Reduction In Brain Weight Research Articles

Treatment with tamoxifen reduces hypoxic–ischemic brain injury in neonatal rats

Tamoxifen, an estrogen receptor modulator, is neuroprotective in adult rats. Does tamoxifen reduce brain injury in the rat pup? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of hypoxia (8% oxygen). Tamoxifen (10 mg/kg) or vehicle was given i.p. 5 min prior to hypoxia, or 5 min after reoxygenation, with a second dose given 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere 22 days following hypoxia and gross and microscopic morphology. Tamoxifen pre-treatment reduced brain weight loss from 21.5±4.0% in vehicle pups ( n=27) to 2.6±2.5% in the treated pups ( n=22, P<0.05). Treatment 5 min after reoxygenation reduced brain weight loss from 27.5±4.0% in vehicle pups ( n=42) to 12.0±3.9% in the treated pups ( n=30, P<0.05). Tamoxifen reduces brain injury in the neonatal rat.

The prenatal methylazoxymethanol acetate treatment: a neurodevelopmental animal model for schizophrenia?

The prenatal methylazoxymethanol acetate (MAM) treatment has been proposed as a suitable model for the neurodevelopmental aspects of schizophrenia since the morphological abnormalities it induces in the brain are subtle and in line with most reports of neuropathology in schizophrenic brains. However, the functional aspects of this treatment have not been investigated with behavioural paradigms that are relevant for the psychopathology of the symptoms of schizophrenia. In the present study, we investigated the validity of the prenatal MAM treatment as a developmental model for schizophrenia with a prepulse inhibition of the acoustic startle reflex, latent inhibition, locomotor activity, and cognition and emotionality with freezing in fear conditioning paradigms. We have conducted two studies: in Study I, MAM was injected from E09 to E12, and in Study II, MAM was administered at later stages in the embryonic development, from E12 to E15. Morphologically, the prenatal MAM treatment induced mild to severe reduction in brain weights and in the entorhinal cortex, prefrontal cortex and striatum volumes, the severity of the effects depending on the timing of administration. However, despite the morphological abnormalities induced by the MAM treatments, no behavioural deficits were observed in the MAM-treated animals when compared to Controls in prepulse inhibition, latent inhibition with the two-way active avoidance, and in the freezing paradigms. Therefore, due to the consistent lack of treatment effect observed in the present investigation, we conclude that the prenatal MAM treatment has no validity as a behavioural model for schizophrenia.

Moderate alcohol exposure compromises neural tube midline development in prenatal brain

We previously reported that fetal alcohol treatment compromised the development of the midline raphe and the serotonin neurons contained in it. In this study, we report that the timely development of midline neural tissue during neural tube formation is sensitive to alcohol exposure. Pregnant dams were treated from embryonic day 7 (E7, prior to neurulation) or E8.5 (at neurulation) with the following diets: (a) alcohol (ALC), given as either a 20% or 25% ethanol-derived calorie (EDC) liquid diet, or (b) isocaloric liquid diet pair-fed (PF), or (c) standard rat chow (Chow). Fetal brains from each group were examined on E13, E15, or E18. Neural tube development was compromised as a result of alcohol exposure in the following ways: (1) approximately 60% of embryos at E13 and 20% at E15 showed perforation of the floor plate in the diencephalic vesicle, (2) although completely closed at E13, 70–80% of embryos failed to complete the formation of neural tissue at the roof as the alcohol exposure continued to E15, and (3) 60–80% of embryos show delayed ‘occlusion’ of the ventral canal by newly formed nestin-positive neuroepithelial cells and S100β-positive glia in the brainstem of E15. The compromised (incomplete) neural tube midline (cNTM) occurred near the ventricles at E13 and E15, but was later completed at E18. In all cases, the cNTM was accompanied by an enlarged ventricle, and dose-dependent brain weight reduction. The midline of the neural tube at the roof and floor plates is known to mediate timely trophic induction for neural differentiation. Prenatal midline deficits also have the potential to affect the development of midline neurons such as raphe, septal nuclei, and the timely crossing of commissural fibers. The results of the liquid diet alcohol exposure paradigm suggest it is more a model for Alcohol-Related Neurodevelopmental Disorder (ARND) featuring neuropsychiatric disorders than for full-blown fetal alcohol syndrome (FAS) with noticeable facial dysmorphogenesis and gross brain retardation.

