Glycine antagonist and NO synthase inhibitor protect the developing mouse brain against neonatal excitotoxic lesions

The prevention of cerebral palsy and neuroprotection of the immature brain continue to be health care priorities. The pathophysiology of perinatal brain lesions associated with cerebral palsy seems to be multifactorial and includes pre- and perinatal factors such as preconceptional events, hormone and growth factors deficiencies, maternal infections with production of cytokines, and hypoxic/ischemic perfusion failures. Excitotoxic cascade could represent a common pathway that leads to neural cell death and subsequent brain damage. Brain injuries induced by ibotenate, a glutamatergic analog, which are essentially mediated through the N-methyl-D-aspartate receptor, mimic some aspects of the white matter cysts and transcortical necrosis observed in human perinatal brain damage. The purpose of the present study was to assess the protective role of several pharmacological agents, administered in conjunction with ibotenate, against induced excitotoxic lesions. We injected ibotenate in the developing mouse brain 5 d postnatally, after the full settlement of neuronal layers. Co-treatment with kynurenic acid, an antagonist of the facilitating glycine site of the N-methyl-D-aspartate receptor, or with N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthesis, induced a dose-dependent neuroprotective effect. Conversely, zinc gluconate, a blocking agent of the channel linked to the N-methyl-D-aspartate receptor, and a free radical scavenger (U74389F), were unable to protect the developing brain against excitotoxic attack. These data help to clarify some molecular mechanisms involved in excitotoxic lesions of the developing mouse brain and permit us to envision new strategies in the prevention of cerebral palsy.     

脑室周围白质软化新生大鼠模型的创建及所伴随的白内障病变

目的：创建与人类早产儿脑室周围白质软化（periventricular leukomalacia，PVL）病理相似的可靠PVL动物模型，并探索本PVL模型所伴随的白内障病变及其形成机制。方法：新生大鼠分为PVL组和假手术对照组，通过双侧颈总动脉结扎和8％低氧下缺氧30 min，建立PVL动物模型。分别于术后1 d进行脑片TTC染色以观察脑梗死情况，术后2 d和21 d进行光镜下脑病理检查，以及术后21 d进行眼部裂隙灯检查和光镜下眼球病理检查。结果：脑片TTC染色显示PVL新生大鼠脑组织呈现大面积白色梗死区，其梗死体积达（53.45±33.90） mm3，梗死百分比为（24.98±15.44）％。光镜下病理研究证实，术后2 d的PVL新生大鼠脑室周围以及皮层下白质呈现囊性坏死和细胞凋亡，皮质神经元损伤轻微。术后21 d，其脑室周围以及皮质下白质可见多个囊性疏松坏死区域形成。相应日龄假手术组大鼠脑组织内则未观察到明显病理改变。术后21 d后，肉眼及裂隙灯下均观察到PVL组所有幼鼠双眼均呈现白内障，光镜下显示球后组织无明显病理改变。假手术组幼鼠眼部均正常。结论：通过对2日龄新生大鼠进行双侧颈总动脉结扎伴缺氧，成功创建了与人类早产儿PVL病理相似的PVL动物模型，效果肯定，重复性好。同时本建模方法也可引起白内障病变，可作为制作白内障动物模型的推荐方法之一。［中国当代儿科杂志，2007，9（3）：220-224］     

Generation of periventricular leukomalacia by repeated umbilical cord occlusion in near-term fetal sheep and its possible pathogenetical mechanisms

Periventricular leukomalacia (PVL) is a major cause of cerebral palsy. However, pathogenetic mechanisms of PVL have not been fully understood. Although it has been postulated that umbilical cord compression is related to the development of PVL, no animal experiments clearly demonstrated an association of umbilical cord occlusion with 'periventricular' white matter lesions. The purpose of this study is to determine whether umbilical cord occlusions could produce periventricular white matter lesions in fetal sheep and to examine how changes in fetal cardiovascular and metabolic variables are related to the induction of brain damage. Fourteen near-term fetal sheep underwent umbilical cord occlusion (3-min total cord occlusions 5 times at 5-min intervals). Dissections performed 24 h after cord occlusion revealed that periventricular white matter lesions were produced in 7 out of 14 sheep fetuses. According to the pattern of brain damage, we classified the fetal sheep into three groups: 5 fetuses with dominant lesions in the periventricular white matter (group I), 4 fetuses with brain lesions in the cerebral cortex and thalamus (group II) and 5 fetuses with no or minimal brain lesions (group III). Group I showed higher blood pressure and higher plasma lipid peroxide levels before cord occlusion compared to the other groups, while group II showed systemic hypotension during cord occlusion. No significant differences in changes in pH, PaCO2, PaO2 and heart rate were found between the three groups. It is speculated that PVL might be produced by an association of preexisting chronic circulatory instability with an acute episode of severe repetitive cord occlusion.     

