BDNF, proBDNF and proBDNF/BDNF ratio with electroencephalographic abnormalities in children with attention deficit hyperactivity disorder: Possible relations to cognition and severity.

Attention deficit hyperactivity disorder (ADHD) with and without subclinical epileptogenic discharges (SED) have been suggested to negatively affect cognitive abilities of children with ADHD. The role of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in ADHD is in need of being investigated. The aims were to evaluate the levels of serum BDNF, proBDNF and the proBDNF/BDNF ratio in addition to the potential impacts of SED on the children's cognitive abilities and the severity of ADHD. The included participants with ADHD were 30 children with normal electroencephalogram (EEG) (G1) and 30 children with SED (G2), together with 30 healthy children (G3). The cognitive abilities and severity of the disorder were evaluated. The biochemical measures were determined by ELISA. The presence of coexisting SED and nocturnal enuresis has led to a deleterious effect on cognitive processes but not on the severity. The focal epileptogenic discharge was the most common among children in G2. The levels of BDNF in Groups 1 and 2 were less than those in G3. The higher proBDNF/BDNF ratio could be related to the low BDNF levels rather than high proBDNF levels. The findings of this study highlight the importance of investigating the presence of SED and nocturnal enuresis in children with ADHD. Targeting strengthening of cognitive abilities in children with coexisting ADHD and SED is advised. The role of proBDNF in the pathophysiology of ADHD needs further investigation.

Expression Patterns of miRNAs in Egyptian Children with ADHD: Clinical Study with Correlation Analysis.

ADHD has huge knowledge gaps concerning its etiology. MicroRNAs (miRNAs) provide promising diagnostic biomarkers of human pathophysiology and may be a novel therapeutic option. The aim was to investigate the levels of miR-34c-3p, miR-155, miR-138-1, miR-296-5p, and plasma brain-derived neurotrophic factor (BDNF) in a group of children with ADHD compared to neurotypicals and to explore correlations between these measures and some clinical data. The participants were children with ADHD in Group I (N = 41; age: 8.2 ± 2) and neurotypical ones in Group II (N = 40; age: 8.6 ± 2.5). Group I was subjected to clinical examination, the Stanford Binet intelligence scale-5, the preschool language scale, and Conner's parent rating scale-R. Measuring the expression levels of the miRNAs was performed by qRT-PCR for all participants. The BDNF level was measured by ELISA. The lowest scores on the IQ subtest were knowledge and working memory. No discrepancies were noticed between the receptive and expressive language ages. The highest scores on the Conner's scale were those for cognitive problems. Participants with ADHD exhibited higher plasma BDNF levels compared to controls (p = 0.0003). Expression patterns of only miR-34c-3p and miR-138-1 were downregulated with significant statistical differences (p˂0.01). However, expression levels of miR-296-5p showed negative correlation with the total scores of IQ (p = 0.03). MiR-34c-3p, miR-138-1, while BDNF showed good diagnostic potential. The downregulated levels of miR-34c-3p and miR-138-1, together with high BDNF levels, are suggested to be involved in the etiology of ADHD in Egyptian children. Gender differences influenced the expression patterns of miRNAs only in children with ADHD.

Childhood Apraxia of Speech: Exploring Gluten Sensitivity and Changes in Glutamate and Gamma-Aminobutyric Acid Plasma Levels.

BACKGROUND: Individuals with childhood apraxia of speech (CAS) were reported to have genetic variations related to gluten sensitivity and some neuroanatomic changes, which could be associated with alterations in neurotransmitters levels such as glutamate and gamma-aminobutyric acid (GABA). The aim was to measure the levels of antigliadin immunoglobulin A (IgA) antibody, glutamate, and GABA in the plasma of children with CAS compared with children with delayed language development (DLD) and neurotypical (NT) children. METHODS: The participants (N = 120) were in three groups: Group I for CAS (N = 30), Group II for DLD (N = 60), and Group III for NT (N = 30). The abilities of children in Groups I and II were evaluated. The plasma levels of antigliadin IgA, glutamate, and GABA were determined by enzyme-linked immunosorbent assay. RESULTS: The intelligence quotient and expressive language age in Group I were low compared with Group II (P = 0.001; 0.004). The levels of antigliadin IgA and glutamate in Group I were higher compared with the other two groups, whereas the level of GABA was lower (P < 0.0001). An imbalance between glutamate and GABA was found in Group I. In Group II, no measures differed from NTs except lower GABA levels (P = 0.0007). CONCLUSIONS: The elevated levels of antigliadin IgA antibody and glutamate demonstrated high sensitivity and specificity, differentiating children with CAS from children with DLD and NT children. The low levels of GABA contributed to the imbalance between the excitatory and inhibitory neurotransmitters' levels detected in children with CAS.