Brain weight differences associated with induced focal microgyria

BackgroundDisrupting neural migration with bilateral focal freezing necrosis on postnatal day 1 (P1) results in the formation of 4-layered microgyria. This developmental injury triggers a pervasive neural reorganization, which is evident at the electrophysiological, behavioral, and anatomical levels. In this experiment, we investigated changes in brain weight as an index of global disruption of neural systems caused by focal damage to the developing cortical plate.ResultsWe found a dramatic reduction in overall brain weight in microgyric subjects. This reduction in brain weight among animals with microgyria is reflected in decreased total brain volume, with a disproportionate decrease in neocortical volume. This effect is so robust that it is seen across varied environments, at variable ages, and across the sexes.ConclusionsThis finding supports previous work suggesting that substantial reorganization of the brain is triggered by the induction of bilateral freezing damage. These results have critical implications for the profound re-organizational effects of relatively small focal injuries early in development to distributed systems throughout the brain, and particularly in the cerebral cortex.

Incidence of cerebrovascular lesions in Alzheimer's disease: a postmortem study.

Recent epidemiological and clinico-pathological data suggest overlaps between Alzheimer's disease (AD) and cerebrovascular lesions (CVL) that may show some synergistic effects, but the results of studies of the relationship between AD and stroke have been controversial. The objective of this study was to compare the frequency of cerebral infarcts, hemorrhages and minor cerebrovascular lesions in autopsy-confirmed AD and age-matched control brains. Using current routine and immunohistochemical methods 173 consecutive cases of autopsy-confirmed AD and 130 age-matched controls were compared. The total incidence of vascular pathology (56.5%) in AD was significantly less than in a previously reported smaller AD autopsy cohort (82.3%) (P<0.01), and was higher than in controls (42.4%). The incidence of severe CVL (old and recent infarcts, hemorrhages) in our cohort was slightly higher (12.7%) than in controls (8.5%), that of minor to moderate CVL (lacunes, cerebral amyloid angiopathy with or without minor vascular lesions) was more frequent in AD (43.8%) than in controls (33.9%), but the results were not statistically significant (P<0.03). The brain weight and severity of cognitive decline did not correspond to the degree of vascular pathology, but higher neuritic Braak scores and reduced brain weight contributed to the production of cognitive impairment. Like previous findings in Parkinson's disease, our data do not indicate a protective effect from stroke or a significantly greater susceptibility to death from stroke in AD in the population studied, but further prospective clinico-pathological studies are necessary.

Deficiency of neuronal nitric oxide synthase (nNOS) worsens alcohol-induced microencephaly and neuronal loss in developing mice

