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1.
J Psychiatr Res ; 169: 105-112, 2024 01.
Article in English | MEDLINE | ID: mdl-38011818

ABSTRACT

In Brazil, as in other countries, it is expected a significant variation of epidemiological and clinical characteristics among individuals with autism spectrum disorder (ASD). This study was performed to explore maternal risk factors and clinical characteristics of children with ASD in a population located in southern Brazil. Data were collected from medical records and analyzed to explore biomarkers associated with ASD. Out of 321 children with ASD, 86.5% were males with a male-to-female ratio of 5.7:1, 50.7% were mild/moderate while 49.3% presented severe ASD. Between the risk factors investigated, gestational infection was significantly associated with severe ASD patients. There was also an association between epilepsy and severe autism. Several gastrointestinal (GI) symptoms were significantly associated with severe ASD. Obesity, followed by lower levels of cholesterol, were also significant factors associated with an ASD diagnosis when compared to age-matched controls. Finally, severe ASD was associated with significantly higher serum serotonin levels when compared to age-matched controls and mild/moderate ASD cases. Our findings demonstrate that our population shares many features associated with ASD around the world, such as GI symptoms, epilepsy, and high serotonin levels. It is worth highlighting the low cholesterol levels associated with obesity as an unusual feature that deserves more attention.


Subject(s)
Autism Spectrum Disorder , Epilepsy , Gastrointestinal Diseases , Child , Humans , Male , Female , Autism Spectrum Disorder/complications , Serotonin , Brazil/epidemiology , Risk Factors , Epilepsy/epidemiology , Obesity/complications , Cholesterol
2.
Life Sci ; 337: 122357, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38123016

ABSTRACT

The gut-brain axis is gaining more attention in neurodevelopmental disorders, especially autism spectrum disorder (ASD). Many factors can influence microbiota in early life, including host genetics and perinatal events (infections, mode of birth/delivery, medications, nutritional supply, and environmental stressors). The gut microbiome can influence blood-brain barrier (BBB) permeability, drug bioavailability, and social behaviors. Developing microbiota-based interventions such as probiotics, gastrointestinal (GI) microbiota transplantation, or metabolite supplementation may offer an exciting approach to treating ASD. This review highlights that RNA sequencing, metabolomics, and transcriptomics data are needed to understand how microbial modulators can influence ASD pathophysiology. Due to the substantial clinical heterogeneity of ASD, medical caretakers may be unlikely to develop a broad and effective general gut microbiota modulator. However, dietary modulation followed by administration of microbiota modulators is a promising option for treating ASD-related behavioral and gastrointestinal symptoms. Future work should focus on the accuracy of biomarker tests and developing specific psychobiotic agents tailored towards the gut microbiota seen in ASD patients, which may include developing individualized treatment options.


Subject(s)
Autism Spectrum Disorder , Gastrointestinal Diseases , Gastrointestinal Microbiome , Microbiota , Humans , Brain-Gut Axis , Autism Spectrum Disorder/therapy , Gastrointestinal Microbiome/physiology , Gastrointestinal Diseases/drug therapy
3.
Metab Brain Dis ; 36(1): 185-192, 2021 01.
Article in English | MEDLINE | ID: mdl-33034842

ABSTRACT

Maple syrup urine disease (MSUD) is characterized by a deficiency in the mitochondrial branched-chain α-keto acid dehydrogenase complex activity and, consequently, accumulation of the branched-chain amino acids and their respective branched-chain α-keto acids in fluids and the tissue. MSUD clinical symptoms include neurological alterations. KIC is considered one of the significant neurotoxic metabolites since its increased plasma concentrations are associated with neurological symptoms. We evaluated the effect of KIC intracerebroventricular (ICV) injection in hippocampal mitochondria function in rats. We also investigated the impact of KIC in cells' metabolic activity (using MTT assay) and reactive species (RS) production in HT-22 cells. For this, thirty-day-old male rats were bilaterally ICV injected with KIC or aCSF. Thus, 1 hour after the administration, animals were euthanized, and the hippocampus was harvested for measured the activities of mitochondrial respiratory chain enzymes and RS production. Furthermore, HT-22 cells were incubated with KIC (1-10 mM) in 6, 12, and 24 h. Mitochondrial complexes activities were reduced, and the formation of RS was increased in the hippocampus of rats after KIC administration. Moreover, KIC reduced the cells' metabolic ability to reduce MTT and increased RS production in hippocampal neurons. Impairment in hippocampal mitochondrial function seems to be involved in the neurotoxicity induced by KIC.


