal LPS was combined with postnatal hypoxia, the levels of TNF-alpha in were further increased when compared with hypoxia alone. Exposure of newborn pups to hyperthermia at 39 degrees C following maternal LPS and hypoxia caused yet more significant increases in brain TNF-alpha, nitrite/nitrate, and MDA/4-HAD compared to that under normal temperature conditions. This study supports the hypothesis that fever is a significant modifier of brain inflammatory response in developing brain particularly in a setting of hypoxia.     

Airway inflammation and central respiratory control: results from in vivo and in vitro neonatal rat

In infants, respiratory infection elicits tachypnea. To begin to evaluate the role of brainstem cytokine expression in modulation of breathing pattern changes, we compared the pattern generated after endotracheal instillation of lipopolysaccharide (LPS) in in vivo rat pups to local pro-inflammatory cytokine injection in the nucleus tractus solitarius (nTS) in an in vitro en bloc brainstem spinal cord preparation. We hypothesized that both challenges would elicit similar changes in patterning of respiration. In anesthetized, spontaneously breathing rat pups, lipopolysaccharide (LPS) or saline was instilled in the airway of urethane-anesthetized rats (postnatal days 10-11). We recorded diaphragm EMG over the subsequent 2h and saw a 20-30% decrease in interburst interval (Te) at 20-80min post-injection in LPS-instilled animals with no significant change in Ti. In contrast, IL-1β injections into the nTS of en bloc in vitro brainstem-spinal cord preparations from 0 to 5 day-old pups maintained Ti and caused an increase in Te as early as 20min later, decreasing frequency for 80-120min after injection. Our results suggest that the neonatal respiratory response to the cytokine IL-1β mediated inflammatory response depends on the site of the inflammatory stimulus and that the direct effect of IL-1β in the nTS is to slow rather than increase rate.     

Maternal stress and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior

Chronic variable prenatal stress or maternal high-fat diet results in offspring that are significantly heavier by the end of the first postnatal week with increased adiposity by weaning. It is unclear, however, what role maternal care and diet play in the ontogenesis of this phenotype and what contributions come from differences already established in the rat pups. In the present studies, we examined maternal behavior and milk composition as well as offspring ingestive behavior. Our aim was to better understand the development of the obese phenotype in offspring from dams subjected to prenatal stress and/or fed a high-fat (HF) diet during gestation and lactation. We found that dams maintained on a HF diet through gestation and lactation spent significantly more time nursing their pups during the first postnatal week. In addition, offspring of prenatal stress dams consumed more milk at postnatal day (PND) 3 and offspring of HF dams consume more milk on PND 7 in an independent ingestion test. Milk from HF dams showed a significant increase in fat content from PND 10-21. Together these results suggest that gestational dietary or stress manipulations can alter the rat offspring's developmental environment, evidence of which is apparent by PND 3. Alterations in maternal care, milk composition, and pup consumption during the early postnatal period may contribute to long-term changes in body weight and adiposity induced by maternal prenatal stress or high-fat diet.     

Effect of methamphetamine exposure and cross-fostering on sensorimotor development of male and female rat pups

The present study tested the hypothesis that cross-fostering influences the development of rat pups. Mothers were exposed daily to injection of methamphetamine (M) (5 mg/kg) or saline for 9 weeks: 3 weeks prior to impregnation, throughout gestation and lactation periods. Control females animals without any injections were used. On postnatal day (PD) 1, pups were cross-fostered so that each mother received four pups of her own and eight pups from the mothers with the other two treatments. Offspring were tested for sensorimotor development in preweaning period by using tests of: negative geotaxis, tail pull, righting reflexes, rotarod and bar-holding. Further, the pups were weighed daily. Our results showed that birth weight in prenatally M-exposed pups was lower than in control or saline-exposed pups. Prenatally M-exposed pups gained less weight than control or saline-exposed pups regardless of postnatal treatment and sex. Further, our data demonstrated that prenatal and postnatal M exposure impairs sensorimotor functions in most of the tests. On the other hand, the negative effect of prenatal M exposure was partially suppressed in prenatally M-exposed pups by cross-fostering to control dams. Our hypothesis that cross-fostering may affect postnatal development of pups was confirmed.     

