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1.
Pharmacol Res ; 188: 106655, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36642113

RESUMO

Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3 g/kg/12 h, p.o.) was administered to C57BL/6 J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30 mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.


Assuntos
Canabidiol , Transtornos do Espectro Alcoólico Fetal , Humanos , Gravidez , Animais , Camundongos , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Encéfalo/metabolismo , Etanol
2.
J Neurodev Disord ; 14(1): 59, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526961

RESUMO

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. METHODS: The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5 to 5 year olds with FASD. Participants in this long-term follow-up study include 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11.0 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up included measures of executive functioning and an MRI scan. RESULTS: Children who received choline had better performance on several tasks of lower-order executive function (e.g., processing speed) and showed higher white matter microstructure organization (i.e., greater axon coherence) in the splenium of the corpus callosum compared to the placebo group. CONCLUSIONS: These preliminary findings, although exploratory at this stage, highlight potential long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that choline may affect white matter development, representing a potential target of choline in this population. TRIAL REGISTRATION: Prior to enrollment, this trial was registered with clinicaltrials.gov ( NCT01149538 ) on June 23, 2010.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Substância Branca , Criança , Gravidez , Feminino , Humanos , Pré-Escolar , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Colina/uso terapêutico , Corpo Caloso/diagnóstico por imagem , Seguimentos , Substância Branca/diagnóstico por imagem
3.
Pediatrics ; 150(4)2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36164844

RESUMO

BACKGROUND AND OBJECTIVES: To date, there has been no large, population-based study estimating the prevalence of psychotropic medication use and cooccurring medical conditions among children with fetal alcohol syndrome disorder (FASD). In addition, it is not known how psychotropic medication use varies by mental health status of the children with FASD and their health insurance coverage. This study attempts to fill this gap by analyzing a large health insurance claims database covering Medicaid and private insurance. METHODS: The study used the 2017 IBM Watson Health MarketScan Multistate Medicaid and Commercial Claims databases. The sample for the analysis includes children between the ages of 0 and 17 with either an FASD diagnosis or a mental health diagnosis (N = 848 721 Medicaid; N = 511 061 private insurance). RESULTS: More than half of the children with an FASD diagnosis were prescribed psychotropic medications (63% Medicaid; 57% private). Utilization rates of psychotropic medication among children with cooccurring FASD and a mental health condition (79% Medicaid; 71% private) were higher compared to children with a mental health diagnosis but no FASD (57% Medicaid; 57% private). Stimulants were the most commonly prescribed. Encephalopathy, attention deficit hyperactivity disorder, and epilepsy were the 3 most common cooccurring diagnosis among children with FASD using psychotropic medication under Medicaid compared to encephalopathy, attention deficit hyperactivity disorder, and anxiety with private insurance. CONCLUSIONS: These results exemplify the complexity of the neurobehavioral profile of children with FASD and the challenge of treatment. Future studies may determine how supportive services for these children will affect psychotropic medication use.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Encefalopatias , Transtornos do Espectro Alcoólico Fetal , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Pré-Escolar , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/epidemiologia , Humanos , Lactente , Recém-Nascido , Medicaid , Gravidez , Psicotrópicos/uso terapêutico , Estados Unidos/epidemiologia
4.
Nutr Rev ; 80(11): 2136-2153, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35568996

