The Fetal Alcohol Spectrum Disorders-An Overview of Experimental Models, Therapeutic Strategies, and Future Research Directions.

Since the establishment of a clear link between maternal alcohol consumption during pregnancy and certain birth defects, the research into the treatment of FASD has become increasingly sophisticated. The field has begun to explore the possibility of intervening at different levels, and animal studies have provided valuable insights into the pathophysiology of the disease, forming the basis for implementing potential therapies with increasingly precise mechanisms. The recent reports suggest that compounds that reduce the severity of neurodevelopmental deficits, including glial cell function and myelination, and/or target oxidative stress and inflammation may be effective in treating FASD. Our goal in writing this article was to analyze and synthesize current experimental therapeutic interventions for FASD, elucidating their potential mechanisms of action, translational relevance, and implications for clinical application. This review exclusively focuses on animal models and the interventions used in these models to outline the current direction of research. We conclude that given the complexity of the underlying mechanisms, a multifactorial approach combining nutritional supplementation, pharmacotherapy, and behavioral techniques tailored to the stage and severity of the disease may be a promising avenue for further research in humans.

The Impact of Prenatal Alcohol Exposure on the Autonomic Nervous System and Cardiovascular System in Rats in a Sex-Specific Manner.

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a consequence of prenatal alcohol exposure (PAE) associated with a range of effects, including dysmorphic features, prenatal and/or postnatal growth problems, and neurodevelopmental difficulties. Despite advances in treatment methods, there are still gaps in knowledge that highlight the need for further research. The study investigates the effect of PAE on the autonomic system, including sex differences that may aid in early FASD diagnosis, which is essential for effective interventions. METHODS: During gestational days 5 to 20, five pregnant female Wistar rats were orally administered either glucose or ethanol. After 22 days, 26 offspring were born and kept with their mothers for 21 days before being isolated. Electrocardiographic recordings were taken on the 29th and 64th day. Heart rate variability (HRV) parameters were collected, including heart rate (HR), standard deviation (SD), standard deviation of normal-to-normal intervals (SDNN), and the root mean square of successive differences between normal heartbeats (RMSSD). Additionally, a biochemical analysis of basic serum parameters was performed on day 68 of the study. RESULTS: The study found that PAE had a significant impact on HRV. While electrolyte homeostasis remained mostly unaffected, sex differences were observed across various parameters in both control and PAE groups, highlighting the sex-specific effects of PAE. Specifically, the PAE group had lower mean heart rates, particularly among females, and higher SDNN and RMSSD values. Additionally, there was a shift towards parasympathetic activity and a reduction in heart rate entropy in the PAE group. Biochemical changes induced by PAE were also observed, including elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST), especially in males, increased creatinine concentration in females, and alterations in lipid metabolism. CONCLUSIONS: PAE negatively affects the development of the autonomic nervous system, resulting in decreased heart rate and altered sympathetic activity. PAE also induces cardiovascular abnormalities with sex-specific effects, highlighting a relationship between PAE consequences and sex. Elevated liver enzymes in the PAE group may indicate direct toxic effects, while increased creatinine levels, particularly in females, may suggest an influence on nephrogenesis and vascular function. The reduced potassium content may be linked to hypothalamus-pituitary-adrenal axis overactivity.

Neuroprotective Activity of Enantiomers of Salsolinol and N-Methyl-(R)-salsolinol: In Vitro and In Silico Studies.

Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that salsolinol colocalizes with dopamine-rich regions and was first detected in the urine of Parkinson's disease patients, its direct role in the process of neurodegeneration has been proposed. Here, we report that R and S enantiomers of salsolinol, which we purified from commercially available racemic mixture by means of high-performance liquid chromatography, exhibited neuroprotective properties (at the concentration of 50 µM) toward the human dopaminergic SH-SY5Y neuroblastoma cell line. Furthermore, within the study, we observed no toxic effect of N-methyl-(R)-salsolinol on SH-SY5Y neuroblastoma cells up to the concentration of 750 µM, either. Additionally, our molecular docking analysis showed that enantiomers of salsolinol should exhibit a distinct ability to interact with dopamine D2 receptors. Thus, we postulate that our results highlight the need to acknowledge salsolinol as an active dopamine metabolite and to further explore the neuroregulatory role of enantiomers of salsolinol.

Expanded insights into the neural component of the activity-based anorexia animal model - morphological changes in the enteric nervous system and altered pain perception.