Previous work conducted in vitro suggests that nitric oxide (NO) protects developing neurons against the toxic effects of alcohol. We tested the hypothesis that neonatal mice carrying a null mutation for neuronal nitric oxide synthase (nNOS), the enzyme which synthesizes NO in neurons, have increased vulnerability to alcohol-induced microencephaly and neuronal loss. Wild-type mice and mutant (nNOS −/−) mice received a single intraperitoneal injection of ethanol (0.0, 2.2, 3.3, or 4.4 g/kg) daily over postnatal days (PD) 4–9 and were sacrificed on PD10. Peak blood alcohol concentrations were approximately 170, 280, and 385 mg/dl for the 2.2, 3.3 and 4.4 g/kg/day treatment groups, respectively, and did not differ significantly between wild-type and nNOS −/− strains. Exposure to alcohol induced dose-dependent reductions in total brain weight, forebrain weight and cerebellum weight in both strains of mice. However, the reductions in brain weight were significantly more severe in the nNOS −/− mice than in wild type. Quantification of cerebellar neurons revealed that alcohol-induced losses of Purkinje cells and granule cells were both significantly greater in the nNOS −/− mice than in wild type. The increased vulnerability of nNOS-deficient neurons to alcohol-induced cell death was confirmed in vitro. Cerebellar granule cell cultures derived from nNOS −/− and wild-type mice were exposed for 24 h to 0, 100, 200 or 400 mg/dl ethanol. At each alcohol concentration, the nNOS −/− neurons had a significantly greater cell loss than did the wild-type neurons. The results demonstrate that deficiency of nNOS decreases the ability of developing neurons to survive the toxic effects of alcohol. Because NO upregulates intracellular cGMP, which can activate cGMP-dependent protein kinase (PKG), we hypothesize that the NO–cGMP–PKG pathway has a neuroprotective role against alcohol toxicity within the developing brain.

Neuroprotective effects of N-acetylaspartylglutamate in a neonatal rat model of hypoxia-ischemia

Neuroprotective effects of N-acetylaspartylglutamate (NAAG), the precursor of glutamate and a selective agonist at the Group II metabotropic glutamate (mGlu) receptor, against hypoxic-ischemic brain injury were examined in a neonatal rat model of cerebral hypoxia-ischemia. The neonatal hypoxia-ischemia procedure (unilateral carotid artery ligation followed by exposure to an 8% oxygen hypoxic condition for 1.5 h) was performed in 7-day-old rat pups. Following unilateral carotid artery ligation, NAAG (0.5 to 20 mg/kg, i.p.) was administered before or after the hypoxic exposure. Brain injury was examined 1-week later by weight reduction in the ipsilateral brain and by neuron density in the hippocampal CA1 area. In the saline-treated rat, neonatal hypoxia-ischemia resulted in severe brain injury as indicated by a 24% reduction in the ipsilateral brain weight. Low doses of NAAG (2–10 mg/kg, but not 0.5 mg/kg), administered before or even if 1 h after the hypoxic exposure, greatly reduced hypoxia-ischemia-induced brain injury (3.8–14.2% reduction in the ipsilateral brain weight). A high dose of NAAG (20 mg/kg) was ineffective. While l(+)-2-Amino-4-phosphonobutyric acid ( l-AP4) and trans-[1S,3R]-1-Amino-cyclopentane-1, 3-dicarboxylic acid ( t-ACPD) were unable to provide protection against hypoxic-ischemic brain injury, 2-(phosphonomethyl) pentanedioic acid (2-PMPA), an inhibitor of N-acetylated alpha-linked acidic dipeptidase (NAALADase), which hydrolyzes endogenous NAAG into N-acetyl-aspartate and glutamate, significantly reduced neonatal hypoxia-ischemia-induced brain injury. (αS)-α-Amino-α-[(1S, 2S)-2-carboxycyclopropyl]-9H-xanthine-9-propanoic acid (LY341495), a selective antagonist at the mGlu 2/3 receptor, prevented the neuroprotective effect of NAAG. Neuron density data measured in the hippocampal CA1 area confirmed that ipsilateral brain weight reduction was a valid measure for hypoxic-ischemic brain injury. Neonatal hypoxia-ischemia stimulated an elevation of cyclic AMP (cAMP) concentration in the saline-treated rat brain. NAAG, l-AP4 and t-ACPD all significantly decreased hypoxia-ischemia-induced elevation of cAMP. LY341495 blocked the effect of NAAG, but not of l-AP4 or t-ACPD, on hypoxia-ischemia-stimulated cAMP elevation. The overall results suggest that the neuroprotective effect of NAAG is largely associated with activation of mGlu 2/3 receptor.

Effects of early undernutrition on the brain insulin-like growth factor-I system.