人参二醇组皂苷对脂多糖攻击大鼠脑皮质NF-κB的影响

目的： 观察人参二醇组皂苷对脂多糖(LPS)攻击大鼠脑皮质NF-κB的影响。方法: 大鼠随机分为实验对照（control）组、脂多糖（LPS）组、脂多糖加地塞米松（LPS+Dex）组和脂多糖加人参二醇组皂苷（LPS+PDS）组。大鼠静脉注射LPS（4 mg·kg^-1）1 h、4 h后检测脑皮质NF-κB的变化。结果:EMSA实验显示人参二醇组皂苷可抑制LPS攻击后1 h、4 h NF-κB的DNA结合活性；抑制细胞核p65和p50蛋白的表达。结论:LPS休克早期脑组织细胞NF-κB激活入核，人参二醇组皂苷通过抑制其活性而减轻脑组织损伤。     

Rosiglitazone,a Peroxisome Proliferator-Activated Receptor-γ Agonist,Restores Alveolar and Pulmonary Vascular Development in a Rat Model of Bronchopulmonary Dysplasia

Purpose

We tested whether rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ agonist, can restore alveolar development and vascular growth in a rat model of bronchopulmonary dysplasia (BPD).

Materials and Methods

A rat model of BPD was induced through intra-amniotic delivery of lipopolysaccharide (LPS) and postnatal hyperoxia (80% for 7 days). RGZ (3 mg/kg/d, i.p.) or vehicle was given daily to rat pups for 14 days. This model included four experimental groups: No BPD+vehicle (V), No BPD+RGZ, BPD+V, and BPD+RGZ. On D14, alveolarization, lung vascular density, and right ventricular hypertrophy (RVH) were evaluated.

Results

Morphometric analysis revealed that the BPD+RGZ group had significantly smaller and more complex airspaces and larger alveolar surface area than the BPD+V group. The BPD+RGZ group had significantly greater pulmonary vascular density than the BPD+V group. Western blot analysis revealed that significantly decreased levels of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 by the combined exposure to intra-amniotic LPS and postnatal hyperoxia were restored by the RGZ treatment. RVH was significantly lesser in the BPD+RGZ group than in the BPD+V group.

Conclusion

These results suggest that RGZ can restore alveolar and pulmonary vascular development and lessen pulmonary hypertension in a rat model of BPD.     

Prenatal exposure to lipopolysaccharide results in cognitive deficits in age-increasing offspring rats

Studies have suggested that maternal infection/inflammation maybe a major risk factor for neurodevelopmental brain damage. In the present study, we evaluated the effects of prenatal exposure to a low level of inflammatory stimulation lipopolysaccharide (LPS) repeatedly on spatial learning and memory performances in rat offspring's lifetime. Sixteen pregnant Sprague–Dawley rats were randomly divided into two groups. The rats in the LPS group were treated i.p. with LPS (0.79 mg/kg) at gestation day 8, 10 and 12; meanwhile the rats in the control group were treated with saline. After delivery, the rat offspring at 3- (young), 10- (adult) and 20-mon-old (aged) were allocated. Spatial learning and memory abilities were tested by Morris water maze. The structure of hippocampal CA1 region was observed by light microscopy. The expression of synaptophysin (SYP) and glial fibrillary acidic protein (GFAP) in hippocampal CA1 region were measured by immunohistochemistry. Results showed that the rat offspring of LPS group needed longer escape latency and path-length in the Morris water maze and presented a significant neuron loss, decreased expression of SYP, increased expression of GFAP in CA1 region in histological studies. All these changes were more significant with the age increasing. These findings support the hypothesis that maternal systemic inflammation may alter the state of astrocytes in rat offspring for a long time, the alteration may affect neurons and synapse development in neural system, increase the neurons' vulnerability to environment especially as the age increasing, at last result in distinct learning and memory impairment.     

Gestational hypoxia induces white matter damage in neonatal rats: a new model of periventricular leukomalacia

