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1.
Dev Neurosci ; 40(1): 84-92, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29216635

RESUMO

Neuropsychiatric disorders that frequently initially emerge during adolescence are associated with deficits in the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA), elevated proinflammatory signaling, and regional reductions in white matter integrity (WMI). This study determined the effects of altering brain DHA accrual during adolescence on WMI in the rat brain by diffusion tensor imaging (DTI), and investigated the potential mediating role of proinflammatory signaling. During periadolescent development, male rats were fed a diet deficient in n-3 fatty acids (DEF, n = 20), a fish oil-fortified diet containing preformed DHA (FO, n = 20), or a control diet (CON, n = 20). In adulthood, DTI scans were performed and brain WMI was determined using voxelwise tract-based spatial statistics (TBSS). Postmortem fatty acid composition, peripheral (plasma IL-1ß, IL-6, and C-reactive protein [CRP]) and central (IL-1ß and CD11b mRNA) proinflammatory markers, and myelin basic protein (MBP) mRNA expression were determined. Compared with CON rats, forebrain DHA levels were lower in DEF rats and higher in FO rats. Compared with CON rats, DEF rats exhibited greater radial diffusivity (RD) and mean diffusivity in the right external capsule, and greater axial diffusivity in the corpus callosum genu and left external capsule. DEF rats also exhibited greater RD than FO rats in the right external capsule. Forebrain MBP expression did not differ between groups. Compared with CON rats, central (IL-1ß and CD11b) and peripheral (IL-1ß and IL-6) proinflammatory markers were not different in DEF rats, and DEF rats exhibited lower CRP levels. These findings demonstrate that deficits in adolescent DHA accrual negatively impact forebrain WMI, independently of elevated proinflammatory signaling.


Assuntos
Ácidos Docosa-Hexaenoicos/deficiência , Neurogênese/fisiologia , Prosencéfalo/patologia , Substância Branca/patologia , Animais , Imagem de Tensor de Difusão , Masculino , Ratos , Ratos Long-Evans
2.
Artigo em Inglês | MEDLINE | ID: mdl-28529008

RESUMO

There is a substantial body of evidence from animal studies implicating polyunsaturated fatty acids (PUFA) in neuroinflammatory, neurotrophic, and neuroprotective processes in brain. However, direct evidence for a role of PUFA in human brain structure and function has been lacking. Over the last decade there has been a notable increase in neuroimaging studies that have investigated the impact of PUFA intake and/or blood levels (i.e., biostatus) on brain structure, function, and pathology in human subjects. The majority of these studies specifically evaluated associations between omega-3 PUFA intake and/or biostatus and neuroimaging outcomes using a variety of experimental designs and imaging techniques. This review provides an updated overview of these studies in an effort to identify patterns to guide and inform future research. While the weight of evidence provides general support for a beneficial effect of a habitual diet consisting of higher omega-3 PUFA intake on cortical structure and function in healthy human subjects, additional research is needed to replicate and extend these findings as well as identify response mediators and clarify mechanistic pathways. Controlled intervention trials are also needed to determine whether increasing n-3 PUFA biostatus can prevent or attenuate neuropathological brain changes observed in patients with or at risk for psychiatric disorders and dementia.