Undernutrition reduces circulating concentrations of insulin-like growth factor (IGF)-I, but how it affects the brain IGF system, especially during development, is largely unknown. We have studied IGF-I, IGF-II, IGF receptor and IGF binding protein (BP)-2 mRNA expression in the hypothalamus, cerebellum and cerebral cortex of neonatal rats that were food restricted beginning on gestational day 16. One group was refed starting on postnatal day 14. Rats were killed on postnatal day 8 or 22. Undernutrition did not produce an overall reduction in brain weight at either age but, at 22 days, both the cerebellum and hypothalamus weighed significantly less. At 8 days, no change was detected in the central IGF axis in response to undernutrition. However, in 22-day-old undernourished rats, IGF-I and IGF receptor mRNA expression were increased in both the hypothalamus and cerebellum, while IGFBP-2 was decreased, but only in the hypothalamus. Refeeding had no effect on any of these parameters. These results suggest that the hypothalamus and cerebellum respond to malnutrition and the decrease in circulating IGF-I, a peptide fundamental for growth and development, by increasing the local production of both the growth factor and its receptor in attempt to maintain normal development.

Comparison between inulin clearance and endogenous creatinine clearance in newborn normal weight and growth restricted newborn piglets

The effect of intrauterine growth restriction (IUGR) and acute oxygen deprivation on renal plasma flow (RPF), renal excretory function (Inulin clearance and endogenous creatinine clearance) and urine flow were studied in twenty newborn piglets 12 to 27 hours old. The experiments were performed on anesthetized animals divided into normal weight piglets and intrauterine growth restricted (IUGR) piglets according to birth weights. The "normal weight" category included animals with a birth weight > 40th percentile (piglets heavier than 1220 g); the IUGR category included animals with a birth weight > 5th and < 10th percentiles (piglets with a birthweight between 733 g and 853 g). This animal model of naturally occurring growth restriction in swine gives asymmetric growth with an increase in the mean ratio of brain weight to liver weight from 1.02 to 2.02 (p < 0.01). There was only a small reduction in brain weight (11%). In contrast, the reduction in weight of liver (55%) and kidney (41%) was proportional to that in body weight (48%). Arterial blood pressure, heart rate, arterial blood gases, pH and RPF were similar in normal weight and IUGR piglets. However inulin clearance and creatinine clearance were significantly lower in the growth restricted piglets (p < 0.01). Severe hypoxia induced a moderate tachycardia, combined with pronounced metabolic acidosis and strongly reduced renal plasma flow and renal excretory function in both groups (p < 0.05). Comparison between inulin and creatinine clearances in normal weight and IUGR piglets revealed a markedly higher clearance of creatinine as of inulin at every experimental stages (p < 0.05, p < 0.01). Alterations of renal excretion due to severe hypoxia and early recovery were similar in both animal groups investigated. Regression analysis rendered a linear correlation between inulin clearance and creatinine clearance among the experimental stages for normal weight as well as IUGR piglets (p < 0.001). Thus, endogenous creatinine clearance is suggested to be a reliable indicator for renal excretory function in newborn piglets. It accurately reflects proportional effects of long-term alterations of renal function due to intrauterine growth restriction as well as acute effects of severe oxygen deprivation. However, using standard methods of plasma and urine creatinine measurement, quantitative determination of GFR by endogenous creatinine clearance is not possible.

Altered renal function in growth-restricted newborn piglets.