经脑室神经干细胞移植对脑室周围白质软化新生大鼠的脑病理评估

目的：对经脑室植入神经干细胞（NSCs）的脑室周围白质软化（Periventricular leukolamacia，PVL）新生大鼠进行光镜下脑病理评估，探讨NSCs移植对治疗早产儿PVL的可行性。方法：采用E14胎鼠大脑皮层制备NSCs。2日龄新生大鼠随机分为PVL对照组（PVL组），PVL＋DMEM/F12培养基对照组（PVL＋DMEM/F12组），PVL＋神经干细胞（NSCs）移植组（PVL＋NSCs组），假手术对照组（Sham组），Sham＋DMEM／F12培养基对照组（Sham＋DMEM/F12组），Sham＋NSCs移植组（Sham＋NSCs组），每组18～21只。对2日龄PVL新生大鼠在建模后72 h进行经脑室NSCs移植，分别于移植后7，14，21 d进行光镜下脑病理评估。结果：随着移植后时间的增加，脑白质病变呈进一步改善。移植后21 d光镜下病理证实，未移植组脑白质呈轻度和重度病变各占50％，神经元病理评分为1.28±0.86。移植组则有30％白质完全正常，轻度和重度病变各占40％和30％，神经元病理评分为0.32±0.16，两组在脑白质病变程度以及神经元病理评分之间的差异均呈非常显著性意义（χ2＝10.7，P<0.01；F=29.664, P<0.01）。结论：经脑室外源性NSCs移植可明显改善脑白质的病理损伤。经脑室NSCs移植对早产儿PVL具有很大的治疗潜力，为今后成功防治早产儿这一最常见的脑损伤顽症提供了新的可行性途径。     

缺血启动未成熟大鼠脑白质内源性修复功能的研究

目的：探讨缺血启动未成熟脑白质的内源性修复机制。方法：5日龄 Sprague-Dawley 新生大鼠随机分为假手术（Sham）组和PVL组。分别于建模后7 d及21 d光镜、电镜下评估脑白质病变及髓鞘形成情况,免疫组化检测脑白质O4+少突胶质细胞（OL）前体,观察SVZ区祖细胞的激活、增殖、迁移和分化情况。结果：与Sham组比较,PVL组在建模后7 d和21 d光镜下脑白质病理均呈轻或重度病变;病理评分均明显增高;髓鞘形成数量明显减少,厚度变薄;免疫组化显示O4+OL前体明显减少。建模48 h后,PVL组SVZ 区 BrdU、NG2共阳性祖细胞明显增殖并向脑室周围迁移,至7 d达到高峰;从72 h开始,脑室周围出现呈BrdU、O4共阳性OL前体,至21 d,新生OL前体明显多于同时段Sham组。结论：缺血可启动新生大鼠脑白质的内源性修复机制,诱导SVZ 区胶质源性神经祖细胞激活、增殖、迁移至脑室周围和分化为OL前体。     

早产儿脑室周围白质软化的影像学改变及其对预后的影响

脑室周围白质软化( periventricular leukomalacia, PVL)是早产儿具有特征性的脑损伤形式之一,易造成小儿神经系统后遗症,严重影响小儿以后的运动发育和生活质量。早产儿PVL无特异性症状,诊断依赖于影像学检查。经颅超声能对PVL做出初步诊断及预后评价。结合MRI可评价PVL患儿的损伤程度,预测可能发生的不良后果,为早期治疗提供依据。该文对早产儿PVL的影像学改变及其对预后的影响进行综述。     

White matter damage in the preterm neonate

The most common form of brain injury in preterm infants is periventricular leukomalacia (PVL). PVL is also the most common cause of cerebral palsy in the smallest and most vulnerable preterm infant. The core theme in its pathogenesis is the effect of hypoxia, ischaemia, and inflammation on the vulnerable white matter of the developing brain. Over the last decade, with improved laboratory and imaging techniques, the complex relationships between the known associated factors involved in causation of PVL is becoming increasingly known. A better understanding of its pathogenesis provides the basis for future protective strategies against PVL.     