Dyslexia with and without Irlen syndrome: A study of influence on abilities and brain-derived neurotrophic factor level.

The presence of comorbid Irlen syndrome (IS) in children with developmental dyslexia (DD) may have an impact on their reading and cognitive abilities. Furthermore, the brain-derived neurotrophic factor (BDNF) was reported to be expressed in brain areas involved in cognitive and visual processing. The aim of this study was to evaluate some cognitive abilities of a group of dyslexic children with IS and to measure and compare the plasma BDNF level to dyslexic children without IS and neurotypical (NT) children. The participants were 60 children with DD (30 in the DD + IS group; 30 in the DD group) and 30 NT children. The Irlen reading perceptual scale, the Stanford Binet intelligence scale, 4th ed, the dyslexia assessment test, and the Illinois test of psycholinguistic abilities were used. The BDNF level was measured using the enzyme-linked immunosorbent assay. One-minute writing and visual closure deficits were more prevalent, while phonemic segmentation deficits were less prevalent in the DD + IS group compared to the DD group. The BDNF level in the DD groups was lower than that in NT children (p < 0.001). Some reading and non-reading tasks were influenced by the presence of a coexisting IS. The reduced BDNF level could play a role in the deficits noticed in the abilities of children with DD.

Curcumin modulation of L-dopa and rasagiline-induced neuroprotection in rotenone model of Parkinson's disease.

Objectives: Parkinson's disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic anti-oxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied. Materials and Methods: Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included. Results: Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline. Conclusion: These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice.

BDNF Val66Met Polymorphism: Suggested Genetic Involvement in Some Children with Learning Disorder.

Brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal survival, especially in areas responsible for memory and learning. The BDNF Val66Met polymorphism has been described as a cognitive modifier in people with neuropsychiatric disorders. BDNF levels have been found to be low in children with learning disorder (LD). However, Val66Met polymorphism has not been studied before in such children. The aim was to investigate the presence of BDNF val66Met polymorphism in a group of children with specific LD and to verify its impact on their cognitive abilities. The participants in this cross-sectional study (N = 111) were divided into two groups: one for children with LD and the other for neurotypical (NT) ones. Children with LD (N = 72) were diagnosed according to the DSM-5 criteria. Their abilities were evaluated using Stanford-Binet Intelligence Scale, dyslexia assessment test, Illinois Test of Psycholinguistic Abilities, and phonological awareness test. Genotyping of BDNF Val66Met polymorphism was performed for all participants. The frequency of the Met allele was 26% among children with LD (6 children had homozygous, 26 had heterozygous genotype). The percentage of participants with deficits in reading, writing, and phonemic segmentation was higher in Met allele carriers when compared to non-Met allele carriers in LD group. The frequency of Met allele among NT children was 3.85% (0 homozygous, 3 children had heterozygous genotype) (p = 0.00001). The high frequency of Val66Met polymorphism among children with LD introduces the BDNF gene as a genetic modifier of learning performance in some children who manifest specific learning disorder (developmental dyslexia).

Kynurenine and oxidative stress in children having learning disorder with and without attention deficit hyperactivity disorder: possible role and involvement.

BACKGROUND: The etiological and pathophysiological factors of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) are currently not well understood. These disorders disrupt some cognitive abilities. Identifying biomarkers for these disorders is a cornerstone to their proper management. Kynurenine (KYN) and oxidative stress markers have been reported to influence some cognitive abilities. Therefore, the aim was to measure the level of KYN and some oxidative stress indicators in children with LD with and without ADHD and to investigate their correlations with the abilities of children with LD. METHODS: The study included 154 participants who were divided into 3 groups: one for children who have LD (N = 69); another for children with LD and ADHD (N = 31); and a group for neurotypical (NT) children (N = 54). IQ testing, reading, writing, and other ability performance evaluation was performed for children with LD. Measuring plasma levels of KYN, malondialdehyde, glutathione peroxidase, and superoxide dismutase by enzyme-linked immunosorbent assay was performed for all participants. RESULTS: Some IQ measures and learning skills differed between the first two groups. The biochemical measures differed between children with LD (with and without ADHD) and NT children (p < 0.001). However, the biochemical measures did not show a significant statistical difference between the first two groups. KYN and glutathione peroxidase levels were correlated with one-minute writing and at-risk quotient, respectively (p = 0.03;0.04). KYN and malondialdehyde showed the highest sensitivity and specificity values. CONCLUSION: These biochemical measures could be involved or have a role in the abilities' performance of children with specific learning disorder.