The effect of intrauterine growth restriction (IUGR) on renal hemodynamics and excretory functions was studied in 76 newborn piglets 12-27 h old. The experiments were performed on anesthetized animals divided into normal-weight piglets and IUGR piglets according to their birth weight. The "normal-weight" category included animals with a birth weight >40th percentile (piglets heavier than 1,220 g); the IUGR category included animals with a birth weight >5th and <10th percentiles (piglets with a birth weight between 733 g and 853 g). Cardiac output and renal blood flow were measured by the colored microsphere technique. Urine was collected from catheters placed in the ureters. This animal model of naturally occurring growth retardation in swine gives asymmetric growth with an increase in the mean ratio of brain weight to liver weight from 1.02 to 1.85 (P<0.01). Thus there was only a small reduction in brain weight (11%). In contrast, the reduction in the weight of liver (50%) and kidney (46%) was proportional to that in body weight (46%). Heart rate, cardiac output, arterial blood gases, and pH were similar in normal-weight and IUGR piglets, but arterial blood pressure and arterial glucose content were significantly reduced in IUGR piglets (P<0.01). Moreover, IUGR piglets had higher plasma catecholamine levels (P<0.05). Renal blood flow and renal vascular resistance were similar in the normal-weight and in the IUGR groups. However, in IUGR animals, glomerular filtration rate was significantly less than in the controls (P<0.05). Normal-weight and IUGR newborn piglets reabsorbed sodium very efficiently, the fractional sodium excretion was less than 1% in both groups. We conclude that renal blood flow is maintained in relation to kidney and body weight in IUGR newborns, but that important renal excretory functions are compromised due to IUGR.

Reduced nitric oxide is involved in prenatal ischemia-induced tolerance to neonatal hypoxic-ischemic brain injury in rats

To explore the role of nitric oxide (NO) in the hypoxic-ischemic (HI) tolerance phenomenon, NO production and brain injury following neonatal hypoxia-ischemia (induced by unilateral common carotid artery ligation followed by hypoxic exposure) were assessed in rat pups with or without HI preconditioning. A previously demonstrated prenatal HI rat model of preconditioning was used in this study. On G17, rat fetuses were subjected to either HI in utero (PreHI) for 30 min or a sham operation (SH). The PreHI treatment provided significant protection against neonatal HI-induced brain injury, as indicated by decreased ipsilateral brain weight reduction, less severe tissue damage, and decreased activation of caspase-3. Concomitant with the protective effect of prenatal HI preconditioning, elevation of nitrite/nitrate content in the ipsilateral cortex of the brain, as an indirect measure of NO production, was significantly lower in the PreHI group than in the SH group following neonatal HI. The protective effect of prenatal HI preconditioning could be reversed by sodium nitroprusside (SNP), a spontaneous NO donor, while SNP had no effect on neonatal HI-induced brain injury in the SH group. Intraperitoneal administration of SNP to pups from the PreHI group (2 mg/kg, 24 and 1.5 h before neonatal HI) increased neonatal HI-induced brain injury similar to that observed in the SH group. On the other hand, l-N G-nitro-arginine (2 mg/kg, i.p., 1.5 h before the hypoxic exposure), an NO synthase inhibitor, significantly attenuated neonatal HI-induced brain injury in the SH group. The overall results indicate that reduced NO production in the preconditioned rat brain contributes to prenatal HI-induced tolerance to neonatal HI brain injury.

Recovery from early cortical damage in rats, VIII. Earlier may be worse: behavioural dysfunction and abnormal cerebral morphogenesis following perinatal frontal cortical lesions in the rat

The size of cortical removal was varied in rats that were given medial frontal lesions on postnatal day 2. In adulthood, the animals were trained on the Morris water task and Whishaw reaching task following which the brains were harvested and dendritic arborization and spine density was examined in the layer III pyramidal cells in Zilles' area Par1. There was a small relationship between lesion size and behavioral outcome as smaller lesions produced somewhat smaller deficits. In contrast, both small and large lesions produced large reductions in brain weight, dendritic arborization, and spine density. The cortex of newborn rats appears to be especially vulnerable to even restricted injury. This contrasts to the effects of similar injury a week later when animals show extensive functional recovery and anatomical compensation.