T3 replacement does not prevent excitotoxic cell death but reduces developmental neuronal apoptosis in newborn mice.

BACKGROUND: Periventricular leukomalacia (PVL) is a major cause of neurological handicap in pre-term infants. At present, there are no effective or causal therapies available. Thyroid hormones play an essential role in brain development and are reported to be decreased in pre-terms and following brain injury in adults. HYPOTHESIS: Excitotoxic brain damage of newborn mice decreases thyroid hormone concentrations. Exogenous T3 administration restores thyroid hormone levels and reduces perinatal brain damage in an animal model of PVL. DESIGN AND METHOD: To create white and gray matter (WM/GM) lesion mimicking several key aspects of PVL, we injected ibotenic acid (Ibo), a glutamate analog, into the right hemisphere (intracranially (i.c.)) of 5-day-old mice. T3 (10 microg/kg body weight (bw)) was injected intraperitoneally (i.p.) 1 h or repeatedly 1/24/48/72/96 h post-insult. We determined lesion size, number of apoptotic cells in WM/GM and serum T3/T4 concentration at 24 and 120 h after injury. Serum T3/T4 concentration was also determined before and 1 and 2h after T3 administration. RESULTS: Excitotoxic brain damage did not alter serum T3/T4 concentrations within 120 h of injury. Serum T3 levels were distinctly elevated within 1 h of T3 injection; however, this elevation was relatively short-lived (half-life estimated to be less than 12 h). Neither single nor repetitive T3 treatment regimen reduced excitotoxic lesion size, but it did reduce apoptosis. CONCLUSIONS: T3 replacement does not prevent excitotoxic cell death, but it does reduce developmental neuronal apoptosis, which could participate to the beneficial neuropsychological effects of hormone therapy. Further study is therefore warranted.     

Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin

Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [beta-amyloid precursor protein (beta-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using beta-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.     

UDP-糖、GDNF和美金胺改善新生大鼠缺血性脑白质病变的光电镜病理评估

目的：通过光镜和电镜下脑病理研究,评估单用或联用UDP-糖、胶质细胞源性神经营养因子（GDNF）和美金胺对缺血型脑室周围白质软化（PVL）新生大鼠脑白质病变的改善效果。方法：一侧颈总动脉结扎伴缺氧2 h,建立5日龄新生大鼠PVL模型,随机分为假手术（Sham）组、PVL组、UDP-糖组（PVL后即刻腹腔注射UDP-糖2000 mg/kg）、GDNF组（PVL后即刻脑内注射GDNF 100 μg/kg）、美金胺组（PVL后即刻腹腔注射美金胺20 mg/kg）以及三联药组（PVL后即刻联用UDP-糖、GDNF和美金胺）,每组各30只。每组大鼠分别于造模后7 d及21 d断头取脑,电镜下观察髓鞘形成情况,计算髓鞘数目及厚度;光镜下对脑白质病变进行病理分级及评分。结果：造模后7 d及21 d电镜结果显示,PVL组大鼠罕见髓鞘形成,排列松散,髓鞘壁明显变薄,髓鞘数量及厚度均明显少于Sham组、UDP-糖组、GDNF组、美金胺组及三联药组（P<0.01）。光镜下脑白质病理分级结果显示,PVL组大鼠在造模后7 d和21 d,其脑白质均呈轻度病变（38%~50%）或重度病变（50%~62%）。4个用药组大鼠在造模后7 d和21 d有50%~88%呈正常脑白质,呈重度病变的比例为13%~25%。病理评分显示,PVL组在造模后7 d及21 d的病理评分最高,显著高于其他5组（P<0.05）。结论：单用或联用UDP-糖、GDNF和美金胺可明显改善PVL大鼠脑白质病变。推测良好的改善作用与这些药物能促进脑内源性的神经再生及改善脑微环境密切相关。     

Early detection of periventricular leukomalacia by diffusion-weighted magnetic resonance imaging techniques