3.
Nutr Neurosci ; : 1-9, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29286866

RESUMO

Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (n = 20) from P21 to P90. During adolescence (P40-60), one-half of each diet group received daily AMPH injections escalated weekly (0.5, 1.0, 2.5, 5.0 mg/kg/d) or drug vehicle. Following a 30-d abstinence period blood oxygen level dependent (BOLD) responses were determined in a 7 T Bruker Biospec system following an AMPH challenge (7.5 mg/kg, i.v). Postmortem erythrocyte and forebrain DHA composition were determined by gas chromatography. Compared with control rats, forebrain and erythrocyte DHA levels were significantly lower in DEF rats and significantly higher in FO rats. Across AMPH doses DEF rats exhibited greater locomotor activity compared to control and FO rats. In AMPH-naïve rats, the AMPH challenge increased BOLD activity in the substantia nigra and basal forebrain and no diet group differences were observed. In AMPH-pretreated control and FO rats, the AMPH challenge similarly increased BOLD activation in the bilateral caudate putamen, thalamus, and motor and cingulate cortices. In contrast, BOLD activation in AMPH-pretreated DEF rats was similar to AMPH-naïve DEF animals, and AMPH-pretreated DEF rats exhibited attenuated frontostriatal BOLD activation compared with AMPH-pretreated control and FO rats. These findings demonstrate that chronic escalating AMPH treatment induces enduring frontostriatal recruitment and that peri-adolescent deficits in brain DHA accrual impair this response.

4.
Psychiatry Res Neuroimaging ; 270: 39-45, 2017 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-29049903

RESUMO

Major psychiatric disorders are associated with dysregulated glutamate homeostasis and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). This study determined the effects of dietary-induced alterations in brain DHA accrual on cortical glutamate homeostasis in the adult rat brain. Adolescent rats were fed a control diet (n = 20), a n-3 fatty acid-deficient diet (DEF, n = 20), or a fish oil-fortified diet containing preformed DHA (FO, n = 20). In adulthood 1H MRS scans were performed with voxels in the prefrontal cortex (PFC) and thalamus. Compared with controls, erythrocyte, PFC, and thalamus DHA levels were significantly lower in DEF rats and significantly higher in FO rats. In the PFC, but not the thalamus, glutamate was significantly elevated in DEF rats compared with controls and FO rats. Glutamine did not differ between groups and the glutamine/glutamate ratio was lower in DEF rats. No differences were observed for markers of excitotoxicity (NAA, GFAP), or astrocyte glutamate transporter (GLAST, GLT-1) or glutamine synthetase expression. Across diet groups, PFC DHA levels were inversely correlated with PFC glutamate levels and positively correlated with GLAST expression. Together these findings demonstrate that rat cortical DHA accrual during adolescence impacts glutamate homeostasis in the adult PFC.


Assuntos
Envelhecimento/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Glutâmico/metabolismo , Homeostase , Córtex Pré-Frontal/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Astrócitos/metabolismo , Dieta , Ácidos Docosa-Hexaenoicos/deficiência , Glutamato-Amônia Ligase/metabolismo , Glutamina/metabolismo , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Long-Evans
5.
Tumour Biol ; 39(10): 1010428317737729, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29072132

RESUMO

Previous in vitro studies have demonstrated that miR-144 inhibits hepatocellular carcinoma cell proliferation, invasion, and migration. We have shown that miR-144, injected intravenously, is taken up by the liver and induces endogenous hepatic synthesis of miR-144. We hypothesized that administered miR-144 has tumor-suppressive effects on liver tumor development in vivo. The effects of miR-144 on tumorigenesis and tumor growth were tested in a diethylnitrosamine-induced hepatocellular carcinoma mouse model. MiR-144 injection had no effect on body weight but significantly reduced diethylnitrosamine-induced liver enlargement compared with scrambled microRNA. MiR-144 had no effect on diethylnitrosamine-induced liver tumor number but reduced the tumor size above 50%, as evaluated by magnetic resonance imaging (scrambled microRNA 23.07 ± 5.67 vs miR-144 10.38 ± 2.62, p < 0.05) and histological analysis (scrambled microRNA 30.75 ± 5.41 vs miR-144 15.20 ± 3.41, p < 0.05). The levels of miR-144 was suppressed in tumor tissue compared with non-tumor tissue in all treatment groups (diethylnitrosamine-phosphate-buffered saline non-tumor 1.05 ± 0.09 vs tumor 0.54 ± 0.08, p < 0.01; diethylnitrosamine-scrambled microRNA non-tumor 1.23 ± 0.33 vs tumor 0.44 ± 0.10, p < 0.05; diethylnitrosamine-miR-144 non-tumor 54.72 ± 11.80 vs tumor 11.66 ± 2.75, p < 0.01), but injection of miR-144 greatly increased miR-144 levels both in tumor and non-tumor tissues. Mechanistic studies showed that miR-144 targets epidermal growth factor receptor and inhibits the downstream Src/AKT signaling pathway which has previously been implicated in hepatocellular carcinoma tumorigenesis. Exogenously delivered miR-144 may be a therapeutic strategy to suppress tumor growth in hepatocellular carcinoma.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , MicroRNAs/administração & dosagem , Administração Intravenosa , Animais , Apoptose/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , MicroRNAs/genética
6.
Hum Mol Genet ; 26(19): 3776-3791, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28934388