RESUMO

CONTEXT: Nutritional interventions for newborns with brain injury are scarce, and there are gaps in the knowledge of their mechanisms of action in preventing the occurrence of cerebral palsy (CP) or the incidence of other developmental disabilities. OBJECTIVE: The objective of this review was to assess the effect of nutritional interventions in preventing nonprogressive congenital or perinatal brain injuries, or in improving outcomes related to neurological development. DATA SOURCES: Randomized trials on any nutritional intervention for pregnant women at risk of preterm delivery, or for children with low birth weight, preterm, or with confirmed or suspected microcephaly, CP, or fetal alcohol syndrome disorders (FASDs) were retrieved from MEDLINE, Embase, Scopus, Web of Science, LILACS, and CENTRAL databases from inception to September 17, 2020. DATA EXTRACTION: Data extraction, risk of bias (Cochrane Risk of Bias tool 2), and quality of evidence (GRADE approach) were assessed by 2 authors. DATA ANALYSIS: Pooled risk ratios (RRs) with 95% confidence intervals were calculated using a random-effects meta-analysis. Seventeen studies were included on intravenous interventions (magnesium sulfate [n = 5], amino acids [n = 4], vitamin A [n = 1], and N-acetylcysteine [n = 1]); enteral interventions (vitamin D [n = 1], prebiotic [n = 1], nutrient-enriched formula [n = 1], and speed of increasing milk feeds [n = 1]); and oral interventions (choline [n = 1] and docosahexaenoic acid, choline, and uridine monophosphate [n = 1]). All studies assessed CP, except 1 on FASDs. Eight studies were judged as having high risk of bias. Five studies (7413 babies) with high-quality evidence demonstrated decreased risk of childhood CP (RR = 0.68, 95% CI: 0.52-0.88) with magnesium sulfate. Interventions with amino acids had no effect on CP prevention or other outcomes. Except for 1 study, no other intervention decreased the risk of CP or FASDs. CONCLUSION: Although different types of nutritional interventions were found, only those with antenatal magnesium sulfate were effective in decreasing CP risk in preterm infants. Well-designed, adequately powered randomized clinical trials are required.


Assuntos
Lesões Encefálicas , Paralisia Cerebral , Transtornos do Espectro Alcoólico Fetal , Acetilcisteína , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/prevenção & controle , Paralisia Cerebral/tratamento farmacológico , Paralisia Cerebral/epidemiologia , Paralisia Cerebral/prevenção & controle , Criança , Colina , Ácidos Docosa-Hexaenoicos , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Sulfato de Magnésio/uso terapêutico , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Uridina Monofosfato , Vitamina A , Vitamina D
5.
Neurotox Res ; 40(2): 605-613, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35386022

RESUMO

Fetal alcohol exposure has permanent effects on the brain structure, leading to functional deficits in several aspects of behavior, including learning and memory. Alcohol-induced neurocognitive impairment in offsprings is included with activation of oxidative- inflammatory cascade followed with wide apoptotic neurodegeneration in several brain areas, such as the hippocampus. Metformin is the first-line treatment for diabetic patients. It rapidly crosses the blood-brain barrier (BBB) and exerts antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we evaluated the protective effects of metformin on ethanol-related neuroinflammation, as well as neuron apoptosis in the hippocampus of adult male rat in animal model of fetal alcohol spectrum disorders. Treatment with ethanol in milk solution (5.25 and 27.8 g/kg, respectively) was conducted by intragastric intubation at 2-10 days after birth. To examine the antioxidant and anti-inflammatory properties of metformin, an ELISA assay was performed for determining the tumor necrosis factor-α (TNF-α) and antioxidant enzyme concentrations. Immunohistochemical staining was conducted for evaluating the glial fibrillary acidic protein (GFAP) and cleaved caspase-3 expression. Based on the results, metformin caused a significant increase in the superoxide dismutase (SOD) (P < 0.05) and glutathione peroxidase (GSH-Px) (P < 0.01) activities. On the other hand, it reduced the concentrations of TNF-α and malondialdehyde, compared to the ethanol group (P < 0.01). In the metformin group, there was a reduction in cell apoptosis in the hippocampus, as well as GFAP-positive cells (P < 0.01). Overall, apoptotic signaling, regulated by the oxidative inflammatory cascade, can be suppressed by metformin in adult brain rats following animal model of fetal alcohol spectrum disorders.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Metformina , Síndromes Neurotóxicas , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/metabolismo , Humanos , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Estresse Oxidativo , Gravidez , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
6.
Brain Res Bull ; 183: 57-72, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35227769

