Cerebral Gene Expression Research Articles

Study of cerebral gene expression densities using Voronoi analysis

As the available public cerebral gene expression image data increasingly grows, the demand for automated methods to analyze such large amount of data also increases. An important study that can be carried out on these data is related to the spatial relationship between gene expressions. Similar spatial density distribution of expression between genes may indicate they are functionally correlated, thus the identification of these similarities is useful in suggesting directions of investigation to discover gene interactions and their correlated functions. In this paper, we describe the use of a high-throughput methodology based on Voronoi diagrams to automatically analyze and search for possible local spatial density relationships between gene expression images. We tested this method using mouse brain section images from the Allen Mouse Brain Atlas public database. This methodology provided measurements able to characterize the similarity of the density distribution between gene expressions and allowed the visualization of the results through networks and Principal Component Analysis (PCA). These visualizations are useful to analyze the similarity level between gene expression patterns, as well as to compare connection patterns between region networks. Some genes were found to have the same type of function and to be near each other in the PCA visualizations. These results suggest cerebral density correlations between gene expressions that could be further explored.

Cerebral gene expression and neurobehavioural development after perinatal exposure to an environmentally relevant polybrominated diphenylether (BDE47)

Nutrients in seafood are known to be beneficial for brain development. Effects of maternal exposure to 2,2′,4,4′ tetrabromo diphenylether (BDE47) was investigated, alongside the potential ameliorating impact of seafood nutrients, through assessment of neurobehaviour and gene expression in brain and liver. Developing mice were exposed during gestation and lactation via dams dosed through casein- or salmon-based feed, spiked with BDE47. Two concentrations were used: a low level (6 μg/kg feed) representing an environmentally realistic concentration and a high level (1,900 μg/kg feed) representing a BDE47 intake much higher than expected from frequents consumption of contaminated seafood. Experimental groups were similar with respect to reproductive success, growth and physical development. Minor, transient changes in neurobehavioural metrics were observed in groups given the highest dose of BDE47. No significant differences in behaviour or development were seen on postnatal day 18 among maternally exposed offspring. Cerebral gene expression investigated by microarray analyses and validated by RT-qPCR showed low fold changes for all genes, despite dose-dependent accumulation of BDE47 in brain tissue. The gene for glutamate ammonia ligase was upregulated compared to control in the casein-based high BDE47diet, suggesting potential impacts on downstream synaptic transmission. The study supported a previously observed regulation of Igfbp2 in brain with BDE47 exposure. Genes for hepatic metabolic enzymes were not influenced by BDE47. Potential neurotoxic effects and neurobehavioural aberrations after perinatal exposure to high levels of BDE47 were not readily observed in mice pups with the present experimental exposure regimes and methods of analysis.Electronic supplementary materialThe online version of this article (doi:10.1007/s10565-011-9192-8) contains supplementary material, which is available to authorized users.

Thyroid hormone suppression of β-amyloid precursor protein gene expression in the brain involves multiple epigenetic regulatory events

Thyroid hormone (T3) suppresses cerebral gene expression of the β-amyloid precursor protein (APP), an integral membrane protein that plays a key role in the onset and progression of Alzheimer's disease. However, the mechanisms by which T3 signaling pathways inhibit APP gene transcription in the brain remain unclear. By carrying out chromatin immunoprecipitation with neuroblastoma cells and primary rat brain tissue, we show for the first time that thyroid hormone receptors (TRs) directly bind at the APP gene in vivo at a promoter region containing a negative T3-response element. We further show that T3 treatment decreases both histone H3 acetylation and histone H3 lysine 4 methylation at the APP promoter and that chemical inhibitors of histone deacetylases and histone lysine demethylase abrogate T3-dependent APP silencing. Our findings thus suggest that TRs actively facilitate T3-dependent silencing of APP gene expression via the recruitment of distinct histone modifying enzymes associated with transcriptional repression.

Cerebral gene expression in response to single or combined gestational exposure to methylmercury and selenium through the maternal diet.