RESUMO

Recently, we identified biallelic mutations of SLC25A46 in patients with multiple neuropathies. Functional studies revealed that SLC25A46 may play an important role in mitochondrial dynamics by mediating mitochondrial fission. However, the cellular basis and pathogenic mechanism of the SLC25A46-related neuropathies are not fully understood. Thus, we generated a Slc25a46 knock-out mouse model. Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells. Increased numbers of small, unmyelinated and degenerated optic nerves as well as loss of retinal ganglion cells indicated optic atrophy. Compound muscle action potentials in peripheral nerves showed peripheral neuropathy associated with degeneration and demyelination in axons. Mutant cerebellar neurons have large mitochondria, which exhibit abnormal distribution and transport. Biochemically mutant mice showed impaired electron transport chain activity and accumulated autophagy markers. Our results suggest that loss of SLC25A46 causes degeneration in neurons by affecting mitochondrial dynamics and energy production.


Assuntos
Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Animais , Ataxia/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Dinâmica Mitocondrial/fisiologia , Mutação , Células Ganglionares da Retina/patologia
7.
J Psychiatr Res ; 95: 143-146, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28846858

RESUMO

Evidence from 31P magnetic resonance spectroscopy (31P MRS) studies suggest that different psychiatric disorders, which typically emerge during adolescence and young adulthood, are associated with abnormalities in mitochondrial bioenergetics and membrane phospholipid metabolism. These disorders are also associated with deficits in omega-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) which accumulates in mitochondrial and synaptic membranes. The present study investigated the effects of dietary-induced alterations in brain DHA accrual during adolescence on phospholipid metabolism and bioenergetics in the adult rat brain using 31P MRS. During the peri-adolescent period (P21-P90), male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (18:3n-3, n = 20). On P90, 31P MRS was performed under isoflurane anesthetic using a 7 T Bruker Biospec system. Compared with controls, brain DHA levels were significantly lower in adult rats fed the DEF diet (-17%, p ≤ 0.0001) and significantly higher in rats fed the FO diet (+14%, p ≤ 0.0001). There were no significant group differences for indices of bioenergetics, including adenosine triphosphate and phosphocreatine levels, or indices of membrane phospholipid metabolism including phosphomonoesters and phosphodiesters. Therefore, the present 31P MRS data suggest that rat brain DHA levels are not a significant predictor of mitochondrial bioenergetics or membrane phospholipid metabolism.


Assuntos
Trifosfato de Adenosina/metabolismo , Encéfalo/metabolismo , Dieta , Ácidos Docosa-Hexaenoicos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Mitocôndrias/metabolismo , Fosfolipídeos/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Metabolismo Energético/fisiologia , Masculino , Fósforo , Ratos , Ratos Long-Evans
8.
Quant Imaging Med Surg ; 5(4): 511-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26435914