Subject(s)
Amino Acids, Branched-Chain/metabolism , Hippocampus/drug effects , Keto Acids/pharmacology , Oxidative Stress/drug effects , Animals , Cell Line , Hippocampus/metabolism , Male , Maple Syrup Urine Disease/metabolism , Mice , Rats , Rats, Wistar
4.
Metab Brain Dis ; 36(2): 247-254, 2021 02.
Article in English | MEDLINE | ID: mdl-33098071

ABSTRACT

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder that affects the activity of the branched-chainα-keto acid dehydrogenase complex (BCDK). This deficiency on BCDK complex results in the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine, and their corresponding α-keto acids. Epigenetic changes can negatively affect the metabolism of BCAA. These changes are catalyzed by the epigenetic regulatory enzymes, e.g., DNA methyltransferase (DNMT), histone deacetylases (HDAC), and histone acetyltransferases (HAT). However, the impacts of BCAA administration on the activity of epigenetic regulatory enzymes in the brain of MSUD patients are still unknown. In this study, we aimed to demonstrate the impact of BCAA administration on the activity of DNMT, HDAC, and HAT in the brain structures of infant rats, an animal model of MSUD. For that, we administered a BCAA pool to infant rats for 21 days. We demonstrated that BCAA administration significantly increased the DNMT and HDAC activities in the hippocampus and striatum, but not in the cerebral cortex of MSUD infant rats. A positive correlation was observed between HDAC and DNMT activities in the hippocampus and striatum of animals exposed to BCAA injections. Our results showed that the BCAA administration could modulate epigenetic regulatory enzymes, mainly DNMT and HDAC, in the brains of infant rats. Therefore, we suggest that the increase in the activity of DNMT and HDAC in the hippocampus and striatum could partially explain the neurological impairments presented in animal models of MSUD.


Subject(s)
Amino Acids, Branched-Chain/administration & dosage , Cerebral Cortex/drug effects , Corpus Striatum/drug effects , Epigenesis, Genetic/drug effects , Hippocampus/drug effects , Maple Syrup Urine Disease/metabolism , Animals , Cerebral Cortex/metabolism , Corpus Striatum/metabolism , Disease Models, Animal , Hippocampus/metabolism , Male , Rats , Rats, Wistar
5.
Metab Brain Dis ; 35(6): 905-914, 2020 08.
Article in English | MEDLINE | ID: mdl-32297169

ABSTRACT

Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched α-ketoacid dehydrogenase complex (BCKDC) activity. Branched-chain amino acids (BCAA) accumulation is, at least in part, responsible for neurological disturbances characteristic of this metabolic disorder. Experimental studies demonstrated that high levels of BCAA induce brain oxidative stress. Considering that many antioxidants are obtained from the diet, the dietary restriction in MSUD patients probably produce deficiency of vitamins and micronutrients involved in antioxidant defenses. Supplementation with synthetic melatonin has been used to prevention and treatment of pathological conditions, including brain diseases. In this study, we aimed at investigating the potential neuroprotective effect of melatonin treatment in a MSUD experimental model. Infant rats (7 day old) received twice daily subcutaneous injections of a BCAA pool (0.21472 g/kg, 190 mmol/L leucine, 59 mmol/L isoleucine and 69 mmol/L valine in saline solution (15.8 µL/g per weight/injection) or saline alone, and supplemented with melatonin (10 mg/kg, intraperitoneal) for 21 days. Oxidative stress parameters, i.e. antioxidant enzyme activity, reactive species production and damage to lipids and proteins, were assessed in the cerebral cortex, hippocampus and striatum at twenty-eight days of age. In addition, the damage to blood cell DNA was evaluated. The chronic administration of BCAA pool in infant rats induced significant oxidative stress (p < 0.05) - such as oxidation of lipids and proteins, imbalance in antioxidant enzymes activities - damages in DNA (p < 0.05) and in brain structures (cerebral cortex, hippocampus and striatum). Notably, melatonin supplementation was able to ameliorate the oxidative (p < 0.05) and antioxidant (p < 0.05) parameters in the brain and blood of the rat model of MSUD. Our results show that melatonin could be a promising therapeutic agent for MSUD.


Subject(s)
Amino Acids, Branched-Chain/toxicity , Antioxidants/therapeutic use , DNA Damage/drug effects , Maple Syrup Urine Disease/drug therapy , Melatonin/therapeutic use , Oxidative Stress/drug effects , Animals , Antioxidants/pharmacology , DNA Damage/physiology , Male , Maple Syrup Urine Disease/chemically induced , Maple Syrup Urine Disease/metabolism , Melatonin/pharmacology , Oxidative Stress/physiology , Rats , Rats, Wistar
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