Controversy remains regarding the safety of consuming certain types of seafood, particularly during pregnancy. While seafood is rich in vital nutrients, it may also be an important source of environmental contaminants such as methylmercury (MeHg). Selenium (Se) is one essential element present in seafood, hypothesised to ameliorate MeHg toxicity. The aim of the present study was to ascertain the impact of Se on MeHg-induced cerebral gene expression in a mammalian model. Microarray analysis was performed on brain tissue from 15-day-old mice that had been exposed to MeHg throughout development via the maternal diet. The results from the microarray analysis were validated using qPCR. The exposure groups included: MeHg alone (2.6 mg kg−1), Se alone (1.3 mg kg−1), and MeHg + Se. MeHg was presented in a cysteinate form, and Se as Se–methionine, one of the elemental species occurring naturally in seafood. Eight genes responded to Se exposure alone, five were specific to MeHg, and 63 were regulated under the concurrent exposure of MeHg and Se. Significantly enriched functional classes relating to the immune system and cell adhesion were identified, highlighting potential ameliorating mechanisms of Se on MeHg toxicity. Key developmental genes, such as Wnt3 and Sparcl1, were also identified as putative ameliorative targets. This study, utilising environmentally realistic forms of toxicants, delivered through the natural route of exposure, in association with the power of transcriptomics, highlights significant novel information regarding putative pathways of selenium and MeHg interaction in the mammalian brain.Electronic supplementary materialThe online version of this article (doi:10.1007/s10565-010-9180-4) contains supplementary material, which is available to authorized users.

Ischemic pre‐conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways

Cerebral gene expression is known to be significantly influenced by a sublethal ischemic event (pre-conditioning; PC) that induces tolerance to future damaging ischemic events. Small non-coding RNAs known as microRNAs (miRNAs) were recently shown to control the mRNA translation. We currently profiled cerebral miRNAs in the cerebral cortex of rats subjected to PC. The miRNAome reacted quickly and by 6 h following PC, levels of 51 miRNAs were altered (26 up- and 25 down-regulated; > 1.5-fold change). Twenty of these stayed at the altered level even at 3 days after PC. At least nine miRNAs showed > 5-fold change at one or more time points between 6 h to 3 days after PC compared with sham. Bioinformatics analysis showed 2007 common targets of the miRNAs that were up-regulated and 459 common targets of the miRNAs that were down-regulated after PC. Pathways analysis showed that MAP-kinase and Mammalian target of rapamycin (mTOR) signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the up-regulated miRNAs, and Wnt and GnRH signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the down-regulated miRNAs after PC. We hypothesize that alterations in miRNAs and their down-stream mRNAs of signaling pathways might play a role in the induction of ischemic tolerance.

Decreased cerebral cortex and liver 5-HT2A receptor gene expression and enhanced ALDH activity in ethanol-treated rats and hepatocyte cultures

Objective: In this work, we evaluated the differential binding of serotonin 2A (5-HT2A) receptor antagonist [3H](±)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] ([3H] MDL 100907) to 5-HT2A receptors in cerebral cortex and liver.Methods: Wistar adult male rats of 180–200 g body weight were given free access to 15% (v/v; ∼ 7·5 g/kg body weight per day) ethanol for 15 days. Brain 5-HT and its metabolites were assayed by a high-performance liquid chromatography. 5-HT2A receptor binding assay was done with different concentrations of [3H] MDL 100907. Hepatocyte culture was done with 10−9–10−3M of 5-HT and ketanserin. The hepatocytes were incubated for 24 hours at 37°C in 5% CO2.Results: Decreased 5-HT content (p<0·05 and p<0·001) and decreased (p<0·001) 5-HT2A receptor binding in cerebral cortex and liver of ethanol-treated rats were observed when compared with control. 5-HT2A receptor mRNA in the cerebral cortex and liver showed an increase in crossing threshold value showing decrease in gene expression in ethanol-treated rats when compared with control. In 24-hour culture works, hepatocytes with 10% ethanol showed an increase in aldehyde dehydrogenase (ALDH) activity (p<0·001), and it decreased (p<0·001) to a near-control level in the case of hepatocytes in a medium with 10% ethanol + 10−5M 5-HT and 10% ethanol + 10−7M 5-HT when compared with the hepatocytes in the medium with 10% ethanol.Conclusion: Our results suggest that the decreased serotonin function mediated through 5-HT2A receptors have a regulatory role on ALDH activity. This will have clinical significance to correct alcoholics from addiction due to allergic aldehyde accumulation.