In the premature infant, periventricular leukomalacia, usually related to hypoxicischemic white matter damage, is the main cause of neurological impairment. We hypothesized that protracted prenatal hypoxia might induce white matter damage during the perinatal period. Pregnant Sprague-Dawley rats were placed in a chamber supplied with hypoxic gas (10% O2-90% N2) from embryonic day 5 (E5) to E20. Neonatal rat brains were investigated by histology, immunocytochemistry, western blotting, in situ hybridization, DNA fragmentation analysis, and in vivo magnetic resonance imaging (MRI). Body weight of pups subjected to prenatal hypoxia was 10 to 30% lower from P0 to P14 than in controls. Specific white matter cysts were detected between P0 and P7 in pups subjected to prenatal hypoxia, in addition to abnormal extra-cellular matrix, increased lipid peroxidation, white matter cell death detected by TUNEL, and increased activated macrophage counts in white matter. Subsequently, gliotic scars and delayed myelination primarily involving immature oligodendrocytes were seen. In vivo MRI with T1, T2, and diffusion sequences disclosed similar findings immediately after birth, showing strong correlations with histological abnormalities. We speculate that protracted prenatal hypoxia in rat induces white matter damage occurring through local inflammatory response and oxidative stress linked to re-oxygenation during the perinatal period.     

LPS-induced transient testicular dysfunction accompanied by apoptosis of testicular germ cells in mice

The aim of this study was to clarify effects of inflammation on spermatogenesis in LPS-administered mice. ICR mice were treated by intraperitoneal injection for 7 days with either physiological saline (control) or 0.1 mg lipopolysaccharide (LPS)/kg body weight/day. Control mice were killed at 24 h after the last injection and the LPS-treated group after 24 h or 1, 3, or 5 weeks. Sperm concentration and motility in the cauda epididymis were examined as well as immunohistochemical localization of Fas and FasL and germ cell apoptosis. Sperm concentration and motility markedly fluctuated in LPS-treated mice. Increase of apoptotic cells was common in all post-LPS treatment groups, with a peak at 24 h after LPS injection. In contrast to the lack of Fas immunoreactivity in control testes, LPS-treated groups demonstrated Fas in many germ cells, especially in spermatocytes and spermatids. Immunoreactivity for FasL, on the other hand, was positive for some Sertoli cells, Leydig cells, and germ cells in both control and LPS-treated groups at all time points. The results suggest that the Fas/FasL system mediates apoptosis of germ cells in LPS-treated mice testes. LPS-administered mice thus provide a good experimental model for the study of transient disruption of spermatogenesis.     

Effects of maternal thiamine deficiencies on the pyramidal and granule cells of the hippocampus of rat pups

To understand the implication of thiamine deficiency in the neuronal atrophy and cell death we undertook to induce thiamine (B1 vitamine) deficiency during three essential periods of the ontogenesis of rat central nervous system (CNS). Female rats were fed with a thiamine deprived diet during the gestation and lactation, and the fetuses and pups were alternately exposed to prenatal, perinatal or postnatal thiamine deficiencies. On the 45th postnatal day, histological studies were done on the brains of the pups and the structure of the hippocampus was analyzed. The effects of each treatment were assessed by measuring the size and the density of cell nuclei throughout the dentate gyrus and fields CA4, CA3 and CA1 of the hippocampal formation. The hippocampus showed a regional vulnerability in the pups exposed to maternal thiamine deficiencies. It appears that the thiamine deficiency decreased nuclear density (27.20%) more severely than nuclear size (10.56%) in the fetal hippocampus. Consequently, the major part of the teratogenic effects of thiamine deficiency was cellular death, rather than cellular atrophy.     

Effects of postnatal dexamethasone or hydrocortisone in a rat model of antenatal lipopolysaccharide and neonatal hyperoxia exposure

The aim of our study was to investigate the differential effects of dexamethasone (DXM) and hydrocortisone (HCS) on somatic growth and postnatal lung development in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was induced by administering intra-amniotic lipopolysaccharide (LPS) and postnatal hyperoxia. The rats were treated with a 6-day (D1-D6) tapering course of DXM (starting dose 0.5 mg/kg/day), HCS (starting dose 2 mg/kg/day), or an equivalent volume of normal saline. DXM treatment in a rat model of BPD induced by LPS and hyperoxia was also associated with a more profound weight loss compared to control and LPS + O(2) groups not exposed to corticosteroid, whereas HCS treatment affected body weight only slightly. Examination of lung morphology showed worse mean cord length in both LPS + O(2) + DXM and LPS + O(2) + HCS groups as compared to the LPS + O(2) alone group, and the LPS + O(2) + DXM group had thicker alveolar walls than the LPS + O(2) group at day 14. The HCS treatment was not significantly associated with aberrant alveolar wall thickening and retarded somatic growth. The use of postnatal DXM or HCS in a rat model of BPD induced by intra-amniotic LPS and postnatal hyperoxia appeared detrimental to lung growth, but there was less effect in the case of HCS. These findings suggest that effect of HCS on somatic growth and pulmonary outcome may be better tolerated in neonates for preventing and/or treating BPD.     