The Magnitude of Brain Lipid Peroxidation Correlates with the Extent of Degeneration but Not with Density of Neuritic Plaques or Neurofibrillary Tangles or with APOE Genotype in Alzheimer's Disease Patients

Numerous post mortem studies have demonstrated increased accumulation of lipid peroxidation products in diseased regions of Alzheimer's disease (AD) brain; however, few have used techniques that quantify the magnitude of lipid peroxidation in vivo. F(2)-isoprostanes (F(2)-IsoP's) are exclusive products of free radical-mediated peroxidation of arachidonic acid, and their quantification has been widely used as an in vivo biomarker of the magnitude of lipid peroxidation. We have determined F(2)-IsoP concentrations in lateral ventricular fluid (VF) from 23 AD and 12 age-matched controls and correlated these with neuropathological and genetic markers of AD. VF F(2)-IsoP levels were significantly elevated in AD patients compared with controls (p < 0.01) and were significantly correlated with three different measures of brain degeneration: reduction in brain weight (p < 0.01), degree of cortical atrophy (p < 0.01), and Braak stage (p = 0.02). When analysis was restricted to AD patients only, VF F(2)-IsoP levels still were significantly correlated to reduction in brain weight and degree of cortical atrophy (p < 0.05). VF F(2)-IsoP concentrations were not related to density of neuritic plaques or neurofibrillary tangles in seven brain regions, or to the number of epsilon4 alleles of the apolipoprotein E gene (APOE). These data suggest that the magnitude of brain lipid peroxidation is closely related to the extent of brain degeneration in AD but is not significantly influenced by the density of neuritic plaques or neurofibrillary tangles, or the number of epsilon4 alleles of APOE.

Exposures of children to organophosphate pesticides and their potential adverse health effects.

Recent studies show that young children can be exposed to pesticides during normal oral exploration of their environment and their level of dermal contact with floors and other surfaces. Children living in agricultural areas may be exposed to higher pesticide levels than other children because of pesticides tracked into their homes by household members, by pesticide drift, by breast milk from their farmworker mother, or by playing in nearby fields. Nevertheless, few studies have assessed the extent of children's pesticide exposure, and no studies have examined whether there are adverse health effects of chronic exposure. There is substantial toxicologic evidence that repeated low-level exposure to organophosphate (OP) pesticides may affect neurodevelopment and growth in developing animals. For example, animal studies have reported neurobehavorial effects such as impairment on maze performance, locomotion, and balance in neonates exposed (italic)in utero(/italic) and during early postnatal life. Possible mechanisms for these effects include inhibition of brain acetylcholinesterase, downregulation of muscarinic receptors, decreased brain DNA synthesis, and reduced brain weight in offspring. Research findings also suggest that it is biologically plausible that OP exposure may be related to respiratory disease in children through dysregulation of the autonomic nervous system. The University of California Berkeley Center for Children's Environmental Health Research is working to build a community-university partnership to study the environmental health of rural children. This Center for the Health Assessment of Mothers and Children of Salinas, or CHAMACOS in Monterey County, California, will assess (italic)in utero(/italic) and postnatal OP pesticide exposure and the relationship of exposure to neurodevelopment, growth, and symptoms of respiratory illness in children. The ultimate goal of the center is to translate research findings into a reduction of children's exposure to pesticides and other environmental agents, and thereby reduce the incidence of environmentally related disease.

Regulation of neuronal and glial proteins by leptin: implications for brain development.