Periventricular leukomalacia (PVL), the principal form of brain injury in the premature infant, is characterized by overt focal necrotic lesions in periventricular white matter and less prominent, more diffuse cerebral white matter injury. The early detection of the latter, diffuse component of PVL is not consistently possible with conventional brain imaging techniques. We demonstrate the early detection of the diffuse component of PVL by diffusion-weighted magnetic resonance imaging (DWI). In a premature infant with no definite cerebral abnormality detectable by cranial ultrasonography or conventional magnetic resonance imaging, DWI showed a striking bilateral decrease in water diffusion in cerebral white matter. The DWI abnormality (ie, decreased apparent diffusion coefficient) was similar to that observed with acute cerebral ischemic lesions in adults. At 10 weeks of age, conventional magnetic resonance imaging and ultrasonography showed striking changes consistent with PVL, including the presence of small cysts. The observations indicate the importance of DWI in the early identification of the diffuse component of PVL and also perhaps the role of ischemia in the pathogenesis of the lesion.     

3-硝基丙酸致未成熟鼠脑室周围脑白质软化的神经行为学及磁共振成像变化

目的 通过脑内定位注射3-硝基丙酸(3-NPA)建立新生鼠脑室周围白质软化(PVL)模型,探讨远期神经行为学和磁共振成像(MRI)变化.方法 新生5 d(P5)SD大鼠随机分成实验组(NPA组)与假手术组(PBS组),脑立体定位仪定位于左侧脑室上方胼胝体,分别注入等量3-NPA和PBS,造模后1、2、3、9 d灌注固定取脑,石蜡切片作HE染色;术后不同时间点观察体重、睁眼时间等生长发育情况;P29-30进行神经行为学检测,观察两组大鼠肢体肌力、随意运动、情感行为能力和学习记忆能力;P30行MRI检查.结果 NPA组大鼠术后睁眼时间延迟,体重增加高于PBS组,差异有统计学意义(P<0.05);HE染色显示NPA组大鼠P6、p7、P8 NPA组注射3-NPA侧皮质下及脑室周围白质出现不同程度疏松及液化灶,P14时出现同侧脑室明显扩大,PBS组无明显变化;神经行为学检测实验组鼠肢体肌力、随意运动、情感行为能力和学习能力较假手术组减退,评分差异有统计学意义(P<0.05);P30 MRI检查显示NPA组脑内注射侧脑室周围局部有脑组织软化信号改变.结论 P5大鼠脑内注射3-NPA制作的脑室周围白质软化模型.能真实地模拟在体病理改变,经神经行为学检测与临床症状相符,MRI检查可显示脑白质损伤的解剖形态学变化,作为诊断PVL的方法具有可行性.     

经脑室神经干细胞移植治疗脑室周围白质软化新生大鼠电镜下脑病理评估

目的对经脑室植入神经干细胞(NSCs)的脑室周围白质软化(PVL)新生大鼠进行电镜下脑病理和髓鞘形成评估,探讨NSCs移植对治疗早产儿PVL的可行性,以及胶质细胞源性神经营养因子(GDNF)对NSCs治疗PVL的影响。方法采用颈部正中切开双侧颈总动脉结扎法制备PVL模型。采用孕14 d SD大鼠大脑皮质制备NSCs。2日龄新生大鼠随机分为PVL对照组(PVL组),PVL加NSCs移植组(PVL加NSCs组),PVL加NSCs移植及GDNF组(PVL加NSCs加GDNF组),假手术对照组(Sham组),Sham加NSCs移植组(Sham加NSCs组),以及Sham加NSCs移植及GDNF组(Sham加NSCs加GDNF组)。NSCs移植组将NSCs调整为5×107L-1,将2μL移植液以0.5μL/min注入侧脑室内。GDNF干预组以100μg/L GDNF加入NSCs移植液中注入侧脑室。对2日龄PVL新生大鼠在建模后72 h进行经脑室NSCs移植,分别于移植第21天行电镜下脑病理和髓鞘形成评估。结果移植第21天,电镜显示,PVL组可见部分神经元固缩变形,细胞器减少,罕见髓鞘形成。PVL加NSCs组皮质部位神经元形态基本正常,脑白质内髓鞘形成明显增加。PVL加NSCs加GDNF组皮质改善以及髓鞘形成增多情况较PVL加NSCs组则更为明显。假手术各组未见明显变化。结论经脑室NSCs移植对早产儿PVL具有很大的治疗潜力,GDNF可能具有增强NSCs的治疗作用。     

