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Lege Artis Medicinae

DECEMBER 10, 2018

[Experimental investigation of the complex energy balance]

GARAMI András

[The complex energy balance includes maintenance of both normal body mass and body temperature. In the homeostasis regulation it is important that the activities of several physiologic processes are balanced with each other, for example, the balance between food intake and energy expenditure is crucial to maintain normal body mass, while the balance between heat production and heat loss is vital in determining body temperature. Obesity and loss of body weight, as well as fever and hypothermia are consequences of the dysregulation in energy balance. In our research, we studied receptorial and neurohumoral mechanisms involved in the maintenance and in the impairment of energy balance. This paper gives an overview of our most important findings, which served as the basis of the application submitted to and awarded with 3rd prize by the Prof. Dr. Laszlo Romics Memorial Foundation. We review the physiologic role of transient receptor potential channels, mostly of vanilloid-1 (formerly: capsaicin receptor) in the regulation of body temperature and body mass. Among the neuropeptides which take part in the maintenance of energy balance, we present the thermoregulatory effects of alpha-melanocyte stimulating hormone and pituitary adenylate cyclase-activating polypeptide. Last, among the molecular mechanisms of systemic inflammation, which is characterized by thermoregulation disorders (e.g., fever, hypothermia), we recap the role of the vanilloid-1 and neurokinin-1 receptor, and bilirubin.]

Clinical Neuroscience

SEPTEMBER 30, 2016

Stress-induced corticosterone rise maintain gastric mucosal integrity in rats

LUDMILA Filaretova, MARINA Myazina, TATIANA Bagaeva

Background - To investigate contribution of glucocorticoids to the maintenance of gastric mucosal integrity during stress we predominantly used ulcerogenic stress models. Using these models we demonstrated that glucocorticoids released in response to the ulcerogenic stimuli attenuated their harmful action on the gastric mucosa. Purpose - In the present study we hypothesized that mild stressors does not damage the gastric mucosa due to gastroprotective action of glucocorticoids released in response to these stressors. Methods - To verify the hypothesis the effects of normally non-ulcerogenic mild stimuli (15-30 min cold-restraint) on the gastric mucosal integrity have been studied under the circumstances of inhibition of the hypothalamic-pituitaryadrenocortical axis in rats. The hypothalamic-pituitary-adrenocortical axis was inhibited by: 1) fast inhibitory action of metyrapone, inhibitor glucocorticoid synthesis; 2) fast inhibitory action of NBI 27914, the selective antagonist of cortricotropin- releasing factor receptor type 1; 3) delayed inhibitory action of a single pharmacological dose of cortisol injected one week before the onset of stress stimulus. Results - Each of these pretreatments significantly decreased 15-30 min cold-restraint-produced corticosterone levels: 37.2±1 vs 22.5±1.2 (p<0.05) after metyrapone; 52.1±0.9 vs 41.4±1 (p<0.05) after NBI, and 64.2±4.2 vs 16.7±1.5 (p<0.05) after cortisol pretreatment. The inhibition of stress-induced corticosterone rise resulted in an ap - pearance of gastric lesions after the onset of these mild stressors in rats. Conclusions - The results suggest that in rats with inhibited stress-induced corticosterone rise normally non-ulcerogenic stimuli are transformed into ulcerogenic ones and confirm the hypothesis. The findings further support for the point of view that glucocorticoids released during acute stress are gastroprotective factors.