L’expression génique dans le cortex cérébral de rats anémiques aigus: une analyse par microarray

Hemodilution in perioperative patients has been associated with neurological morbidity and increased mortality by undefined mechanisms. This study assesses whether hemodilutional anemia up-regulated inflammatory cerebral gene expression (microarray) to help define the mechanism. Hemodilution was performed in anesthetized rats by exchanging 50% of the estimated blood volume (30 mL kg(-1)) with pentastarch. Two groups of control animals were utilized, i.e., a non-anesthetized control (Normal Control) and an anesthetized control group (Anesthesia Control). Blood pressure, hemoglobin concentration, and arterial blood gas analysis were performed before and after hemodilution. Cerebral cortex was harvested from isoflurane-anesthetized rats (n = 6) after 6 and 24 hr of recovery and was used to perform complimentary DNA (cDNA) microarray analyses. Pro-inflammatory chemokine and cytokine protein levels were also measured. Microarray analysis demonstrated up-regulation of 72 and 27 genes (6 and 24 hr, respectively) in anemic cerebral cortex. These genes were involved in a number of biological functions, including (1) inflammatory responses; (2) angiogenesis; (3) vascular homeostasis; (4) cellular biology; and (5) apoptosis. Chemokine ribonucleic acid (RNA) expression (CXCL-1, -10, and -11) was highest in anemic brain tissue (P < 0.0125 for each). Protein measurements demonstrated a significant increase in interleukin-6, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 (P < 0.05 for each). This study utilizes microarray technology to elucidate changes in cerebral cortical gene expression in response to acute hemodilution. These findings demonstrate an increase in pro-inflammatory chemokines (RNA, protein) and cytokines (protein). An improved understanding of the inflammatory response to anemia may help to minimize associated morbidity and mortality.

Closed Head Injury in a Mouse Model Results in Molecular Changes Indicating Inflammatory Responses

Cerebral gene expression changes in response to traumatic brain injury will provide useful information in the search for future trauma treatment. In order to characterize the outcome of mild brain injury, we studied C57BL/6J mice in a weight-drop, closed head injury model. At various times post-injury, mRNA was isolated from neocortex and hippocampus and transcriptional alterations were studied using quantitative reverse transcriptase PCR and gene array analysis. At three days post-injury, the results showed unilateral injury responses, both in neocortex and hippocampus, with the main effect seen on the side of the skull hit by the dropping weight. Upregulated transcripts encoded products characterizing reactive astrocytes, phagocytes, microglia, and immune-reactive cells. Markers for oligodendrocytes and T-cells were not altered. Notably, strong differences in the responses among individual mice were seen (e.g., for the Gfap transcript expressed by reactive astrocytes and the chemokine Ccl3 transcript expressed by activated microglial cells). In conclusion, mild TBI chiefly activates transcripts leading to tissue signaling, inflammatory processes, and chemokine signaling, as in focal brain injury, suggesting putative targets for drug development.

Repeated stress in combination with pyridostigmine: Part II: Changes in cerebral gene expression