The complete absence of leptin causes severe obesity in mice and humans, but its physiological roles are incompletely defined. Earlier studies reported decreased brain weight and impaired myelination in ob/ob and db/db mice. Here we have examined the effects of leptin deficiency and postnatal leptin treatment on brain weight, the expression of a broad array of neuronal and glial markers, and locomotor activity. ob/ob and db/db mice have reduced brain weight and an immature pattern of expression of synaptic and glial proteins, with growth-associated protein being elevated in the neocortex and hippocampus, and syntaxin-1, synaptosomal-associated protein-25, and synaptobrevin being decreased. The expression of myelin basic protein, proteolipid protein, and glial fibrillary acidic protein was also decreased in the neocortex, hippocampus, and striatum of ob/ob and db/db mice. Six weeks of leptin treatment initiated at week 4 increased brain weight and protein content, increased locomotor activity, and normalized levels of growth-associated protein, syntaxin-1, and synaptosomal-associated protein-25 in ob/ob mice without affecting synaptobrevin and glial proteins. In contrast with ob/ob and db/db mice, obese agouti (AY/a) mice had normal brain weight and expression of synaptic and glial proteins. These findings suggest that leptin, a peripheral signal of energy stores in adult animals, is required for normal neuronal and glial maturation in the mouse nervous system.

Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein.

We previously have reported corpus callosum defects in transgenic mice expressing the beta-amyloid precursor protein (betaAPP) with a deletion of exon 2 and at only 5% of normal levels. This finding indicates a possible involvement of betaAPP in the regulation or guidance of axon growth during neural development. To determine to what degree the betaAPP mutation interacts with genetic background alleles that predispose for forebrain commissure defects in some mouse lines, we have assessed the size of the forebrain commissures in a sample of 298 mice. Lines with mixed genetic background were compared with congenic lines obtained by backcrossing to the parental strains C57BL/6 and 129/SvEv. Mice bearing a null mutation of the betaAPP gene also were included in the analysis. We show that, independently of genetic background, both lack and underexpression of betaAPP are associated with reduced brain weight and reduced size of forebrain commissures, especially of the ventral hippocampal commissure. In addition, both mutations drastically increase the frequency and severity of callosal agenesis and hippocampal commissure defects in mouse lines with 129/SvEv or 129/Ola background.

Carbamazepine‐Induced Brain Weight Reduction in Chick Embryos

Abstract The antiepileptic drug carbamazepine (CBZ) had been considered to be relatively safe for the fetus. We examined the teratogenicity of CBZ using chick embryos, with particular focus on the brain. A single dose of 5 mg was injected into the yolk sac of White Leghorn chick embryos at 24, 72, 120, 168 or 216 hours of incubation. On day 19 of incubation, embryos were removed, and counted and recorded as either live or dead. Each live embryo was inspected for the presence of external abnormalities, and body and brain weight were measured. There was no statistically significant difference between treated groups and control groups at all hours of incubation for mean body weight and incidence of embryo death. Mean brain weight was significantly lighter in treated groups at 120 and 168 hours of incubation. A significant difference in mean brain/body weight ratio was observed only at 120 hours of incubation. External abnormalities in treated embryos were not found with any consistency and these incidences were not significantly higher compared to those in the control groups. This experiment provides evidence regarding the risk of teratogenesis due to CBZ in the brain of chick embryo. The 120 hours of incubation in chick embryos corresponds to the 34‐36th day after conception in humans.

Methylazoxymethanol acetate-induced abnormalities in the entorhinal cortex of the rat; parallels with morphological findings in schizophrenia

It has been suggested repeatedly that the non-heritable factors in the pathogenesis of schizophrenia involve abnormalities of prenatal neurodevelopment. Furthermore, post-mortem studies show neuropathology of apparently developmental origin in the entorhinal cortex and other brain regions of schizophrenic subjects. In an attempt to model a developmental defect of the entorhinal region in the rat, cerebrocortical proliferation was briefly interrupted during its earliest stages, when the entorhinal area is thought to undergo major cell division. Specifically, the experimental set-up involved the administration of methylazoxymethanol acetate (MAM) on 1 of 4 consecutive days of embryonal development, from E9 to E12. Analysis of the forebrain in adult animals shows reduction of the entorhinal cortex in rats treated on each of these days. This effect shifts from lateral to medial divisions of the entorhinal cortex with later administration of MAM, following a known developmental gradient. Morphological consequences of MAM administration appear to be largely confined to the entorhinal cortex in the groups treated on E9 to E11, although slight reductions of the frontal and occipital neocortex were also observed in these animals. MAM treatment on E12 produces relatively more widespread damage, as reflected among other in a small reduction of brain weight. The described brain abnormalities are not accompanied by obvious phenotypical changes in any, but the E12-treated group. They, moreover, involve cortical thinning, disorganised cortical layering, and abnormal temporal asymmetries. These finding bare some similarity to observations in brains of schizophrenic subjects. The possible relevance of this approach in modeling neurodevelopmental aspects of schizophrenia is discussed.

