Impairment of neuromotor development and cognition associated with histopathological and neurochemical abnormalities in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase deficient mice.

Patients with glutaric acidemia type I (GA I) manifest motor and intellectual disabilities whose pathogenesis has been so far poorly explored. Therefore, we evaluated neuromotor and cognitive abilities, as well as histopathological and immunohistochemical features in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase (GCDH) deficient knockout mice (Gcdh), a well-recognized model of GA I. The effects of a single intracerebroventricular glutaric acid (GA) injection in one-day-old pups on the same neurobehavioral and histopathological/immunohistochemical endpoints were also investigated.

LDL Exposure Disrupts Mitochondrial Function and Dynamics in a Hippocampal Neuronal Cell Line.

Hypercholesterolemia has been associated with cognitive dysfunction and neurodegenerative diseases. Moreover, this metabolic condition disrupts the blood-brain barrier, allowing low-density lipoprotein (LDL) to enter the central nervous system. Thus, we investigated the effects of LDL exposure on mitochondrial function in a mouse hippocampal neuronal cell line (HT-22).

Short-Term Alterations in Behavior and Astroglial Function After Intracerebroventricular Infusion of Methylglyoxal in Rats.

Methylglyoxal (MG) is a by-product of glycolysis. In pathological conditions, particularly diabetes mellitus, this molecule is unbalanced, causing widespread protein glycation. In addition to protein glycation, other effects resulting from high levels of MG in the central nervous system may involve the direct modulation of GABAergic and glutamatergic neurotransmission, with evidence suggesting that the effects of MG may be related to behavioral changes and glial dysfunction.

Zika virus-induced brain malformations in chicken embryos.

Background: Zika virus (ZIKV) was confirmed to be related to microcephaly in 2016. However, there is still a need for understanding the embryonic morphological changes induced by ZIKV and when they occur. Here, chicken embryos were chosen as experimental model of ZIKV to evaluate virus-associated morphological alterations that might take place during embryonic development.

The Brazilian-Portuguese version of the Sleep Hygiene Index (SHI): validity, reliability and association with depressive symptoms and sleep-related outcomes.

Objective: To translate the Sleep Hygiene Index (SHI) to Brazilian Portuguese, to describe its psychometric properties and to show its association with sleep quality, daytime sleepiness, risk for sleep apnea and depressive symptoms.

Methods: Thirty subjects participated in the cultural adaptation and the item clarity evaluation. Twenty subjects answered the instrument in three different time-points for test-retest reliability.

Neuroinflammation and Neuromodulation in Neurological Diseases.

Neuroimmunology is a relatively young science. This discipline has emerged today from the research field as a mature and fully developed innovative research area that integrates not only pure topics of neuroimmunology, but also expands on wider fields such as neuroplasticity, neuronal reserve and neuromodulation in association with clinical events, amongst which behavioral disorders stand out. The Cuban School of Neuroimmunology-a recent meeting that took place in Havana, Cuba-focused on topics based on the molecular mechanisms of neuroinflammation in neurological disorders involving behavioral manifestations, such as multiple sclerosis (MS), autism, cerebellar ataxias, Alzheimer´s disease and stroke among others, as well as on the use of new interventional technologies in neurology.

Guanosine protects against Ca-induced mitochondrial dysfunction in rats.

Mitochondria play an important role in cell life and in the regulation of cell death. In addition, mitochondrial dysfunction contributes to a wide range of neuropathologies. The nucleoside Guanosine (GUO) is an endogenous molecule, presenting antioxidant properties, possibly due to its direct scavenging ability and/or from its capacity to activate the antioxidant defense system.

Neuroprotective Effects of Guanosine Administration on In Vivo Cortical Focal Ischemia in Female and Male Wistar Rats.

Guanosine (GUO) has neuroprotective effects in experimental models of brain diseases involving glutamatergic excitotoxicity in male animals; however, its effects in female animals are poorly understood. Thus, we investigated the influence of gender and GUO treatment in adult male and female Wistar rats submitted to focal permanent cerebral ischemia in the motor cortex brain. Female rats were subdivided into non-estrogenic and estrogenic phase groups by estrous cycle verification.

Long-term effect of uncomplicated Plasmodium berghei ANKA malaria on memory and anxiety-like behaviour in C57BL/6 mice.

Background: Cerebral malaria, the main complication of Plasmodium falciparum infection in humans, is associated with persistent neurocognitive sequels both in human disease and the murine experimental model. In recent years, cognitive deficits related to uncomplicated (non-cerebral) malaria have also been reported in chronically exposed residents of endemic areas, but not in some murine experimental models of non-cerebral malaria. This study aimed at evaluating the influence of uncomplicated malaria on different behavioural paradigms associated with memory and anxiety-like parameters in a murine model that has the ability to develop cerebral malaria.