Anorexia nervosa (AN) is an eating disorder characterized by distinct etiopathogenetic concepts that are gradually being linked together to unravel the dominant pathophysiological pathways underlying the disease. Excessive food restrictions, often accompanied by over-exercise and undertaken to lose weight, lead to the development of numerous complications. The biological concept of neurohormonal dysfunction in AN seems incomplete without demonstrating or excluding the role of the enteric nervous system (ENS). Using an animal model of activity-based anorexia (ABA), we conducted the preliminary assessment of the ENS structure. Here we show, in preparations stained by immunohistochemistry with anti- ChAT, anti-NOS, anti-PGP 9.5, anti-c-fos, and anti-TH antibodies, a lower density of cholinergic and nitrergic nerve fibers as well as reduced neuronal activity in myenteric plexus. Such structural and functional damage to the ENS may be responsible for a number of gastrointestinal symptoms that worsen the course of the disease. In addition, we expanded the study to address the unresolved issue of mechanical and thermal pain sensitivity in AN. The Von Frey and hot plate tests revealed, that in ABA animals, the pain threshold for mechanical stimulus decreases while for thermal increases. In this way, we have significantly supplemented the background of AN with potentially observable nervous system changes which may influence the evolution of the therapeutic approach in the future.

The autonomic nervous system in anorexia nervosa - an implication for the fat tissue.

Eating disorders are a heterogeneous group of diseases affecting mainly young people in developed countries. Among them, anorexia nervosa (AN) is the one with the highest mortality, up to five times higher compared to healthy individuals. The etiology of this medical condition is complex and still un- certain. However, disturbances of the autonomic nervous system (ANS) and increased lipolysis resulting in a decrease of the adipose tissue volume are common findings among AN patients. Since ANS is directly connected to adipocyte tissue, thus significantly affecting the body's metabolic homeostasis, we suspect that this relationship may be a potential pathophysiological underpinning for the development of AN. In this narrative review, we have analyzed scientific reports on ANS activity in AN considering different phases of the disease in humans as well as animal models. Due to the different effects of the disease itself on the ANS as well as specific variations within animal models, the common feature seems to be dysregulation of its function without the identification of one universal pattern. Nonetheless, higher norepinephrine concentrations have been reported in adipocyte tissue, suggesting local dominance of the sym- pathetic nervous system. Further studies should explore in depth the modulation of sympathetic in adipose tissue factor and help answer key questions that arise during this brief narrative review.

Is the Activity-Based Anorexia Model a Reliable Method of Presenting Peripheral Clinical Features of Anorexia Nervosa?

Anorexia nervosa (AN) causes the highest number of deaths among all psychiatric disorders. Reduction in food intake and hyperactivity/increased anxiety observed in AN are also the core features of the activity-based anorexia animal model (ABA). Our aim was to assess how the acute ABA protocol mimics common AN complications, including gonadal and cardiovascular dysfunctions, depending on gender, age, and initial body weight, to form a comprehensive description of ABA as a reliable research tool. Wheel running, body weight, and food intake of adolescent female and male rats were monitored. Electrocardiography, heart rate variability, systolic blood pressure, and magnetic resonance imaging (MRI) measurements were performed. Immediately after euthanasia, tissue fragments and blood were collected for further analysis. Uterine weight was 2 times lower in ABA female rats, and ovarian tissue exhibited a reduced number of antral follicles and decreased expression of estrogen and progesterone receptors. Cardiovascular measurements revealed autonomic decompensation with prolongation of QRS complex and QT interval. The ABA model is a reliable research tool for presenting the breakdown of adaptation mechanisms observed in severe AN. Cardiac and hormonal features of ABA with underlying altered neuroendocrine pathways create a valid phenotype of a human disease.

Backstage of Eating Disorder-About the Biological Mechanisms behind the Symptoms of Anorexia Nervosa.

Anorexia nervosa (AN) represents a disorder with the highest mortality rate among all psychiatric diseases, yet our understanding of its pathophysiological components continues to be fragmentary. This article reviews the current concepts regarding AN pathomechanisms that focus on the main biological aspects involving central and peripheral neurohormonal pathways, endocrine function, as well as the microbiome-gut-brain axis. It emerged from the unique complexity of constantly accumulating new discoveries, which hamper the ability to look at the disease in a more comprehensive way. The emphasis is placed on the mechanisms underlying the main symptoms and potential new directions that require further investigation in clinical settings.

Hypothalamic and brain stem neurochemical profile in anorectic rats after peripheral administration of kisspeptin-10 using 1 H-nmr spectroscopy in vivo.