Cerebrospinal fluid levels of F2-isoprostanes in patients with neurodegerative diseases: [formula omitted], Thomas J. Montine, M. Flint Beal, Merit E. Cudkowicz, Robert H. Brown, Heather O;Donnell, Jason D. Morrow. Vanderbilt University and Harvard University

Numerous post mortem studies have demonstrated increased accumulation of lipid peroxidation products in diseased regions of Alzheimer's disease (AD) brain; however, few have used techniques that quantify the magnitude of lipid peroxidation in vivo. F2-isoprostanes (F2-IsoP's) are exclusive products of free radical-mediated peroxidation of arachidonic acid, and their quantification has been widely used as an in vivo biomarker of the magnitude of lipid peroxidation. We have determined F2-IsoP concentrations in lateral ventricular fluid (VF. from 23 AD and 12 age-matched controls and correlated these with neuropathological and genetic markers of AD. VF F2-IsoP levels were significantly elevated in AD patients compared with controls (p < 0.01) and were significantly correlated with three different measures of brain degeneration. reduction in brain weight (p < 0.01), degree of cortical atrophy (p < 0.01), and Braak stage (p = 0.02). When analysis was restricted to AD patients only, VF F2-IsoP levels still were significantly correlated to reduction in brain weight and degree of cortical atrophy (p < 0.05). VF F2-IsoP concentrations were not related to density of neuritic plaques or neurofibrillary tangles in seven brain regions, or to the number of ε4 alleles of the apolipoprotein E gene (APOE). These data suggest that the magnitude of brain lipid peroxidation is closely related to the extent of brain degeneration in AD but is not significantly influenced by the density of neuritic plaques or neurofibrillary tangles, or the number of ε4 alleles of APOE.

Effect of chronic administration of NMDA antagonists on synaptic development.

The current research assessed the role of the N-methyl-D-aspartate (NMDA) receptor in developmental synaptic plasticity. This was accomplished by quantitative analysis of synaptic number and morphology following pharmacological manipulation of NMDA receptor activity using either the competitive antagonist 2-amino-5-phosphonovaleric acid (APV) or the noncompetitive antagonist phencyclidine (PCP). In the first group, 15-day-old male Long-Evans rats were implanted with osmotic minipumps, which administered 50 mM APV or vehicle at a rate of 0.5 microliter per h into the subjects' occipital cortex for 14 days. At age 30 days (P30), the rats were sacrificed and their occipital neocortices were examined. A second group of rats was given subcutaneous injections of 10 mg/kg PCP or vehicle once daily beginning on P5 for a period of 15 days, and was sacrificed on P20. To determine the effects following withdrawal from long-term NMDA antagonism, a third group of animals was given the same PCP injection routine until P20, but was sacrificed on P21, P26, P36, and P56. Developmental administration of APV was associated with a decreased molecular layer depth and estimated total number of synapses. Similarly, PCP induced a reduction in brain weight, molecular layer depth, and estimated total number of synapses. Withdrawal from NMDA antagonism was initially associated with similar results, i.e., reduced brain weight, cortex depth, synaptic density, and estimated total number of synapses, along with an increase in synaptic length. By P36, however, there was a transitory rebound associated with increased molecular layer depth and estimated total number of synapses. These results support the suggestion that NMDA receptor activation is integral to naturally occurring developmental synaptogenesis, and underscore the importance of NMDA receptor involvement in the process of synaptic plasticity.