Organophosphates (OP) represent a potential threat in terrorism or during military conflicts. Due to its faculty to protect cholinesterase (ChE) activity against irreversible inactivation by OP, pyridostigmine bromide (PB) was used as a prophylaxis treatment during the first Persian Gulf War. To explain dysfunctions reported by Gulf War Veterans (GWV), it was suggested a potentiation of the operational stress effects by PB given to soldiers. Our companion paper (see part 1 in the same journal issue) describes that PB treatment administered in repeated stress conditions results in long-term perturbations of learning and social behaviour. The present paper examines, in adult male Wistar rats, consequences of the association of repeated stress and PB treatment on gene expression in hypothalamus and hippocampus. PB treatment (1.5 mg/kg/day) was orally administered 30 min before each stress session to inhibit 40% of blood ChE as recommended by NATO. 10 days of stress alone induce a decrease in hypothalamic Il-1α expression. Treatment with PB alone increases mineralocorticoid receptor expression in hypothalamus which means that PB may thus modify stress perception by animals. Stressed-PB animals showed increase in hippocampal expression of BDNF, TrkB and CamKIIα, three genes implicated in memory development. As a supplement to previous studies showing behavioural and biochemical effects of the association of stress with PB, our data reveal that behavioural effects of this association may be linked with genomic changes in hippocampus. Mechanisms underlying these modifications and their link with memory disturbances reported by GWV remain to be further determined.

Cerebral Gene Expression of Superantigen Encephalitis in the Lewis Rat Induced by Staphylococcal Enterotoxin A

Superantigens were suggested to play a role in the pathogenesis of different autoimmune diseases including multiple sclerosis (MS). Previously, it was demonstrated that local expression of the superantigen, staphylococcal enterotoxin A (SEA) in the brain of rats may lead to encephalitis which was amplified by using intravenous injection of concanavalin A (ConA)-activated splenocytes. In the present investigation, gene expression was studied in the rat brain 8 days after an injection of 50 mul of 1 mg/ml SEA or saline and 5 days after an intravenous injection of 1 x 10(7) ConA-activated spleen cells. Of 8800 genes investigated (Affymetrix, rat genome U34A), the expression of 106 genes was significantly and at least threefold increased with SEA, while the expression of 29 genes was decreased at least threefold. Increased gene expression was compatible with an intracerebral inflammatory response mediated by antigen-presenting cells and CD8+ T lymphocytes. Elevated chemokines comprised RANTES (CCL5), osteopontin, MCP-1 (CCL2) and CXCL10. Further, genes with increased expression were assigned to the extracellular matrix, microglia/macrophage cell elements, astrocytes (GFAP) and phagocytosis. There was considerable conformity between previously reported gene expression profiles for experimental autoimmune encephalomyelitis (EAE) or MS and the present findings. Our data are in line with the concept that T-cell superantigen locally expressed in the central nervous system induces an inflammatory response. Therefore, the study of gene expression profiles does not seem to allow clear conclusions with respect to the aetiology of central nervous system autoimmune diseases.

Induction of Cerebral Ischemic Tolerance by Erythromycin Preconditioning Reprograms the Transcriptional Response to Ischemia and Suppresses Inflammation

A single dose of the macrolide antibiotic erythromycin can induce tolerance against cerebral ischemia in vivo (pharmacologic preconditioning). This study identified potential mechanisms of tolerance induction by assessing effects of erythromycin preconditioning on the cerebral transcriptional response to transient global cerebral ischemia. Preconditioned and nonpreconditioned rats were exposed to 15 min of global cerebral ischemia, and changes in cerebral gene expression were identified by complementary DNA expression array and quantified by real-time reverse-transcription polymerase chain reaction. Ischemia caused a widespread up-regulation of transcription in nonpreconditioned brains in this model. Tolerance induction by erythromycin preconditioning reversed this pattern and caused a net down-regulation of a majority of genes, effectively reprogramming the brain's response pattern to ischemia. The most striking change in transcriptional response found in preconditioned animals was an almost complete suppression of the otherwise profound induction of proinflammatory genes by global ischemia. In contrast, the same treatment had little effect on the expression of apoptosis-inducing genes after ischemia. These findings present a new molecular correlate for the induction of ischemic tolerance achieved by erythromycin preconditioning and will further the understanding of this clinically important new regimen of preemptive neuroprotection.

UTEROPLACENTAL INSUFFICIENCY CAUSES CHANGES IN LEPTIN RECEPTOR EXPRESSION IN THE INTRAUTERINE GROWTH RETARDED RAT BRAIN.