RESUMO

BACKGROUND: Childhood lead exposure has been linked to adult gray matter loss accompanied by changes in myelination and neurochemistry noninvasively revealed by magnetic resonance imaging (MRI) methods. However, the extent, duration and timing of lead exposure required to produce such imaging changes in humans are difficult to ascertain. METHODS: To determine if such changes are related to early exposure to low levels of lead, we treated mouse dams with 0, 3, or 30 ppm of lead acetate in drinking water for 2 months prior to mating through gestation until weaning of the offspring at post-natal day 21. Two male and two female pups from each litter were imaged at post-natal day 60. Volumetric, diffusion tensor imaging and magnetic resonance spectroscopy (MRS) measurements were obtained using a seven Tesla Bruker animal MRI scanner. RESULTS: Postnatal blood lead levels were identical between groups at the time of imaging. No effects of lead exposure were detected in the volumetric or MRS data. Mean diffusivity in the hippocampus showed significant effects of lead exposure and gender. CONCLUSIONS: These data suggest that low-level, gestational lead exposure in a mouse model produces minimal changes observed by MRI.

9.
Neurotoxicology ; 46: 92-100, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25530354

RESUMO

Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend toward negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Chumbo/toxicidade , Caracteres Sexuais , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Mapeamento Cromossômico , Ilhas de CpG/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo
10.
J Neurosci ; 34(49): 16467-81, 2014 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-25471584

RESUMO

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.


Assuntos
Movimento Celular/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/prevenção & controle , Inflamação/prevenção & controle , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Propilenoglicóis/farmacologia , Esfingosina/análogos & derivados , Animais , Animais Recém-Nascidos , Atrofia/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corioamnionite/tratamento farmacológico , Corioamnionite/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Cloridrato de Fingolimode , Humanos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Recém-Nascido , Lipopolissacarídeos , Linfócitos/citologia , NF-kappa B/metabolismo , Gravidez , Propilenoglicóis/uso terapêutico , Ratos , Receptores de Interleucina/metabolismo , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
11.
PLoS One ; 9(6): e98807, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24911517

RESUMO

Edaravone, a potent antioxidant, may improve thrombolytic therapy because it benefits ischemic stroke patients on its own and mitigates adverse effects of tissue plasminogen activator (tPA) in preclinical models. However, whether the combined tPA-edaravone therapy is more effective in reducing infarct size than singular treatment is uncertain. Here we investigated this issue using a transient hypoxia-ischemia (tHI)-induced thrombotic stroke model, in which adult C57BL/6 mice were subjected to reversible ligation of the unilateral common carotid artery plus inhalation of 7.5% oxygen for 30 min. While unilateral occlusion of the common carotid artery suppressed cerebral blood flow transiently, the addition of hypoxia triggered reperfusion deficits, endogenous thrombosis, and attenuated tPA activity, leading up to infarction. We compared the outcomes of vehicle-controls, edaravone treatment, tPA treatment at 0.5, 1, or 4 h post-tHI, and combined tPA-edaravone therapies with mortality rate and infarct size as the primary end-points. The best treatment was further compared with vehicle-controls in behavioral, biochemical, and diffusion tensor imaging (DTI) analyses. We found that application of tPA at 0.5 or 1 h--but not at 4 h post-tHI--significantly decreased infarct size and showed synergistic (p<0.05) or additive benefits with the adjuvant edaravone treatment, respectively. The acute tPA-edaravone treatment conferred >50% reduction of mortality, ∼ 80% decline in infarct size, and strong white-matter protection. It also improved vascular reperfusion and decreased oxidative stress, inflammatory cytokines, and matrix metalloproteinase activities. In conclusion, edaravone synergizes with acute tPA treatment in experimental thrombotic stroke, suggesting that clinical application of the combined tPA-edaravone therapy merits investigation.


Assuntos
Antipirina/análogos & derivados , Trombose Intracraniana/complicações , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Antipirina/farmacologia , Antipirina/uso terapêutico , Hipóxia Celular/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Edaravone , Humanos , Hipóxia-Isquemia Encefálica/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tecidual/uso terapêutico , Substância Branca/efeitos dos fármacos , Substância Branca/lesões
12.
Int J Dev Neurosci ; 35: 7-15, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24594360