谷氨酸受体2和钙离子在新生大鼠脑室周围白质软化症发病机制中的作用探讨

目的：观察α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（α-3-hydroxy-5-methylisoxazole-4-propionie acid，AMPA）受体亚单位谷氨酸受体2（GluR2）在2日龄缺氧缺血新生鼠脑白质中的表达，并检测脑白质细胞内游离Ca2+浓度在缺氧缺血后不同时间点的变化及其意义。方法：建立2日龄SD大鼠缺氧缺血脑室周围白质软化(periventricular leukomalacia, PVL）模型，分别应用荧光定量PCR和Western Blot检测脑白质缺氧缺血后12，24，48 h和72 h GluR2 mRNA和蛋白表达的变化；用Furo 2/ AM荧光探针和双波长荧光分光光度计分别检测脑白质细胞内游离Ca2+浓度。结果：与对照组相比，PVL组大鼠脑白质GluR2 mRNA 和蛋白含量在缺氧缺血后24 h开始降低，并持续降低至72 h（P<0.05）； PVL组大鼠脑白质细胞内游离Ca2+浓度在缺氧缺血后12 h开始升高，持续增高至72 h（P<0.05）。结论：GluR2表达减少可能导致脑白质细胞内钙离子超载，引起细胞损害。［中国当代儿科杂志，2007，9（4）：313-316］     

Iron supplementation aggravates periventricular cystic white matter lesions in newborn mice

Periventricular leukomalacia (PVL) is the main cause of neurological impairment in premature newborns. The pathogenesis of PVL remains unclear but may involve glutamate excitotoxicity and free radical production. Oxygen and iron, which are widely used in premature newborns, are oxidizing agents with a potential for promoting free radical production. We previously described a mouse model of excitotoxic neonatal white matter lesions mimicking several aspects of human PVL. In the present study, we used this mouse model to investigate whether iron pretreatment or 100% oxygen exposure worsened excitotoxic lesions. We found that iron pretreatment but not hyperoxia significantly increased white matter lesions, suggesting that high doses of iron may aggravate PVL in premature newborns.     

Fetal and neonatal origins of altered brain development

Abnormal development of the brain during fetal life is now thought to contribute to the aetiology of many neurological disorders that manifest throughout life. Many factors are likely to underlie such abnormal development including genetic makeup and an adverse intrauterine environment. This review will focus on prenatal hypoxic/ischaemic injury, inflammatory/infective insults and preterm birth. A range of experimental models have been used to characterize lesions formed in response to these insults and to determine mechanisms of damage resulting from such events. Relatively brief periods of fetal hypoxia result in neuronal death (cerebellum, hippocampus, and cerebral cortex), white matter damage and reduced growth of neural processes. These effects are more profound at mid than late gestation. Chronic mild placental insufficiency can result in fetal growth restriction and deficits in neural connectivity and myelination. Exposure of the preterm fetus to inflammatory agents causes brain damage particularly in the white matter and this is exacerbated by hypoxia. Premature birth without potentiating factors can result in subtle neuropathologies including cerebral white matter gliosis, hippocampal sclerosis and subarachnoid haemorrhage; the extent of the damage appears to be related to the regimen of ventilatory support. These studies show that the timing, severity and nature of specific insults are critical in determining the pattern of injury and thus the extent to which neurological function will be affected postnatally. Defining the causes, patterns and mechanisms of brain injury is crucial if we are to develop rational neuroprotective strategies to reduce the burden of altered brain growth and poor functional and behavioural outcomes.     