RESUMO

Fetal alcohol spectrum disorder (FASD) caused by mother's exposure to alcohol during pregnancy is a congenital neurological disease of the fetus resulting in fetal developmental and intellectual disabilities, cognitive impairment, and coordination disorder. Excess oxidative stress and neuroinflammatory responses were an important factor in neuropathological changes in FASD. Astaxanthin (AST) was a potent antioxidant and anti-inflammatory carotenoid. Therefore, this study proposed to explore how AST treatment can ameliorate morphological changes in the hippocampus and cognitive impairment in FASD rats by reducing oxidative stress and neuroinflammation in the brain. An alcohol atomizer was used from postnatal day (P) 2 to P10 to induce the FASD rat model. They were treated with AST (10 mg/kg body weight/day, intraperitoneal injection) for 8 consecutive days starting at P53 and sacrificed at P60. FASD rats had growth retardation and facial dysmorphologies, excessive oxidative stress and neuroinflammation in the hippocampus, decreased choline acetyltransferase (ChAT) expression in MS nucleus, spine loss on hippocampal CA1 pyramidal neurons, and poor performance in spatial learning and memory and sensory-motor coordination. After AST treatment, oxidative stress, neuroinflammation, cholinergic system, excitatory synaptic structure and behavior of FASD rats improved. Therefore, our study provided evidence to support the proposal that AST could be considered to treat FASD.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Animais , Etanol/metabolismo , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/metabolismo , Hipocampo/metabolismo , Gravidez , Ratos , Xantofilas/metabolismo , Xantofilas/farmacologia , Xantofilas/uso terapêutico
7.
Neurochem Res ; 47(4): 1001-1011, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35040027

RESUMO

Several experimental and clinical findings suggest that ethanol consumption during pregnancy activates an oxidative-inflammatory cascade followed by wide apoptotic neurodegeneration within several brain areas, including the hippocampus. Crocin can protect neurons because of its antioxidant, anti-inflammatory, and antiapoptotic effects. This study evaluated the crocin protective impact on ethanol-related neuroinflammation and neuronal apoptosis in the hippocampus of rat pups exposed to alcohol over postnatal days. Ethanol (5.25 g/kg) was administrated in milk solution (27.8 ml/kg) by intragastric intubation 2-10 days after birth. The animals received crocin (15, 30, and 45 mg/kg) 2-10 days after birth. The hippocampus-dependent memory and spatial learning were evaluated 36 days after birth using the Morris water maze task. Further, the concentrations of TNF-α and antioxidant enzymes were determined using ELISA assay to examine the antioxidant and anti-inflammatory activities. Also, immunohistochemical staining was performed to evaluate the glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1(Iba-1), and caspase-3 expression. The administration of crocin significantly attenuated spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also, crocin led to a significant enhancement in SOD (P < 0.05) and GSH-PX (P < 0.01), whereas it caused a reduction in the TNF-α and MDA concentrations compared to the ethanol group (P < 0.01). Moreover, the hippocampal level of caspase-3 (P < 0.01) and the number of GFAP and Iba-1-positive cells decreased in the crocin group (P < 0.001). Crocin suppresses apoptotic signaling mediated by the oxidative-inflammatory cascade in rat pups exposed to ethanol after birth.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Fármacos Neuroprotetores , Animais , Apoptose , Carotenoides , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Gravidez , Ratos , Ratos Wistar
8.
J Neurosci Res ; 100(8): 1585-1601, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35014067

RESUMO

Ethanol exposure during the early stages of embryonic development can lead to a range of morphological and behavioral differences termed fetal alcohol spectrum disorders (FASDs). In a zebrafish model, we have shown that acute ethanol exposure at 8-10 hr postfertilization (hpf), a critical time of development, produces birth defects similar to those clinically characterized in FASD. Dysregulation of the Sonic hedgehog (Shh) pathway has been implicated as a molecular basis for many of the birth defects caused by prenatal alcohol exposure. We observed in zebrafish embryos that shh expression was significantly decreased by ethanol exposure at 8-10 hpf, while smo expression was much less affected. Treatment of zebrafish embryos with SAG or purmorphamine, small molecule Smoothened agonists that activate Shh signaling, ameliorated the severity of ethanol-induced developmental malformations including altered eye size and midline brain development. Furthermore, this rescue effect of Smo activation was dose dependent and occurred primarily when treatment was given after ethanol exposure. Markers of Shh signaling (gli1/2) and eye development (pax6a) were restored in embryos treated with SAG post-ethanol exposure. Since embryonic ethanol exposure has been shown to produce later-life neurobehavioral impairments, juvenile zebrafish were examined in the novel tank diving test. Our results further demonstrated that in zebrafish embryos exposed to ethanol, SAG treatment was able to mitigate long-term neurodevelopmental impairments related to anxiety and risk-taking behavior. Our results indicate that pharmacological activation of the Shh pathway at specific developmental timing markedly diminishes the severity of alcohol-induced birth defects.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Animais , Embrião não Mamífero/metabolismo , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Gravidez , Peixe-Zebra/metabolismo
9.
Child Psychiatry Hum Dev ; 53(2): 268-277, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502703