RESUMO

Ventriculomegaly occurs when there is imbalance between creation and absorption of cerebrospinal fluid (CSF); even when treated, long-term behavioral changes occur. Kaolin injection in the cisterna magna of rats produces an obstruction of CSF outflow and models one type of hydrocephalus. Previous research with this model shows that neonatal onset has mixed effects on Morris water maze (MWM) and motoric performance; we hypothesized that this might be because the severity of ventricular enlargement was not taken into consideration. In the present experiment, rats were injected with kaolin or saline on postnatal day (P)21 and analyzed in subgroups based on Evan's ratios (ERs) of the severity of ventricular enlargement at the end of testing to create 4 subgroups from least to most severe: ER0.4-0.5, ER0.51-0.6, ER0.61-0.7, and ER0.71-0.82, respectively. Locomotor activity (dry land and swimming), acoustic startle with prepulse inhibition (PPI), and MWM performance were tested starting on P28 (122cm maze) and again on P42 (244cm maze). Kaolin-treated animals weighed significantly less than controls at all times. Differences in locomotor activity were seen at P42 but not P28. On P28 there was an increase in PPI for all but the least severe kaolin-treated group, but no difference at P42 compared with controls. In the MWM at P28, all kaolin-treated groups had longer path lengths than controls, but comparable swim speeds. With the exception of the least severe group, probe trial performance was worse in the kaolin-treated animals. On P42, only the most severely affected kaolin-treated group showed deficits compared with control animals. This group showed no MWM learning and no memory for the platform position during probe trial testing. Swim speed was unaffected, indicating motor deficits were not responsible for impaired learning and memory. These findings indicate that kaolin-induced ventriculomegaly in rats interferes with cognition regardless of the final enlargement of the cerebral ventricles, but final size critically determines whether lasting locomotor, learning, and memory impairments occur.


Assuntos
Modelos Animais de Doenças , Hidrocefalia/fisiopatologia , Transtornos de Aprendizagem/fisiopatologia , Transtornos da Memória/fisiopatologia , Transtornos Mentais/fisiopatologia , Transtornos dos Movimentos/fisiopatologia , Animais , Doença Crônica , Hidrocefalia/induzido quimicamente , Caulim , Transtornos de Aprendizagem/induzido quimicamente , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos Mentais/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Desmame
13.
PLoS One ; 8(11): e80558, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24260418

RESUMO

Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb), an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD). Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC) into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons), and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents.


Assuntos
Encéfalo/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Chumbo/toxicidade , Exposição Materna , Neurônios/citologia , Neurônios/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camundongos , Gravidez
14.
Sci Transl Med ; 5(193): 193ra90, 2013 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-23843451

RESUMO

Intracranial hemorrhage in preterm neonates may result in neonatal mortality and functional disabilities, but its pathogenic mechanisms are poorly defined and better therapies are needed. We used a tetracycline-regulated transgenic system to test whether the induction of vascular endothelial growth factor (VEGF) in the germinal matrix leads to intracranial hemorrhage. This genetic strategy initially induced a dense network of loosely adjoined endothelial cells and pericytes near lateral ventricles, similar to the immature vascular rete in human fetal brains. Yet, this rich vascular network transformed into low-vasculature patches correlated with hemorrhage and caspase-3 activation near birth. Gene expression and biochemical analyses suggested that downstream mediators of VEGF in this network include transcriptional factors ETS1 and HIF2α (hypoxia-inducible factor 2α), components of the PDGFß (platelet-derived growth factor ß) and TGFß (transforming growth factor-ß) receptor signaling pathways, matrix metalloproteinase-9 (MMP-9), and cathepsins. Prenatal administration of glucocorticoids markedly reduced mortality and cerebral hemorrhage in mutant animals, as in human neonates. This protective effect was not due to blocking vasculogenesis, but was instead associated with inhibition of neurovascular proteases, notably MMP-9, cathepsin B, and caspase-3. Collectively, these results support a causative role of VEGF in perinatal cerebral hemorrhage and implicate its downstream proteases as potential therapeutic targets.