α-Ketoadipic Acid and α-Aminoadipic Acid Cause Disturbance of Glutamatergic Neurotransmission and Induction of Oxidative Stress In Vitro in Brain of Adolescent Rats.

Tissue accumulation of α-ketoadipic (KAA) and α-aminoadipic (AAA) acids is the biochemical hallmark of α-ketoadipic aciduria. This inborn error of metabolism is currently considered a biochemical phenotype with uncertain clinical significance. Considering that KAA and AAA are structurally similar to α-ketoglutarate and glutamate, respectively, we investigated the in vitro effects of these compounds on glutamatergic neurotransmission in the brain of adolescent rats.

Experimental evidence that overexpression of NR2B glutamate receptor subunit is associated with brain vacuolation in adult glutaryl-CoA dehydrogenase deficient mice: A potential role for glutamatergic-induced excitotoxicity in GA I neuropathology.

Glutaric aciduria type I (GA I) is biochemically characterized by accumulation of glutaric and 3-hydroxyglutaric acids in body fluids and tissues, particularly in the brain. Affected patients show progressive cortical leukoencephalopathy and chronic degeneration of the basal ganglia whose pathogenesis is still unclear. In the present work we investigated parameters of bioenergetics and redox homeostasis in various cerebral structures (cerebral cortex, striatum and hippocampus) and heart of adult wild type (Gcdh(+/+)) and glutaryl-CoA dehydrogenase deficient knockout (Gcdh(-/-)) mice fed a baseline chow.

Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial.

Background: In a recent phase 2 clinical trial in spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD), a neurogenetic disorder without specific therapy, benefits of lithium carbonate were found only on secondary efficacy outcomes, all related to ataxic features. In order to help designing future studies, we further analyzed the trial data searching for treatment response modifiers and metric properties of spinocerebellar ataxia (SCA) scales.

Methods: Efficacy analysis was performed with the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) subscores and with the subgroup of patients with independent gait according to the 8-meter walking-time (8MW).

Changes in Brain 14-3-3 Proteins in Response to Insulin Resistance Induced by a High Palatable Diet.

The 14-3-3 protein family takes part in a wide range of cellular processes and is expressed in all eukaryotic organisms. In mammals, seven isoforms (β, ε, η, γ, τ, ζ, and σ) have been identified. 14-3-3 proteins are suggested to modulate the insulin-signaling cascade in the brain.

Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: possible implications for the neuropathology of glutaric acidemia type I.

The role of excitotoxicity on the neuropathology of glutaric acidemia type I (GA I) is still under debate. Therefore, in the present work, we evaluated glutamate uptake by brain slices and glutamate binding to synaptic membranes, as well as glutamine synthetase activity in cerebral cortex and striatum from glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice along development (7, 15, 30 and 60 days of life) in the hopes of clarifying this matter. We also tested the influence of glutaric acid (GA) added exogenously on these parameters.

Pristanic acid provokes lipid, protein, and DNA oxidative damage and reduces the antioxidant defenses in cerebellum of young rats.

Zellweger syndrome (ZS) and some peroxisomal diseases are severe inherited disorders mainly characterized by neurological symptoms and cerebellum abnormalities, whose pathogenesis is poorly understood. Biochemically, these diseases are mainly characterized by accumulation of pristanic acid (Prist) and other fatty acids in the brain and other tissues. In this work, we evaluated the in vitro influence of Prist on redox homeostasis by measuring lipid, protein, and DNA damage, as well as the antioxidant defenses and the activities of aconitase and α-ketoglutarate dehydrogenase in cerebellum of 30-day-old rats.

Cellular senescence induced by prolonged subculture adversely affects glutamate uptake in C6 lineage.

Several researchers have recently used C6 cells to evaluate functional properties of high-affinity glutamate transporters. However, it has been demonstrated that this lineage suffers several morphological and biochemical alterations according to the number of passages in culture. Currently, there are no reports showing whether functional properties of high-affinity glutamate transporters comply with these sub culturing-dependent modifications.

Increased glutamate receptor and transporter expression in the cerebral cortex and striatum of gcdh-/- mice: possible implications for the neuropathology of glutaric acidemia type I.

We determined mRNA expression of the ionotropic glutamate receptors NMDA (NR1, NR2A and NR2B subunits), AMPA (GluR2 subunit) and kainate (GluR6 subunit), as well as of the glutamate transporters GLAST and GLT1 in cerebral cortex and striatum of wild type (WT) and glutaryl-CoA dehydrogenase deficient (Gchh-/-) mice aged 7, 30 and 60 days. The protein expression levels of some of these membrane proteins were also measured. Overexpression of NR2A and NR2B in striatum and of GluR2 and GluR6 in cerebral cortex was observed in 7-day-old Gcdh-/-.