RESUMO

Psychiatric symptoms in children with Fetal Alcohol Spectrum Disorders (FASD) present with high prevalence and morbidity, often across symptom domains, e.g. ADHD-like symptoms, emotional dysregulation and sleep problems. Polypharmacy is often used, but no empirically-based guidelines exist regarding optimal treatment for these children. Moreover, stimulant use in these children is controversial as their responsiveness may be different due to altered neural circuitry associated with prenatal alcohol exposure. The objective of this review is to give an overview of existing data on pharmacological treatments of neurobehavioral symptoms in FASD. Our literature review yielded limited and conflicting clinical data on the effectiveness of pharmacological treatments for psychiatric symptoms in children with FASD, with some symptom domains lacking data altogether. We emphasize the need for clinical trials to guide pharmacological treatments in this complex population.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Criança , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Prevalência
10.
BMC Pediatr ; 21(1): 512, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34784904

RESUMO

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental condition resulting from pre-natal alcohol exposure. In Canada, an estimated 1.4-4% of newborns are affected by FASD. FASD is often associated with behavioural comorbidities and many individuals require psychotropic medication. However, to date there are no FASD specific guidelines for prescribing medication. Recently, Mela and colleagues described four behavioural symptom clusters commonly seen in FASD with suggested pharmacologic treatment for each cluster within an algorithm. The primary objective was to compare the proposed treatment algorithm retrospectively to actual treatment in a real-world FASD pediatric practice. The secondary objective was to refine the description of symptom clusters which will be targeted with treatment. METHODS: We collected the diagnostic and medication history from all patient visits of a Regina Developmental Pediatrician who specializes in FASD diagnosis and medication treatment. Three hundred fifty-four FASD patients were identified between 2005 to 2020. The medications that would be predicted from the algorithm were compared to the real-world historical data. A positive case was defined as all algorithm-predicted medications matching the historical data; a negative case had one or more medications failing to match. RESULTS: Of the 354 patients, 36 were removed for insufficient information. Of the remaining 318 cases, 172 (54.1%) were positive compared to 146 (45.9%) negatives. In single prescription cases (n=147), the incidence of positives was 67.3%; in multi-prescriptions (n=72) it was 27.8%; and in cases where no prescription was needed (n=99), the positive incidence was 53.5%. CONCLUSIONS: The prescription algorithm is promising but requires further refinement to accommodate the range of presentations in children with FASD. With respect to unclassified symptoms, we propose the following: sleep onset difficulty as hyperarousal; gender dysphoria and obsessive compulsive disorder as cognitive inflexibility; grief as emotional regulation; and autism spectrum disorder as hyperactive/neurocognitive.


Assuntos
Transtorno do Espectro Autista , Transtornos do Espectro Alcoólico Fetal , Transtornos do Neurodesenvolvimento , Criança , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/epidemiologia , Humanos , Recém-Nascido , Gravidez , Psicotrópicos/efeitos adversos , Estudos Retrospectivos
11.
Neurotoxicol Teratol ; 87: 107015, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34256161