Clinical Neuroscience

MAY 30, 2016

[Experiences of hypothalamic hamartoma surgeries]

NOVÁK László, KISS Máté Tamás, KLEKNER Álmos, NAGY Andrea, FEDORCSÁK Imre, BOGNÁR László

[Background and purpose - Hypothalamic hamartomas are focal, benign congenital malformations that frequently associated with gelastic seizures. Behavioural disturbances, cognitive decline and the appearance of precocious puberty can also be observed. The most effective way to relieve the symptoms is the surgical disconnection between the hamartoma and the hypothalamus. In our study, we retrospectively analyzed the surgical indications and effectiveness of each approach. Methods - Between 1996 and 2014 we operated on 10 hypothalamic hamartomas. Endoscopic assisted resection was performed in three patients. Six patients underwent direct microsurgical resection in various approaches and one patient was treated with Gamma Knife. Results - We achieved significant decrease in the number of seizures in every patient presenting with various seizure types. The surgical resection was effective in the arresting of the puberty praecox as well. However the surgery of these lesions at their special location holds the danger of the appearance of new endocrinological symptoms. According to our observations the operation on hamartoma less effectively ameliorates the psychiatric symptoms than the others. Conclusion - The surgical treatment is effective in the reduction of the initial symptoms and we had no mortality. According to our analysis therapeutic success is anticipated but we couldn’t archive total symptomatic relief in every case. The first approach to these lesions should be the surgery which type must be tailored to each patient.]

Clinical Neuroscience

MARCH 30, 2014

[CENTRAL NEUROENDOCRINE MECHANISMS OF GASTROPROTECTION]

GYIRES Klára

[Selye recognized the importance of activation of hypothalamic- pituitary-adrenal axis during stress and the connection between central nervous system and neuroendocrine regulation. This concept basically contributed to initiation of the studies, which revealed the importance of brain gut axis in regulation of gastric mucosal integrity. Several neuropeptides, such as thyreotrop releasing hormones, adrenomedullin, peptide YY, amylin, opioid peptides, nociceptin, nocisatin, substance P, ghrelin, leptin, orexin-A, angiotensin II were shown to induce gastroprotective effect injected centrally. Though the involvement of dorsal vagal complex and vagal nerves in conveying the central action to the periphery has been well documented, additional mechanisms have also been raised. The interaction between neuropeptides further component that may modify the gastric mucosal resistance to noxious stimulus.]

Clinical Neuroscience

MARCH 30, 2014

[HANS SELYE AND THE STRESS RESPONSE: FROM “THE FIRST MEDIATOR” TO THE IDENTIFICATION OF THE HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR]

TACHÉ Yvette

[Selye pioneered the stress concept that is ingrained in the vocabulary of daily life. This was originally build on experimental observations that divers noxious agents can trigger a similar triad of endocrine (adrenal enlargement), immune (involution of thymus) and gut (gastric erosion formation) responses as reported in a letter to Nature in 1936. Subsequently, he articulated the underlying mechanisms and hypothesized the existence of a “first mediator” in the hypothalamus able to orchestrate this bodily changes. However he took two generations to identify this mediator. The Nobel Laureate, Roger Guillemin, a former Selye’s PhD student, demonstrated in 1955 the existence of a hypothalamic factor that elicited adrenocorticotropic hormone release from the rat pituitary and named it corticotropin releasing factor (CRF). In 1981, Wylie Vale, a former Guillemin’s Ph Student, characterized CRF as 41 amino acid and cloned the CRF1 and CRF2 receptors. This paves the way to experimental studies establishing that the activation of the CRF signaling pathways in the brain plays a key role in mediating the stress-related endocrine, behavioral, autonomic and visceral responses. The unraveling of the biochemical coding of stress is rooted in Selye legacy continues to have increasing impact on the scientific community.]

Clinical Neuroscience

MARCH 30, 2012

[Botulinum neurotoxin-A therapy in migraine]

TAJTI János, SZOK Délia, TUKA Bernadett, CSÁTI Anett, KURIS Anikó, MAJLÁTH Zsófia, LUKÁCS Melinda, VÉCSEI László