Assuntos
Hemorragia Cerebral/enzimologia , Hemorragia Cerebral/patologia , Peptídeo Hidrolases/biossíntese , Prosencéfalo/enzimologia , Prosencéfalo/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Betametasona/farmacologia , Betametasona/uso terapêutico , Caspase 3/metabolismo , Catepsina B/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/genética , Modelos Animais de Doenças , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/patologia , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Neovascularização Patológica/tratamento farmacológico , Fenótipo , Prosencéfalo/irrigação sanguínea , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Tetraciclina/farmacologia
15.
Radiol Clin North Am ; 51(4): 721-42, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23830795

RESUMO

This review describes various quantitative magnetic resonance imaging techniques that can be used to objectively analyze the composition (T2 relaxation time mapping, Dixon imaging, and diffusion-weighted imaging), architecture (diffusion tensor imaging), mechanical properties (magnetic resonance elastography), and function (magnetic resonance spectroscopy) of normal and pathologic skeletal muscle in the pediatric population.


Assuntos
Imagem por Ressonância Magnética/métodos , Doenças Musculares/diagnóstico , Doenças Musculares/fisiopatologia , Adolescente , Criança , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Análise Espectral
16.
NMR Biomed ; 26(9): 1152-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23401319

RESUMO

In previous work at 4.7 T, the individual components of biexponential (7) Li transverse (T2 ) spin relaxation in rat brain in vivo were tentatively identified with intra- and extracellular Li. The goal in this work was to estimate Li's compartmental distribution as a function of total Li concentration in brain from the biexponential decays. Here a localized, biexponential (7) Li T2 MR spin-relaxation study with isotopically enriched (7) LiCl is reported in rat brain in vivo at 7 T. Additionally, a simple linear interpolation using the biexponential T2 values to estimate intracellular Li from individual monoexponential T2 decays was assessed. Intracellular T2 was 14.8 ± 4.3 ms and extracellular T2 was 295 ± 61 ms. The fraction of intracellular brain Li ranged from 37.3 to 64.8% (mean 54.5 ± 6.7%) and did not correlate with total Li concentration. The estimated intracellular Li concentration ranged from 47 to 80% (mean 68.3 ± 8.5%) of the total brain Li concentration and was highly correlated with it. The monoexponential estimates of the intracellular-Li fractions and derived concentrations averaged about 15% higher than the corresponding biexponential estimates. This work supports the previous conclusion that a large fraction of Li in the brain is within the intracellular compartment.


Assuntos
Encéfalo/metabolismo , Lítio/metabolismo , Espectroscopia de Ressonância Magnética , Animais , Encéfalo/citologia , Lítio/análise , Masculino , Prótons , Ratos , Ratos Sprague-Dawley
17.
Exp Neurol ; 247: 447-455, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23353638

RESUMO

Perinatal infection aggravates neonatal hypoxic-ischemic (HI) brain injury and may interfere with therapeutic hypothermia. While the NF-κB signaling pathway has been implicated in microglia activation in infection-sensitized HI, the current therapeutic strategies rely on systemic intervention, which could impair neonatal immunity and increase the risk of severe infection. To devise a brain-targeted anti-NF-κB strategy, we examined the effects of intranasal delivery of tat-NBD peptides in two animal models of neonatal infection-sensitized HI. Kinetic experiments showed that tat-NBD peptides entered the olfactory bulbs rapidly (10-30 min) and peaked in the cerebral cortex around 60 min after intranasal application in P7 rats. Further, intranasal delivery of 1.4 mg/kg tat-NBD, which is only 7% of the intravenous dose in past studies, markedly attenuated NF-κB signaling, microglia activation, and brain damage triggered by HI with 4 or 72 h pre-exposure to the bacterial endotoxin lipopolysaccharide (LPS). In contrast, intranasal delivery of mutant tat-NBD peptides or systemic application of minocycline failed to block LPS-sensitized HI injury. Yet, intranasal delivery of up to 5.6 mg/kg tat-NBD peptides immediately after pure-HI insult showed little protection, likely due to its rapid clearance from the brain and inability to inhibit parenchymal plasminogen activators. Together, these results suggest a novel therapy of infection-sensitized HI brain injury in newborns.