RESUMO

Fetal alcohol spectrum disorders (FASD) are alarmingly common and result in significant personal and societal loss. Neuropathology of the hippocampus is common in FASD leading to aberrant cognitive function. In the current study, we evaluated the effects of ethanol on the expression of a targeted set of molecules involved in neuroinflammation, myelination, neurotransmission, and neuron function in the developing hippocampus in a postnatal model of FASD. Mice were treated with ethanol from P4-P9, hippocampi were isolated 24 h after the final treatment at P10, and mRNA levels were quantitated by qRT-PCR. We evaluated the effects of ethanol on both pro-inflammatory and anti-inflammatory molecules in the hippocampus and identified novel mechanisms by which ethanol induces neuroinflammation. We further demonstrated that ethanol decreased expression of molecules associated with mature oligodendrocytes and greatly diminished expression of a lacZ reporter driven by the first half of the myelin proteolipid protein (PLP) gene (PLP1). In addition, ethanol caused a decrease in genes expressed in oligodendrocyte progenitor cells (OPCs). Together, these studies suggest ethanol may modulate pathogenesis in the developing hippocampus through effects on cells of the oligodendrocyte lineage, resulting in altered oligodendrogenesis and myelination. We also observed differential expression of molecules important in synaptic plasticity, neurogenesis, and neurotransmission. Collectively, the molecules evaluated in these studies may play a role in ethanol-induced pathology in the developing hippocampus and contribute to cognitive impairment associated with FASD. A better understanding of these molecules and their effects on the developing hippocampus may lead to novel treatment strategies for FASD.


Assuntos
Etanol/farmacologia , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Animais , Modelos Animais de Doenças , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Neurogênese/fisiologia , Oligodendroglia/patologia
12.
Biomed Pharmacother ; 141: 111813, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34126352

RESUMO

Foetal alcohol spectrum disorder (FASD) is the umbrella term used to describe the physical and mental disabilities induced by alcohol exposure during development. Early alcohol exposure induces cognitive impairments resulting from damage to the central nervous system (CNS). The neuroinflammatory response accompanied by neurodegenerative mechanisms contribute to those detrimental alterations. Cannabidiol (CBD) has recently emerged as an anti-inflammatory drug that might be useful to treat several neuropsychiatric disorders. In our study, we assessed the effects of CBD on long-lasting cognitive deficits induced by early alcohol exposure. Furthermore, we analysed long-term pro-inflammatory and apoptotic markers within the prefrontal cortex and hippocampus. To model alcohol binge drinking during gestational and lactation periods, we used pregnant C57BL/6 female mice with time-limited access to 20% v/v alcohol solution. Following the prenatal and lactation alcohol exposure (PLAE), we treated the male and female offspring with CBD from post-natal day (PD) 25 until PD34, and we evaluated their cognitive performance at PD60. Our results showed that CBD treatment during peri-adolescence period ameliorates cognitive deficits observed in our FASD-like mouse model, without sex differences. Moreover, CBD restores the PLAE-induced increased levels of TNFα and IL-6 in the hippocampus. Thus, our study provides new insights for CBD as a therapeutic agent to counteract cognitive impairments and neuroinflammation caused by early alcohol exposure.


Assuntos
Canabidiol/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Encefalite/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Animais , Consumo Excessivo de Bebidas Alcoólicas/complicações , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Feminino , Hipocampo/patologia , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/patologia , Gravidez , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Fator de Necrose Tumoral alfa/metabolismo
13.
Behav Brain Res ; 410: 113326, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-33940050

RESUMO

Perinatal alcohol exposure can lead to fetal alcohol spectrum disorders (FASD), usually first diagnosed in childhood, that are characterized by hyperactivity, impulsivity and learning and memory disability, among others. To test the hypothesis that dopamine signaling is one of the main factors underlying these impairments, a new atypical dopamine transporter (DAT) inhibitor, CE-123 (1, 3 or 10 mg/kg) was assessed for its potential to overcome the ethanol-induced behavioral effects in a rat model of FASD. In the present study, neonatal rats were exposed to alcohol intubations across the neonatal period (postnatal day (PND)4-9, the third trimester equivalent of human gestation) and, after weaning, the animals (male rats) were assigned randomly to three groups. The first group was tested at PND21 (hyperactivity test). A second group was tested at PND45 (anxiety test), at PND47 (locomotor activity test), at PND49 (spatial cognitive test in the Barnes maze) and PND50 (reversal learning in the Barnes maze). The third group was tested at PND50 (dopamine receptor mRNA expression). Our results support the hypothesis that dopamine signaling is associated with FASD because the dopamine (D1, D2 and D5) receptor mRNA expression was altered in the striatum, hippocampus and prefrontal cortex in adult rats exposed to ethanol during neonatal period. CE-123 (3 and 10 mg/kg) inhibited the hyperactivity and ameliorated (10 mg/kg) the impairment of reversal learning in alcohol-exposed rats. Thus, these findings provide support that CE-123 may be a useful intervention for same of the deficits associated with neonatal ethanol exposure.