[Although migraine is a common, paroxysmal, highly disabling disorder, the primary cause and the pathomechanism of migraine attacks are enigmatic. Experimental results suggest that activation of the trigeminovascular system is crucial in its pathogenesis. This activation leads to the release of vasoactive neuropeptides (calcitonin gene-related peptide - CGRP, and substance P - SP) and to neurogenic inflammation, and peripheral and central sensitisation are expressed. Botulinum neurotoxin-A (BoNT-A), a potent toxin produced by Clostridium botulinum, affects the nervous system through specific cleavage of the soluble NSF-attachment protein receptor complex (SNARE), like synaptosomal-associated protein of 25 kDa (SNAP-25). The result of this multistage process is blockade of the presynaptic release of pain neurotransmitters such as CGRP, SP and glutamate. A pooled analysis of the data from two programmes of Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT 1 and 2) with BoNT-A in chronic migraine demonstrated significant benefit of BoNT-A over placebo with regard to the numbers of headache days and migraine episodes. BoNT-A diminished the frequency of acute headache pain medication intake, and resulted in reductions in headache impact and improvements in scores on the Migraine-Specific Quality of Life Questionnaire. The treatments with BoNT-A proved safe and were well tolerated.]

Clinical Neuroscience

MARCH 20, 2007

[EFFECT OF LOCAL (INTRACEREBRAL AND INTRACEREBROVENTRICULAR) ADMINISTRATION OF TYROSINE HYDROXYLASE INHIBITOR ON THE NEUROENDOCRINE DOPAMINERGIC NEURONS AND PROLACTIN RELEASE]

BODNÁR Ibolya, HECHTL Dániel, SZÉKÁCS Dániel, OLÁH Márk, NAGY M. György

[Background and purpose - Hypothalamic dopamine (DA), the physiological regulator of pituitary prolactin (PRL) secretion, is synthesized in the neuroendocrine DAergic neurons that projects to the median eminence and the neurointermediate lobe of the pituitary gland. The rate-limiting step of DA biosynthesis is catalyzed by the phosphorylated, therefore activated, tyrosine hydroxylase (TH) that produces L-3,4-dihydroxy- phenylalanine from tyrosine. The aims of our present study were to investigate 1. the effect of local inhibition of the DA biosynthesis in the hypothalamic arcuate nucleus on PRL release, and to get 2. some information whether the phosphorylated TH is the target of enzyme inhibition or not. Methods - A TH inhibitor, α-methyl-p-tyrosine was injected either intracerebro-ventricularly or into the arcuate nucleus of freely moving rats and plasma PRL concentration was measured. Immunohistochemistry, using antibodies raised against to native as well as phosphorylated TH were used to compare their distributions in the arcuate nucleus-median eminence region. Results - Intracerebro-ventricular administration of α-methyl-p-tyrosine has no effect, unlike the intra-arcuatus injection of enzyme inhibitor resulted in a slight but significant elevation in plasma PRL. Parallel with this, the level of DA and DOPAC were reduced in the neurointermediate lobe while no change in norepinephrine concentration can be detected indicating a reduced biosynthesis of dopamine following TH inhibition. On the other hand, systematic application of the α-methyl-p-tyrosine that inhibits TH activity located in DA terminals of the median eminence and the neurointermediate lobe, resulted in the most significant elevation of PRL. Conclusion - Our results suggest that α-methyl-p-tyrosine administered close to the neuroendocrine DAergic neurons was able to inhibit only a small proportion of the TH. Moreover, it also indicate that the majority of the activated TH can be found in the axon terminals of DAergic neurons, therefore, the DA released into the pituitary portal circulation is synthesized at this site.]

