👤 Necati Uzun

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a complex and not fully understood etiology. Increasing evidence suggests that neurotrophic factors involved in neurodevelopment and synaptic plasticity, as well as hormones of the hypothalamic-pituitary-adrenal (HPA) axis that regulate the stress response, may contribute to the pathophysiology of ADHD. This cross-sectional study aimed to compare children diagnosed with ADHD and healthy controls with respect to serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), neurotrophin-3 (NT-3), adrenocorticotropic hormone (ACTH), and cortisol. A total of 80 children aged 6-18 years with a diagnosis of ADHD and 81 healthy controls were included in the study. The severity of ADHD symptoms was assessed using the Conners' Parent Rating Scale-Short Version (CPRS-SV). Serum levels of biochemical parameters were measured using commercially available electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay kits. Compared with the healthy control group, the ADHD group exhibited significantly higher serum levels of BDNF, GDNF, VEGF, ACTH, and cortisol, whereas NT-3 levels did not differ between the groups. These group differences remained statistically significant after controlling for potential confounding variables. Correlation analyses revealed no significant associations between neurotrophic factors, hypothalamic-pituitary-adrenal (HPA) axis hormones, and CPRS-SV subscale scores. The present findings indicate that neurotrophic factors and hormones related to the hypothalamic-pituitary-adrenal (HPA) axis are altered in medication-naïve children and adolescents with ADHD. The absence of a direct correlation between neurotrophic factors and HPA axis hormones suggests that these systems may contribute to the pathophysiology of ADHD through parallel yet partially independent and complex mechanisms. Future longitudinal and multimodal studies are warranted to elucidate the dynamic interactions between stress-related neuroendocrine processes and neurodevelopmental pathways in ADHD. Show less

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and repetitive behaviors, with currently limited therapeutic options. Oxidative stress is suggested as significant in ASD pathophysiology, making antioxidant strategies a promising therapeutic direction. Exercise reduces oxidative stress, alleviates ASD symptoms, and increases tetrahydrobiopterin (BH4) and brain-derived neurotrophic factor (BDNF) levels through AMP-activated protein kinase (AMPK) activation. MOTS-c, a mitochondrial-derived peptide acting through AMPK, mimics the effects of exercise but reportedly does not cross the blood-brain barrier (BBB). Considering the challenges in exercise adherence in ASD, our study hypothesizes that MOTS-c could increase circulating BH4 and BDNF, both of which are BBB-permeable, and alleviate oxidative stress and ASD symptoms. To evaluate this hypothesis, we investigated the effects of MOTS-c in the valproic acid-induced rat model of autism. Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12. Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46. Following behavioral testing, animals were sacrificed, and histological and biochemical analyses were performed. Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage. No significant changes in plasma BH4 or BDNF levels were detected. Through its neuroprotective and antioxidant effects independent of BH4 and BDNF, MOTS-c may alleviate autism-like behaviors, suggesting its potential as a therapeutic candidate for ASD. Show less

Gradual loss of cognitive abilities is common during ageing but might also result in mild cognitive impairment and dementia. Research suggests that neurotrophins, such as brain derived neurotrophic factor (BDNF), and neurosteroids, such as dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), play crucial role in cognitive functions and are often dysregulated in neurocognitive disorders. This study aimed to investigate variations in the genes for BDNF and sulfotransferase 2A1 (SULT2A1), the enzyme converting DHEA into DHEAS, as well as plasma BDNF and DHEAS levels, in individuals with normal cognition, and mild, moderate, and severe cognitive impairment. Cognitive functions of 453 participants were evaluated using Mini-Mental State Examination (MMSE) and Clock Drawing test (CDT). Genotyping of BDNF (rs6265) and SULT2A1 (rs2637125) polymorphisms was conducted, and plasma BDNF and DHEAS concentrations were determined by enzyme-linked immunosorbent assays (ELISA). Obtained results demonstrated that participants with moderate to severe cognitive impairment had significantly lower plasma BDNF and DHEAS levels, compared to individuals with normal cognition. In contrast to DHEAS, BDNF changes were more pronounced in men than in women. However, no significant associations of BDNF rs6265 and SULT2A1 rs2637125 polymorphisms with cognitive decline, or with plasma BDNF and DHEAS levels, respectively, were observed. Compared to CDT, MMSE was superior in distinguishing plasma BDNF and DHEAS variations, especially between individuals with mild and moderate to severe cognitive impairment. Further studies should investigate the potential of BDNF and DHEAS as peripheral biomarkers of cognitive decline and possible benefits of their replacement therapy in neurocognitive disorders. Show less

Disorders of sex development (DSD) constitutes a group of congenital conditions that affect urogenital differentiation and are associated with chromosomal, gonadal and phenotypic sex abnormalities. To evaluate the clinical and genetic features of childhood DSD cases. DSD patients followed up between the years of 2002-2018 were evaluated in terms of their complaints, demographic, clinical features and genetic diagnoses. Out of 289 patients, 143(49.5%) were classified as 46XY DSD, 62(21.5%) as 46XX DSD and 84(29%) as sex chromosomal DSD. Genetic diagnosis was achieved in 150 patients (51.9%). The distribution of the molecular diagnosis of the 46XY DSD patients were; 12 (26.6%) SRD5A2, 10 (22.2%) AR, 7 (15.5%) HSD17B3, 3 (6.6%) WT-1, 2 (4.4%) AMHR2, 2 (4.4%) AMH, 2 (4.4%) LHCGR, 2 (4.4%) HSD3B2, 1 (2.2%) NR5A1, 1 (2.2%) CYP17A1 and 1 (2.2%) SRY mutation. Fifty (80.6%) of the 46XX DSD patients received a diagnosis with clinical and laboratory findings. Twenty-four (38.7%) of them were 21-hydroxylase deficiency, 9(14.5%) Rokitansky-Küster-Hauser Syndrome, 4 (6.5%) 11-β hydroxylase deficiency, 3 (4.8%) gonadal dysgenesis and 2 (3.2%) aromatase deficiency. In 46XX group pathogenic mutations were detected in 21(33.8%) of the patients. Eighty-four (29%) patients were diagnosed as sex chromosomal disorder. Of these 66 (78.5%) were Turner Syndrome, 6 (7.2%) Klinefelter Syndrome and 10 (11.9%) mix gonadal dysgenesis. Gender re-assignment was decided in 11 patients. Malignant and pre-invasive lesions was diagnosed in 8 (2.7%) patients. Many of DSD's are clinically similar and etiology of numerous of them still cannot be established. A multi-disciplinary approach and new rapid genetic diagnostic methods are needed in the process from diagnosis to gender assignment and follow-up. Show less