Assuntos
Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Dopaminérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Agitação Psicomotora/tratamento farmacológico , Animais , Animais Recém-Nascidos , Compostos Benzidrílicos/administração & dosagem , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Dopaminérgicos/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar
14.
Biomolecules ; 11(5)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924998

RESUMO

Ethanol exposure during pregnancy alters the mammalian target of rapamycin (mTOR) signaling pathway in the fetal brain. Hence, in adult rats exposed to ethanol during the neonatal period, we investigated the influence of rapamycin, an mTOR Complex 1 (mTORC1) inhibitor, on deficits in spatial memory and reversal learning in the Barnes maze task, as well as the ethanol-induced rewarding effects (1.0 or 1.5 g/kg) using the conditioning place preference (CPP) paradigm. Rapamycin (3 and 10 mg/kg) was given before intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). Spatial memory/reversal learning and rewarding ethanol effect were evaluated in adult (PND60-70) rats. Additionally, the impact of rapamycin pre-treatment on the expression of the GluN2B subunit of NMDA receptor in the brain was assessed in adult rats. Our results show that neonatal ethanol exposure induced deficits in spatial memory and reversal learning in adulthood, but the reversal learning outcome may have been due to spatial learning impairments rather than cognitive flexibility impairments. Furthermore, in adulthood the ethanol treated rats were also more sensitive to the rewarding effect of ethanol than the control group. Rapamycin prevented the neonatal effect of ethanol and normalized the GluN2B down-regulation in the hippocampus and the prefrontal cortex, as well as normalized this subunit's up-regulation in the striatum of adult rats. Our results suggest that rapamycin and related drugs may hold promise as a preventive therapy for fetal alcohol spectrum disorders.


Assuntos
Etanol/toxicidade , Sirolimo/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Alcoolismo/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/metabolismo , Aprendizagem Espacial/fisiologia
15.
Am J Clin Nutr ; 114(2): 617-627, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33876196

RESUMO

BACKGROUND: The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. OBJECTIVE: Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. METHODS: Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n = 26) or placebo (n = 26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. RESULTS: When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). CONCLUSIONS: These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.


Assuntos
Antígenos CD/metabolismo , Colina/farmacologia , Suplementos Nutricionais , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Polimorfismo de Nucleotídeo Único , Administração Oral , Antígenos CD/genética , Pré-Escolar , Colina/administração & dosagem , Cognição , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/patologia , Genótipo , Humanos , Masculino , Proteínas de Transporte de Cátions Orgânicos/genética , Estudos Retrospectivos
16.
Cannabis Cannabinoid Res ; 6(1): 74-76, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33614955

RESUMO

Background: Fetal alcohol spectrum disorder (FASD) has been recently estimated to afflict up to 5% of American children. Most of these children exhibit different degrees of symptomatology of disruptive behaviors. Yet, there has been very little research on the efficacy and safety of pharmacological modalities, limited mostly to stimulants for attention deficit hyperactive disorder or second generation atypical antipsychotics for aggression. Recently, the use of cannabinoids has been described for symptoms related to autistic spectrum disorder with apparent favorable effects, as well as for other disruptive behaviors. The objective of our study was to follow up in a retrospective case series the effect of cannabis in children and young adults diagnosed with FASD. Methods: In two children and three FASD young adults with severe disruptive behavior, changes in behavior after cannabis use were measured by the parent version of the Nisonger Child Behavior Rating Form. Results: In all five cases, there was a highly statistical decrease in the disruptive behavior score from 18±1.0 before cannabis use to 6±2.1 after introduction of cannabis (p=0.0002). Discussion: In children and young adults with FASD, cannabis, mostly cannabidiol (CBD), has been associated with a marked and statistically significant improvement in serious disruptive behavior. These cases suggest that the efficacy and safety of CBD should be tested in well-controlled studies.