儿童脑室周围白质软化磁共振表现与临床的关系

目的 探讨儿章脑室周围白质软化(PVL)MRI表现与临床症状的相关性.方法 选取本科47例PVL患儿.回顾性调查其围生期感染、出生体质量、胎龄及窄息情况;分析其MRI表现,包括脑室周围异常高信号、脑室扩大、皮质损伤、脑白质减少程度和胼胝体发育不良,进行PVL、腩性瘫痪(脑瘫)程度及语占障碍分级及视听觉筛查、智力检测,语言发育明显落后的患儿进行孤独症筛查:≥2岁应用孤独症行为量表(ABC),<2岁应用孤独症儿童评定量表(CARS),有抽搐发作的患儿进行脑电图(EEG)检查.分析PVL分级与胎龄、出牛体质量、围生期感染、窒息、脑瘫及语言障碍程度、视听觉障碍、智力及癫痫的相关性.结果 47例患儿中3例运动发育正常,其中完伞性耳聋2例,孤独症1例,余44例均诊断为脑瘫,其中听力障碍24例,视觉障碍19例,其中1例皮质盲,发育商正常仅1例,并癫痼发作11例,其中West综合征2例.按照白质异常信号的范围.脑室扩大及白质减少程度、胼胝体发育情况及有无皮质损害将PVL分为3级.其中Ⅰ级14例,Ⅱ级21例,Ⅲ级12例.围生期感染可导致PVL分级上升(P=0.011);胎龄、出生体质量、窒息与PVL.分级无明显相关性(P>0.05);随着PVL级别的上升,脑瘫、智力低下程度加重(P=0.019、0.000),视觉障碍增多(P=0.024);脑白质减少程度与语言障碍、智力低下、听觉障碍程度及视觉障碍均有相关性(P=0.000、0.000、0.001、0.000);脑室扩大程度与语言发育障碍、智力低下程度及视觉障碍有明显相关性(P=0.000、0.000、0.000);伴随皮质损害时,听觉障碍程度加重(P=0.000);胼胝体发育不良时,脑瘫、语言障碍、智力低下程度加重(P=0.008、0.001、0.000);癫痼的发生与PVL分级及MRI表现无明显相关.结论 减少围牛期感染町减轻PVL程度;PVL影响患儿的运动、语言、视听觉及智力发育,其MRI表现可反映临床及预后,程度越重,预后越差,合并胼胝体发育不良时预后不良.     

Neurobiology of periventricular leukomalacia in the premature infant

Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achievable because of recent neurobiologic insights into pathogenesis. The pathogenesis of this lesion relates to three major interacting factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter, and a maturation-dependent impairment in regulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturation-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals, known to be generated in abundance with ischemia-reperfusion. This vulnerability of OLs is maturation-dependent, with the OL precursor cell highly vulnerable and the mature OL resistant, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation. The result is generation of deadly reactive oxygen species and apoptotic OL death. Important contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PVL in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important contributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vasculature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elevations in extracellular glutamate, caused by ischemia-reperfusion, is suggested by demonstrations that glutamate causes toxicity to OL precursors by both nonreceptor- and receptor-mediated mechanisms. The former involves an exacerbation of the impairment in antioxidant defenses, and the latter, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-mediated cell death. Most importantly, these new insights into the pathogenesis of PVL suggest potential preventive interventions. These include avoidance of cerebral ischemia by detection of infants with impaired cerebrovascular autoregulation, e.g. through the use of in vivo near-infrared spectroscopy, the use of free radical scavengers to prevent toxicity by reactive oxygen species, the administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor antagonists to prevent glutamate-mediated injury, or the use of maternal antibiotics or anticytokine agents to prevent toxicity from maternal/fetal infection or inflammation and cytokines.     

Animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury

To better understand outcomes after early brain injuries, studies must address multiple variables including age at injury, the mechanisms and severity of injury, environmental factors (before and after injury) and developmental factors. Animal models are helpful for elucidating these different aspects. First, this paper describes a new model of shaken baby syndrome (SBS) in mice, without impact or hypoxia. Mortality was 27%; 75% of survivors had focal brain lesions consisting of haemorrhagic or cystic lesions of the white matter, corpus callosum and cerebellum. All shaken animals, with and without focal lesions, showed delayed white matter atrophy. White matter damage and atrophy were reduced by pre-treatment with an NMDA receptor antagonist, indicating that excess glutamate release contributed to the pathophysiology of the lesions. Secondly, it discusses data on neuroprotection after early brain injuries; drugs targeting the NMDA receptors cannot be used in clinical practice but indirect neuroprotection strategies including anti-NO, anti-free radicals and trophic factors hold promise for limiting the excitotoxic white matter damage induced by early injury, in particular caused by shaking, during brain development. Thirdly, it describes two experimental models in which SBS outcomes are determined when the trauma is combined with environmental influences, namely medications during the acute phase, most notably anti-epileptic drugs and rearing conditions.