Impact of Bisphenol A on Gonadotropic Hormone Levels in Children with Autism Spectrum Disorders.

Early developmental exposures to endocrine disruptors including bisphenol A (BPA) may affects the body's endocrine system producing adverse neurologic, reproductive, cardiovascular, metabolic, and immune effects in humans. Many studies show the effect of BPA on human reproduction at lower concentrations than that of the safety limit recommendations. However, limited studies have been associated between environmental exposure of BPA and gonadotropic hormone levels in children with autism spectrum disorders (ASDs). This study was done to evaluate association between the serum levels of hormones; follicle-stimulating (FSH), inhibin B (INHB), and estradiol (E2) and BPA in 49 ASD children compared with 40 healthy control children. Serum levels of FSH, INHB, and E2 were lower in ASD group than that of control. Correlations between BPA and FSH, INHB, and E2 within autistic children were not significant. The observed results revealed that BPA may cause endocrine dysfunction in ASD children.

Combined neurotoxic effects of cannabis and nandrolone decanoate in adolescent male rats.

Polydrug use among adolescence is a widespread phenomenon and has increased in the last few years. In particular, most nandrolone decanoate (Nan) abusers combine its use with cannabis (Can); thus, studying the consequences of this combination in adolescent subjects is important because potentiation of their effects may increase their neurotoxicity. The present study was designed to study the neurotoxic effects of Nan and Can, alone and in combination, in adolescent male rats by studying the behavioural, biochemical, and histopathological effects. Nan (15 mg/kg, s.c.) and Can (20 mg/kg, s.c.) were given alone or in combination to rats once daily for one month. The combined administration of Can and Nan induced learning and spatial memory deficits, hypo-locomotion, anxiety and aggression in adolescent rats as evidenced by the Morris water maze, open field, elevated plus maze, and defensive aggression tests. In parallel, rats treated with the combination showed severe deleterious effects in the hippocampal and prefrontal cortex (PFC) neural architecture along with a decrease in brain-derived neurotropic factor. Furthermore, combined administration of Can and Nan increased oxidative stress (significantly increased malondialdehyde and nitric oxide levels and reduced glutathione content), elevated brain pro-inflammatory cytokines (tumour necrosis factor alpha and interleukin 1 beta), and upregulated caspase-3, caspase-8, and caspase-9 mRNA expression and cytochrome c levels. In conclusion, abuse of both Can and Nan conferred greater neurotoxic effects than either drug alone that were at least partially attributed to oxidative stress, inflammation, and intrinsic and extrinsic apoptosis in the hippocampus and PFC of rats.

Association between circulating microRNA-126 expression level and tumour necrosis factor alpha in healthy smokers.

Introduction: Smoking contributes to the death of a million people worldwide each year. Smokers experience an alteration in tumour necrosis factor-alpha (TNF-α), and the risk of expected lung cancer. The study aimed at investigating the expression levels of mir-126 and mir-124, as well as TNF-α as possible biomarkers of expected smoking-related diseases. Methods: Twenty-five male smokers' age and sex-matched with 25 non-smokers were recruited for the present study. Plasma expression levels of mir-126 and mir-124 were evaluated using quantitative real-time PCR. Lipid profile, TNF-α, interleukin-6 and C-reactive protein were assessed in plasma of each participant. Results: Plasma miR-126 was statistically down-regulated in smokers relative to non-smokers; however, mir-124 did not show any significant changes between groups. Among the measured parameters, mir-126 and tumour necrosis factor alpha (TNF-α) displayed a good discrimination and sensitivity between smokers and non-smokers (AUC = 0.809 (95% CI: 0.668-0.95; p < 0.001) and 0.742(95% CI: 0.584-0.9; p < 0.01), respectively. Also, the combined evaluation of miR-126 and TNF-α levels showed high discrimination (AUC= 0.889 (95% CI: 0.779-1.00; p < 0.0001), sensitivity = 85%, and specificity = 80% in the diagnosis of smokers with non-smokers. Conclusions: MiR-126 and TNF-α are potential biomarkers of smoking-related diseases and are important in assessing the expected tobacco-related harm.