Assuntos
Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Transtornos do Comportamento Infantil/complicações , Transtornos do Comportamento Infantil/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Masculino , Comportamento Problema , Estudos Retrospectivos , Adulto Jovem
17.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450816

RESUMO

Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate.


Assuntos
Catequina/análogos & derivados , Transtornos do Espectro Alcoólico Fetal/etiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Animais , Astrócitos/metabolismo , Biomarcadores , Catequina/farmacologia , Catequina/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Proteína Duplacortina , Etanol/efeitos adversos , Etanol/sangue , Etanol/metabolismo , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Imuno-Histoquímica , Masculino , Camundongos , Neurogênese/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Placenta/patologia , Gravidez
18.
Int J Dev Neurosci ; 81(1): 71-81, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33175424

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase10A (PDE10A) has been shown to provide benefits in various brain conditions. We investigated the role of papaverine, a selective PDE10A inhibitor on core phenotypes in prenatal alcohol exposure (PAE) model of ADHD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neuronal survival-BDNF, neuronal transcription factor-pCREB, brain inflammation (IL-6, IL-10, and TNF-α), and brain oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, and striatum. PAE resulting hyper-locomotion, inattention, and anxiety were studied by the use of open-field, y-maze, and elevated plus maze, respectively. Administration of papaverine (15/30 mg kg-1 ) to PAE group of animals resulted in amelioration of hyperactivity, inattention, and anxiety. Also, papaverine resulted in significant increase of the levels in BDNF, pCREB, IL-10, and GSH along with significant decrease of TNF-α, IL-6, and TBARS in different brain areas of PAE group. Papaverine, a selective PDE10A inhibitor rectified behavioural phenotypes associated with ADHD, possibly by altering the protein markers associated with neuronal survival, neuronal transcription factor, brain inflammation, and brain oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ADHD phenotypes.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Encefalite/tratamento farmacológico , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Papaverina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Animais , Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Comportamento Animal , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Transtornos do Espectro Alcoólico Fetal/psicologia , Aprendizagem em Labirinto , Atividade Motora , Neurônios/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar
19.
Nutrients ; 12(10)2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33023237

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in children characterized by inattention and hyperactivity. Prenatal alcohol exposure (PAE) can disrupt fetal neuronal development and cause an ADHD-like hyperactive behavior in the offspring. In this study, we hypothesized that metabolic disturbance would involve in ADHD neuropathology and aimed to investigate the changes in metabolite profile in PAE-induced ADHD-like model and the effects of HX106, a nutraceutical, on ADHD-like pathophysiology and metabolite changes. To this end, we administered HX106 to the mouse offspring affected by PAE (OPAE) and assessed the hyperactivity using the open field test. We observed that HX106-treated OPAE showed less hyperactive behavior than vehicle-treated OPAE. The effects of HX106 were found to be related to the regulation of dopamine transporter and D2 dopamine receptor expression. Furthermore, using gas chromatography time-of-flight mass spectrometry-based metabolomics, we explored the metabolite changes among the experimental groups. The metabolite profile, particularly related with the amino acids, linoleic acid and amino sugar pathways, was altered by PAE and reversed by HX106 treatment partially similar to that observed in the control group. Overall, this study suggest that metabolite alteration would be involved in ADHD pathology and that HX106 can be an efficient supplement to overcome ADHD by regulating dopamine signaling-related protein expression and metabolite changes.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Suplementos Nutricionais , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Extratos Vegetais/farmacologia , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Animais , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Feminino , Transtornos do Espectro Alcoólico Fetal/psicologia , Cromatografia Gasosa-Espectrometria de Massas/métodos , Metabolômica , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/psicologia
20.
Nat Neurosci ; 23(4): 533-543, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203497

RESUMO

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Deficiências da Aprendizagem/tratamento farmacológico , Aprendizagem/efeitos dos fármacos , Córtex Motor/efeitos dos fármacos , Venenos de Escorpião/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Animais , Forma Celular/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Modelos Animais de Doenças , Deficiências da Aprendizagem/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Córtex Motor/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Venenos de Escorpião/uso terapêutico , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo
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