Clinical Neuroscience

MARCH 20, 2007

[SYNAPTIC CONNECTIONS OF GLUTAMATERGIC NERVE FIBRES IN THE RAT SUPRACHIASMATIC NUCLEUS]

KISS József, CSÁKI Ágnes, CSABA Zsolt, HALÁSZ Béla

[Background and purpose - The hypothalamic suprachiasmatic nucleus functioning as the principal circadian pacemaker in mammals, has a rich glutamatergic innervation. Nothing is known about the terminations of the glutamatergic fibres. The aim of the present investigations was to study the relationship between glutamatergic axon terminals and vasoactive intestinal polypeptide (VIP), GABA and arginine-vasopressin (AVP) neurons in the cell group. Methods - Double label immunocytochemistry was used and the brain sections were examined under the electron microscope. Vesicular glutamate transporter type 2 was applied as marker of the glutamatergic elements. Results - Glutamatergic fibers were detected in synaptic contact with GABAergic, VIP- and AVP-positive neurons forming asymmetric type of synapses. Conclusion - The findings are the first data on the synaptic contacts of glutamatergic axon terminals with neurochemically identified neurons in the suprachiasmatic nucleus.]

Clinical Neuroscience

MARCH 20, 2007

[BRAIN INSULIN SIGNALLING IN THE REGULATION OF ENERGY BALANCE AND PERIPHERAL METABOLISM]

MICHAELA Diamant

[The unparalleled global rates of obesity and type 2 diabetes, together with the associated cardiovascular morbidity and mortality, are referred to as the "diabesity pandemic". Changes in lifestyle occurring worldwide, including the increased consumption of high-caloric foods and reduced exercise, are regarded as the main causal factors. Central obesity and insulin resistance have emerged as important linking components. Understanding the aetiology of the cluster of pathologies that leads to the increased risk is instrumental in the development of preventive and therapeutic strategies. Historically, skeletal muscle, adipose tissue and liver were regarded as key insulin target organs involved in insulinmediated regulation of peripheral carbohydrate, lipid and protein metabolism. The consequences of impaired insulin action in these organs were deemed to explain the functional and structural abnormalities associated with insulin resistance. The discovery of insulin receptors in the central nervous system, the detection of insulin in the cerebrospinal fluid after peripheral insulin administration and the well-documented effects of intracerebroventricularly injected insulin on energy homeostasis, have identified the brain as an important target for insulin action. In addition to its critical role as a peripheral signal integrating the complex network of hypothalamic neuropeptides and neurotransmitters that influence parameters of energy balance, central nervous insulin signalling is also implicated in the regulation of peripheral glucose metabolism. This review summarizes the evidence of insulin action in the brain as part of the multifaceted circuit involved in the central regulation of energy and glucose homeostasis, and discuss the role of impaired central nervous insulin signalling as a pathogenic factor in the obesity and type 2 diabetes epidemic.]

Clinical Neuroscience

OCTOBER 20, 2003

[Hypothalamic regulation of the food intake]

PALKOVITS Miklós

[The central regulation of the food intake is organized by a long-loop mechanism involving humoral signals and afferent neuronal pathways to the hypothalamus, obligatory processing in hypothalamic neuronal circuits, and descending commands through vagal and spinal neurons to the body. Receptors sensitive to glucose metabolism, body fat reserves, distension of the stomach, as well as neuropeptide and cannabinoid receptors have been identified and localized in the hypothalamus. Five groups of cells in the hypothalamus - arcuate, paraventricular, ventromedial and dorsomedial nuclei, and the dorsolateral hypothalamic area - contain neurons with either anorexic actions (α-MSH, CART peptide, corticotropin-releasing hormone, urocortin III, cholecystokinin, glucagon-like peptides) or that stimulate food intake (neuropeptide Y, agouti-related peptide, orexins, melanin concentrating hormone, galanin). Intrahypothalamic neuronal circuits exist between these peptidergic neurons including the arcuate-paraventricular and arcuate-dorsolateral hypothalamic projections. Circulating substances carrying signals connected to changes in body food homeostasis and energy balance (leptin, ghrelin, insulin, glucose) enter the hypothalamus mainly through the arcuate nucleus. Neurons in the medulla oblongata that express leptin and insulin receptors, as well as neuropeptide mediators project to the hypothalamus. Vica versa, hypothalamic neurons give rise to projections to autonomic centers in the brainstem and the spinal cord with potential for stimulation or inhibition of food intake, energy balance and ingestion behavior.]