Study of the Effect of Bisphenol A on Oxidative Stress in Children with Autism Spectrum Disorders.

The role of bisphenol A (BPA) in autism was investigated in 49 children (mean age = 5.950 ± 1.911 years) with autism spectrum disorders (ASDs) and 40 comparable age and sex matched children used as controls (mean age = 5.333 ± 2.279 years). In addition, 8-Hydroxydeoxyguanosine (8-oxodG) was also studied as a biomarker of oxidative stress in the same set of two selected groups. The results showed that both BPA and 8-oxodG were significantly higher in children with autism than those of control children (p values = 0.025 and 0.0001, respectively). There were positive correlations between both BPA and 8-oxodG with ASDs severity (r = 0.400 and 0.805, respectively), these correlations were highly significant (p values = 0.004 and 0.001, respectively). There was a significance positive correlation between BMI and BPA, but the correlation between BMI and 8-oxodG was not significant in children with autism. The observed results revealed that BPA may increase oxidative stress resulting in mitochondrial dysfunction that affecting the behavior and functioning of ASDs children.

Eco-friendly Synthesis of Pyrido[2,3-d]pyrimidine Analogs and Their Anticancer and Tyrosine Kinase Inhibition Activities.

BACKGROUND: One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives. OBJECTIVE AND METHOD: Efficient synthesis of a novel series of 18 new 1,8-naphthyridine-3-carbonitrile, 2-amino pyrido[2,3-d]pyrimidine derivatives via multi-component reactions of aromatic aldehydes, active methylene, and an aromatic amine under microwave irradiation and evaluation of their anticancer activity and possible mechanisms. RESULTS: Only compounds 5 (a-c) had a significant antiproliferative activity in hepatic HepG2 cells at submicromolar concentration (7.5-10 µM). Similarly, only compound 11 (a-c) had a significant activity in breast MCF7 cells at (4-7 µM). Derivatives with one methoxyphenyl substitution (5a and 11a) were not different from derivatives having dimethoxyphenyl substitution (5b and 11b). However, thiophene substitution (5c and 11c) enhanced the anticancer activity in both cells lines examined by 25% in HepG2 and by ~45% in MCF7 cells compared to a and b derivatives. All compounds were safe to both normal human lung cells (WI-38) and RBCs at concentrations up to 40 mM. The antiproliferative activity of compounds 5 (a-c) in HepG2 could be attributed to an induction of intrinsic apoptotic pathway as evidenced from the induction of initiator caspase 9 by ~ 4 folds. While, the activity of compounds 11 (a-c) could be attributed to their potential to inhibit tyrosine kinases (TK) by up to 85%. The IC50 of derivative 11c against TK was at 173 nM. CONCLUSION: The present study reported that derivatives 5 and 11 have merit for further investigation as anticancer and TK inhibitors.

Potential Renoprotective Effects of Rosemary and Thyme Against Gentamicin Toxicity in Rats.

Gentamicin (GM) is a drug used commonly against gram-negative bacteria. Its therapeutic use is mainly limited by its nephrotoxicity. This investigation was aimed at evaluating the nephroprotective effects of rosemary (RM; Rosmarinus officinalis) and thyme (TV; Thymus vulgaris) against GM toxicity. Rats were divided into four groups. Normal control group was treated intraperitoneally (i.p.) with saline; positive control group was administered GM 60 mg/kg/day i.p.; RM group was co-administered 8% RM aqueous extract, 10 mL/kg/day, orally with GM; and TV group was co-administered 8% TV aqueous extract orally, 10 mL/kg/day with GM. Both RM and TV groups extracted significantly ameliorated plasma kidney function biomarkers, and reduced malondialdhyde and glucose levels. Meanwhile, RM extract significantly modulated the electrolyte concentration and increased plasma insulin levels as compared with the GM group. However, the aqueous extract of RM showed more pronounced effects than TV extract. Our data were confirmed by histopathological examination and deoxyribonucleic acid (DNA) fragmentation analysis. Deleterious histopathological changes and increased DNA fragmentation induced by GM treatment were markedly controlled by the co-administration of RM and TV. Such renoprotective influence of RM and TV suggests their concurrent supplementation with GM therapy to limit GM toxicity.