Assuntos
Hipóxia-Isquemia Encefálica/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , NF-kappa B/antagonistas & inibidores , Peptídeos/administração & dosagem , Administração Intranasal , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Hipóxia-Isquemia Encefálica/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas dos Microfilamentos/metabolismo , Mutação/fisiologia , Ratos , Sais de Tetrazólio
18.
Cereb Cortex ; 23(5): 1218-29, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22556277

RESUMO

Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.


Assuntos
Lesões Encefálicas/metabolismo , Lesões Encefálicas/prevenção & controle , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/prevenção & controle , Lipopolissacarídeos , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Ativador de Plasminogênio Tecidual/metabolismo , Animais , Animais Recém-Nascidos , Encefalite/induzido quimicamente , Encefalite/metabolismo , Encefalite/prevenção & controle , Hipóxia-Isquemia Encefálica/induzido quimicamente , Camundongos , Ratos
19.
J Clin Invest ; 122(8): 2837-46, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22751104

RESUMO

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Cognição/efeitos dos fármacos , Creatinina/análogos & derivados , Proteínas de Membrana Transportadoras/deficiência , Animais , Sequência de Bases , Encéfalo/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Creatinina/metabolismo , Creatinina/farmacologia , Primers do DNA/genética , Modelos Animais de Doenças , Feminino , Humanos , Imidazolidinas/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/fisiologia , Memória/efeitos dos fármacos , Retardo Mental Ligado ao Cromossomo X/tratamento farmacológico , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Retardo Mental Ligado ao Cromossomo X/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Neurológicos , Fosfocreatina/análogos & derivados , Fosfocreatina/metabolismo
20.
PLoS One ; 7(2): e32767, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22393447

RESUMO

Recent evidence in multiple sclerosis (MS) suggests that active CMV infection may result in more benign clinical disease. The goal of this pilot study was to determine whether underlying murine CMV (MCMV) infection affects the course of the Theiler's murine encephalitis virus (TMEV) induced murine model of MS. A group of eight TMEV-infected mice were co-infected with MCMV at 2 weeks prior to TMEV infection while a second group of TMEV-infected mice received MCMV two weeks post TMEV. We also used 2 control groups, where at the above time points MCMV was replaced with PBS. Outcome measures included (1) monthly monitoring of disability via rotarod for 8 months; (2) in vivo MRI for brain atrophy studies and (3) FACS analysis of brain infiltrating lymphocytes at 8 months post TMEV infection. Co-infection with MCMV influenced the disease course in mice infected prior to TMEV infection. In this group, rotarod detectable motor performance was significantly improved starting 3 months post-infection and beyond (p≤0.024). In addition, their brain atrophy was close to 30% reduced at 8 months, but this was only present as a trend due to low power (p = 0.19). A significant reduction in the proportion of brain infiltrating CD3+ cells was detected in this group (p = 0.026), while the proportion of CD45+ Mac1+ cells significantly increased (p = 0.003). There was also a strong trend for a reduced proportion of CD4+ cells (p = 0.17) while CD8 and B220+ cell proportion did not change. These findings support an immunomodulatory effect of MCMV infection in this MS model. Future studies in this co-infection model will provide insight into mechanisms which modulate the development of demyelination and may be utilized for the development of novel therapeutic strategies.


Assuntos
Infecções por Citomegalovirus/terapia , Esclerose Múltipla/virologia , Animais , Encéfalo/patologia , Complexo CD3/biossíntese , Antígenos CD8/biossíntese , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/virologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Encefalite/virologia , Feminino , Citometria de Fluxo/métodos , Sistema Imunitário , Inflamação , Antígenos Comuns de Leucócito/biossíntese , Camundongos , Esclerose Múltipla/complicações , Esclerose Múltipla/terapia , Reprodutibilidade dos Testes , Fatores de Tempo
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