Background Uteroplacental insufficiency causes intrauterine growth retardation (IUGR). IUGR has been linked to a variety of metabolic and developmental disorders, including diabetes, obesity, infertility, stunted skeletal growth, and impaired brain growth. Such disorders may be mediated through the direct affect of IUGR on cerebral proteins and receptors involved in reproductive and metabolic pathways. Leptin and ghrelin have been linked to energy homeostasis, reproductive development, and neuronal synthesis, but the expression of leptin and ghrelin receptors (Ob-Rb and GHS-R, respectively) in the whole brain of IUGR rat pups is unknown. Additionally, the effect of IUGR on kisspeptin (KiSS-1), a protein regulated by leptin and recently implicated in development of the reproductive axis, is unknown. Objectives We hypothesized that uteroplacental insufficiency would cause increased expression of Ob-Rb and GHS-R and decreased expression of KiSS-1 in the whole brain of IUGR rats. Methods To test this, we measured expression of Ob-Rb, GHS-R, and KiSS-1 in the whole brain of IUGR pups obtained by bilateral uterine artery ligation. Sham surgeries were used as controls. Brains were harvested and flash frozen. Real-time RT-PCR was used to measure mRNA expression on day 0 (D0) and day 21 (D21) of life. Results Although there was no significant difference between IUGR and SHAM rats in GHS-R or KiSS-1 expression, D0 IUGR pups had significantly higher expression of Ob-Rb mRNA in whole brain than D0 SHAM pups (p = .003). Preliminary results indicate a trend toward decreased expression of Ob-Rb mRNA in whole brain of D21 IUGR rats (p = .09). Conclusion We conclude that uteroplacental insufficiency up-regulates Ob-Rb expression at D0 in the IUGR rat brain. We have shown that the IUGR insult epigenetically regulates cerebral gene expression, and we speculate that Ob-Rb expression may be modulated through changes in chromatin structure. Additionally, recent research has demonstrated that leptin signaling affects adrenal glucocorticoid production as well as CNS glucocorticoid receptor expression. We have previously shown that IUGR affects glucocorticoid receptor expression in the rat brain, and we postulate that this effect may be mediated through up-regulation of cerebral Ob-Rb receptors.

Persistent brain infection and disease reactivation in relapsing fever borreliosis

Relapsing fever, an infection caused by Borrelia spirochetes, is generally considered a transient, self-limiting disease in humans. The present study reveals that murine infection by Borrelia duttonii can be reactivated after an extended time as a silent infection in the brain, with no bacteria appearing in the blood and spirochete load comparable to the numbers in an infected tick. The host cerebral gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor cause noticeable tissue damage. Silent infection can be reactivated by immunosuppression, inducing spirochetemia comparable to that of initial densities. B. duttonii has never been found in any host except man and the tick vector. We therefore propose the brain to be a possible natural reservoir of the spirochete. The view of relapsing fever as an acute disease should be extended to include in some cases prolonged persistence, a feature characteristic of the related spirochetal infections Lyme disease and syphilis.

Probing the molecules of the mind

The molecular dimension of biology has been finding practical applications in all fields of medicine over the last few decades, but arguably one of the most challenging and exciting areas is that of molecular psychiatry. Much progress has been gained from traditional linkage studies into gene candidates for various psychiatric disorders, including schizophrenia, bipolar states, bulimia, autism and attention deficit hyperactivity disorder. This review outlines basic principles of molecular medicine from the perspective of the human genome project and its role in enabling rapid progress in the understanding of molecular neuro-anatomy, physiology and pathology. These insights have facilitated rather than complicated the diagnostic process, and have paved the way, in what has been termed the “post-genome era”, for a rational approach to therapy in a growing range of disorders. A patient's inherited genetic constitution is but one aspect of molecular medicine, and rich insights are also being gained into the operation of the genome as it interacts with its environment, including its pharmacological environment. From parallel processing technologies and genomic expression profiling, massive knowledge is being gained into the anatomical and physiological patterns of gene expression in different tissues and organs, their derangements in disease and their pharmacological manipulation. The brain is no exception, and an appreciation is being accumulated of the three dimensional anatomical localization of cerebral gene expression patterns, of great relevance to a fundamental understanding of neurobiology. From this new paradigm and others, insights are now being gained into the molecular biology of a variety of topics previously thought to be beyond the scope of molecular dissection, such as language and emotion. Key words : Gene expression, Micro array, Pharmacogenetics, Psychiatric South African Psychiatry Review Vol. 8 (3) 2005: 89-94