A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease.

Background: Because lithium exerts neuroprotective effects in preclinical models of polyglutamine disorders, our objective was to assess the safety and efficacy of lithium carbonate (0.5-0.8 milliequivalents per liter) in patients with Machado-Joseph disease (spinocerebellar ataxia type 3 [MJD/SCA3]).

Disruption of brain redox homeostasis in glutaryl-CoA dehydrogenase deficient mice treated with high dietary lysine supplementation.

Deficiency of glutaryl-CoA dehydrogenase (GCDH) activity or glutaric aciduria type I (GA I) is an inherited neurometabolic disorder biochemically characterized by predominant accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and other tissues. Affected patients usually present acute striatum necrosis during encephalopathic crises triggered by metabolic stress situations, as well as chronic leukodystrophy and delayed myelination. Considering that the mechanisms underlying the brain injury in this disease are not yet fully established, in the present study we investigated important parameters of oxidative stress in the brain (cerebral cortex, striatum and hippocampus), liver and heart of 30-day-old GCDH deficient knockout (Gcdh(-/-)) and wild type (WT) mice submitted to a normal lysine (Lys) (0.

Neurodevelopmental and cognitive behavior of glutaryl-CoA dehydrogenase deficient knockout mice.

Aims: The establishment of a genetic knockout murine model of glutaric acidemia type I (GAI) with complete loss of glutaryl-CoA dehydrogenase (GCDH) activity has been used to investigate the pathological mechanisms underlying neurological symptoms in this disorder. However, very little has been reported on the neurobehavior of GCDH deficient mice (Gcdh(-/-)).

Main Methods: In the present study we evaluated physical (body and weight gain) and neuromotor development (appearance of coat, upper incisor eruption, eye-opening day, motor coordination, muscular strength and climbing), as well as cognitive behavior (inhibitory avoidance) in Gcdh(-/-), as compared to wild type (WT) mice.

Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice: a possible mechanism for brain injury in glutaric aciduria type I.

Mitochondrial dysfunction has been proposed to play an important role in the neuropathology of glutaric acidemia type I (GA I). However, the relevance of bioenergetics disruption and the exact mechanisms responsible for the cortical leukodystrophy and the striatum degeneration presented by GA I patients are not yet fully understood. Therefore, in the present work we measured the respiratory chain complexes activities I-IV, mitochondrial respiratory parameters state 3, state 4, the respiratory control ratio and dinitrophenol (DNP)-stimulated respiration (uncoupled state), as well as the activities of α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and Na+, K+-ATPase in cerebral cortex, striatum and hippocampus from 30-day-old Gcdh-/- and wild type (WT) mice fed with a normal or a high Lys (4.

Marked reduction of Na(+), K(+)-ATPase and creatine kinase activities induced by acute lysine administration in glutaryl-CoA dehydrogenase deficient mice.

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric (GA) and 3-hydroxyglutaric (3HGA) acids in the brain and other tissues. Affected patients usually present with hypotonia and brain damage and acute encephalopathic episodes whose pathophysiology is not yet fully established. In this study we investigated important parameters of cellular bioenergetics in brain, heart and skeletal muscle from 15-day-old glutaryl-CoA dehydrogenase deficient mice (Gcdh(-/-)) submitted to a single intra-peritoneal injection of saline (Sal) or lysine (Lys - 8 μmol/g) as compared to wild type (WT) mice.

Induction of oxidative stress in brain of glutaryl-CoA dehydrogenase deficient mice by acute lysine administration.

In the present work we evaluated a variety of indicators of oxidative stress in distinct brain regions (striatum, cerebral cortex and hippocampus), the liver, and heart of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice. The parameters evaluated included thiobarbituric acid-reactive substances (TBA-RS), 2-7-dihydrodichlorofluorescein (DCFH) oxidation, sulfhydryl content, and reduced glutathione (GSH) concentrations. We also measured the activities of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD) and glucose-6-phosphate dehydrogenase (G6PD).

High-glucose and S100B stimulate glutamate uptake in C6 glioma cells.

Diabetes mellitus is a disease associated with several changes in the central nervous system, including oxidative stress and abnormal glutamatergic neurotransmission, and the astrocytes play an essential role in these alterations. In vitro studies of astroglial function have been performed using cultures of primary astrocytes or C6 glioma cells. Herein, we investigated glutamate uptake, glutamine synthetase and S100B secretion in C6 glioma cells cultured in a high-glucose environment, as well as some parameters of oxidative stress and damage.