新生大鼠早期感染致脑白质损伤自噬相关蛋白的表达

目的:研究新生大鼠生后早期感染对脑白质中自噬相关蛋白Beclin1 和LC3 表达的影响。方法:将64 只新生SD 大鼠随机分为实验组与对照组,实验组新生大鼠于生后第2、3、4、5、6 天腹腔注射脂多糖0.6 mg/ (kg•d)1 次,建立新生大鼠感染致脑白质损伤模型,对照组注射等量生理盐水;分别在造模完成后的12 h、1、3、5 d 处死大鼠并取脑白质;HE 染色后观察脑白质区病理变化;通过Western blot 和半定量RT-PCR 法检测各组脑白质中Beclin1、LC3 蛋白和mRNA 水平的表达变化。结果:实验组HE 染色显示脑白质病变明显;与对照组相比,实验组Beclin1、LC3 蛋白和mRNA 水平在造模后12 h 表达升高,1 d 达高峰,随后下降,各时间点均高于对照组(P<0.05)。结论:新生大鼠早期感染可以引起脑白质损伤;Beclin1 和LC3 蛋白所呈现的表达变化规律表明自噬可能参与了感染致脑白质损伤的病理过程。     

Effect of prenatal and postnatal methamphetamine exposure on nociception in adult female rats

The aim of the present study was to determine effects of methamphetamine (MA) exposure and cross‐fostering on thermal nociceptive thresholds in different estrous phases in adult female rats. Rat mothers were exposed daily to injection of MA (5 mg/kg) or saline for 9 weeks: prior to impregnation, throughout gestation and lactation periods. Dams without any injections were used as an absolute control. On postnatal day 1, pups were cross‐fostered so that each mother raised four pups of her own and eight pups from the mothers with the other two treatments. Offspring females were tested in adulthood (85–90 days) for thermal nociception as latency [s] of withdrawal reaction of forelimbs, hind limbs, and tail. Our results showed that prenatal MA exposure did not affect the nociception in adulthood, while postnatal MA exposure (i.e., MA administration to lactating mothers) had pro‐nociceptive effects. The effect of postnatal MA exposure was apparent in both, fore‐ and hind limbs, while the latency to tail withdrawal reaction was the same among the groups. In addition, the pro‐nociceptive effect of postnatal MA exposure did not depend on estrous cycle. This study indicates that postnatal but not prenatal exposure to MA affects nociception in adult female rats. However, it is still not clear whether the pro‐nociceptive effect of postnatal MA exposure is linked to direct action of MA on neuronal organization, or to indirect action of MA mediated by impaired maternal care. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 52: 71–77, 2010     

DJ-1缺失增加出生前脂多糖暴露引起的出生后小鼠多巴胺能神经元丢失(英文)

目的:观察DJ-1缺失和出生前脂多糖(lipopolysaccharide,LPS)暴露对出生后小鼠多巴胺能(dopam-inergic,DA)系统和神经炎症的影响。方法:妊娠第10.5 d DJ-1基因敲除的小鼠腹腔注射脂多糖(10,000 EU/kg体重)后自然分娩的后代在4月和14月龄时处死。免疫组织化学染色结合体视学计数定量黑质酪氨酸羟化酶(Tyrosine hydroxylase,TH)和CD11b阳性细胞数量。高效液相色谱法测定纹状体DA代谢物水平。免疫荧光法测定TNF-α和IL-1β蛋白水平。结果:4月和14月龄的DJ-1基因敲除的小鼠均没有明显的DA神经元减少和脑内神经炎症改变。出生前接触过LPS的4月和14月龄野生型小鼠,黑质DA能神经元分别减少13.6%和23.1%,纹状体DA含量分别减少19.0%和26.2%,同时神经炎症改变明显。出生前接触过LPS的4月和14月龄DJ-1基因敲除小鼠,黑质DA能神经元分别减少22.5%和35.4%,纹状体DA含量分别减少34.3%和39.3%,同时脑内炎症反应更明显。结论:以上结果提示遗传因素缺失和环境因素可能共同引发帕金森病发生,进一步验证了帕金森病多因素损伤引发的发病假说。