Does the penumbra recover: Pharmacological versus hemodynamic interventions

The ischemic penumbra can be defined in many ways, based on measurements of electrophysiologic function, cerebral blood flow, metabolism, and gene expression. But perhaps the most clinically relevant definition is the pharmacologic penumbra, i.e. any brain tissue that can be salvaged after stroke. In theory, there are two non-mutually exclusive ways to salvage the penumbra: hemodynamic reperfusion and pharmacologic treatment. In this presentation, we will (1) review the experimental animal model data to verify how robust neuroprotection data really are for permanent versus transient focal cerebral ischemia, (2) examine the profiles of penumbral collapse as defined by spreading peri-infarct depolarizations with or without reperfusion, and (3) assess existing in vivo imaging data to see how the penumbra responds to reperfusion and therapy. If available, data from the SAINT trials that combine tPA with NXY-059 may also be discussed. Overall, these experimental and clinical data may give insight into the question of whether true neuroprotection in stroke is feasible in the absence of reperfusion.

Cerebral gene expression profiles in sporadic Creutzfeldt–Jakob disease

The pathomechanism of sporadic Creutzfeldt-Jakob disease (sCJD) in the central nervous system is insufficiently understood. The aims of this study were to identify differentially regulated genes in the frontal cortex of sCJD and to profile the gene expression patterns in sCJD by using Affymetrix HGU133A microarrays (Affymetrix, Santa Clara, CA). The microarray data were generated by dChip and analyzed by Significance Analysis of Microarray (SAM) software. A comparison between control and sCJD samples identified 79 upregulated and 275 downregulated genes, which showed at least 1.5- and 2-fold changes, respectively, in sCJD frontal cortex, with an estimated false discovery rate of 5% or less. The major alterations in sCJD brains included upregulation of the genes encoding immune and stress-response factors and elements involved in cell death and cell cycle, as well as prominent downregulation of genes encoding synaptic proteins. A comparison of the molecular subtypes of sCJD showed various expression patterns associated with particular subtypes. The range of the upregulated genes and the degree of the increased expression appeared to be correlated with the degree of the neuropathological alterations in particular subtypes. Conspicuously, sCJD brains showed a great similarity with ageing human brains, both in the global expression patterns and in the identified differentially expressed genes.

Effect of the Chinese Traditional Medicine "Bushen Yinao Pian" on the Cerebral Gene Expression of the Senescence-Accelerated Mouse Prone 8/Ta

The effect of Chinese traditional medicine "Bushen Yinao Pian," a complex prescription used for anti-aging, on the cerebral gene expression of the senescence-accelerated mouse prone 8/Ta (SAMP8/Ta) had been studied with messenger ribonuclear acids reverse transcription differential display polymerase chain reaction (mRNA DDRT-PCR). Eight differential displayed bands had been discerned and sequenced. The sequences of those fragments are matched to adipocyte-specific protein-5; low density lipoprotein receptor-related protein associated protein-1; reticulon-3; cysteine and histidine-rich domain (CHORD)-containing, zinc-binding protein-1; cytochrome c oxidase subunit-2 (Cox-2); cytochrome c gene, MC1; DNA sequence from clone RP23-72M11 on chromosome X, respectively and a novel sequence fragment. Most of these genes are aging-related. It can be proved that the "Bushen Yinao Pian" truly has anti-aging function.

Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency

Severe uteroplacental insufficiency causes cerebral apoptosis in the fetus. Moderate uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and increases the risk of postnatal neurological morbidity. In the rat, uteroplacental insufficiency and IUGR affect cerebral gene expression of Bcl-2 and predispose the newborn IUGR rat toward cerebral apoptosis when challenged with perinatal hypoxia. Expression of Bcl-2, as well as the proapoptotic protein Bax, is regulated by p53. p53 also induces MDM2 transcription, which functions to limit further p53-induced apoptosis. The predisposition of the IUGR fetus toward cerebral apoptosis suggests that the p53-MDM2 "functional" circuit may be perturbed in the newborn IUGR rat brain. We hypothesized that MDM2 cerebral expression does not increase in response to increased p53 expression or increased levels of phospho-p53 (Ser15), an activated form of p53. To prove this hypothesis, we induced IUGR through bilateral uterine ligation of the pregnant rat. Uteroplacental insufficiency significantly increased p53 mRNA, total p53 protein, and phospho-p53 (Ser15) protein levels in the brain at term. Increased expression of phospho-p53 (Ser15) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were localized to the CA1 region of the hippocampus, the subcortical and periventricular white matter, and the amygdala of the IUGR rat brain. In contrast, uteroplacental insufficiency decreased cerebral MDM2 mRNA and phospho-MDM2 (Ser166) protein levels in the IUGR rat pups. We conclude that the cerebral MDM2 response to increased p53 expression is not present in the newborn IUGR rat pup, and we speculate that this contributes to the predisposition of the IUGR fetus toward perinatal and long-term neurodevelopmental morbidities.

Challenges for basic research in glutaryl‐CoA dehydrogenase deficiency

During the last decades, efforts have been made to elucidate the complex mechanisms underlying neuronal damage in glutaryl-CoA dehydrogenase deficiency. A combination of in vitro and in vivo investigations have facilitated the development of several hypotheses, including the probable pathogenic role of accumulating glutaric acid and 3-hydroxyglutaric acid. However, there are still many shortcomings that limit an evidence-based approach to treating this inborn error of metabolism. Major future goals should include generation of a suitable animal model for acute striatal necrosis, investigation of the formation, distribution and exact intra- and extracellular concentrations of accumulating metabolites, a deeper understanding of striatal vulnerability, and systematic investigation of effects on cerebral gene expression during development and of the modulatory role of inflammatory cytokines.

Anaemia and the brain

This article reviews the physiological and pathophysiological effects of anaemia on the brain, focusing on the hypothesis that anaemia-induced cerebral hypoxia contributes to anaemic cerebral dysfunction and injury. It also reviews evidence that the regulated increase in cerebral blood flow observed during anaemia represents a compensatory neuroprotective mechanism invoked to optimize cerebral oxygen delivery, thereby protecting the brain from hypoxic injury. Severe anaemia, or low haematocrit, has been associated with cognitive dysfunction, impaired cerebral vascular regulation, neurological injury, and increased mortality, which suggests that the brain is vulnerable to anaemia-induced injury. Reduced cerebral tissue oxygen tension has been measured directly at haemoglobin concentrations near 35 g/l, suggesting that hypoxia may contribute to anaemic cerebral injury. A demonstration of increased hypoxic cerebral gene expression, including neuronal nitric oxide synthase, may provide a more sensitive means of determining the minimum haemoglobin concentration at which anaemia-induced cerebral hypoxia can be detected. The measurement of increased cerebral cortical neuronal nitric oxide synthase messenger RNA and protein levels in rats, at haemoglobin concentrations between 50 and 60 g/l, suggests that cerebral hypoxia occurred at these higher haemoglobin concentrations. Mechanisms regulating anaemic cerebral vasodilation and increased cerebral oxygen delivery, including nitric oxide, require further elucidation to establish their role in protecting the brain during anaemia. Characterization of mechanisms of anaemia-induced cerebral injury will contribute to the development of optimal therapeutic strategies for anaemic patients. Such strategies would include a clearer definition of transfusion triggers based on physiological endpoints. The overall goal of these efforts would be to minimize morbidity and mortality associated with anaemia.