PURPOSE: Although anorexia nervosa is classified as a psychiatric disorder associated with socio-environmental and psychological factors, a deeper insight into the dominant neurobiological basis is needed to develop a more effective approach of treatment. Given the high contribution of genetic predisposition and the underlying pathophysiology of neurohormonal circuits, it seems that pharmacological targeting of these mechanisms may provide us with better therapeutic outcomes. METHODS: 1 H-NMR spectroscopy was used to measure concentrations of the hypothalamus and brain stem metabolites in an activity-based rodent model (ABA) after subcutaneous administration of kisspeptin-10. Because anorexia mainly affects young women and often leads to hypogonadotropic-hypogonadism, we investigated the influence of this neuropeptide, which is involved in reproductive function by regulating the hypothalamic-pituitary-gonadal axis, on the ABA model development. RESULTS: Kisspeptin reinforced food consumption in an activity-based rodent model of anorexia changing a pattern of weight loss. 1 H-NMR spectroscopy of the hypothalamus and brain stem of ABA rats revealed a statistically significant change in the concentration of creatine (Cr; decreased, P = 0.030), phosphocreatine (PCr; increased, P = 0.030), γ-aminobutyric acid (GABA; decreased, P = 0.011), glutathione (GSH; increased, P = 0.011) and inositol (INS; increased, P = 0.047) compared to the control group. Subcutaneous administration of kisspeptin reversed the decrease in GABA (P = 0.018) and Cr (P = 0.030) levels in the hypothalamus as well as restored glutamate (GLU; P = 0.040) level in the brain stem. CONCLUSIONS: We suspect that kisspeptin through modulation of hypothalamic GABAergic signaling increases food intake, and thus positively alters brain metabolism.

Prenatal alcohol exposure and autonomic nervous system dysfunction: A review article.

Alcohol is a recognized teratogen that affects various aspects of fetal development. Tissue that is particularly susceptible to its teratogenicity is neuronal tissue. The effect of prenatal alcohol exposure (PAE) on the central nervous system has been extensively studied, yet the knowledge on the influence of PAE on the autonomic nervous system is scarce. The purpose of this article is to review the current state of knowledge about the impact of PAE on the autonomic nervous system. Studies conducted on the PAE animal model have shown that prenatal alcohol exposure is associated with significant alterations in the autonomic nervous system, but the mechanisms and consequences are not yet clearly defined. It was established that PAE causes decreased heart rate variability (HRV) in fetal cardiotocography. Several studies have revealed that later, in infancy and childhood, reduced parasympathetic activity with or without compensating sympathetic activity is observed. This may result in behavioral and attention disorders, as well as an increased predisposition to sudden infant death syndrome. Both animal and human studies indicate that the relationship between PAE and autonomic dysfunction exists, however large, well-designed, prospective studies are needed to con rm the causal relationship and characterize the nature of the observed changes.

Aberrations in the female reproductive organs and a role of telocytes in a rat model of anorexia nervosa.

BACKGROUND: Anorexia nervosa is a widely prevalent eating disorder that o en leads to life-threatening complications. Since it mostly concerns females, many authors have focused on studying the reproductive system in anorexic women. Recently discovered telocytes may give a new insight into the pathophysiology of gynecological complications in these patients. MATERIAL AND METHODS: We adopted an animal model of anorexia nervosa induced by voluntary physical activity. Sixteen female Wistar rats were divided into two groups: control and activity-based anorexia. When the weight loss of activity-based anorexia (ABA) rats reached 25% animals were euthanized. Size and weight measurements as well as histopathological analysis of the reproductive organs were performed. Additionally, we used immunohistochemical staining for detection of telocytes. RESULTS: Telocytes were identified in uteri of anorectic rats but no differences were observed when compared to the control group. Nevertheless, in the ABA group the weight of the uteri and the number of follicles in the ovaries decreased significantly. CONCLUSIONS: Our rat model of anorexia nervosa mimics the effects of this eating disorder that occur in the female reproductive system since we reported ovarian dysfunction and uterine involution in the experimental animals. It supports its potential role in the further studies of anorexia pathophysiology and treatment possibilities.

The role of vitamin D in the pathogenesis of ocular diseases.

The prevalence of vitamin D deficiency in the American and European population is estimated to be extremely high. Although fewer people today su er from serious health problems related to calcium and phosphate metabolism resulting from vitamin D deficiency, there are more and more studies suggesting that calcitriol may play an important role in the pathogenesis of other diseases in virtually every body system. A growing body of research shows that through its ubiquitously expressed receptor, calcitriol displays potent anti-angiogenic an anti-inflammatory activity. This review summarizes recent discoveries regarding these non-classical effects of vitamin D and their clinical implications. Data collection focused on the prevention and treatment of ocular diseases as well as on the underlying mechanisms.