Both Basal and Acute Restraint Stress-Induced c-Fos Expression Is Influenced by Age in the Extended Amygdala and Brainstem Stress Centers in Male Rats

The hypothalamus-pituitary-adrenal axis (HPA) is the main regulator of the stress response. The key of the HPA is the parvocellular paraventricular nucleus of the hypothalamus (pPVN) controlled by higher-order limbic stress centers. The reactivity of the HPA axis is considered to be a function of age, but to date, little is known about the background of this age-dependency. Sporadic literature data suggest that the stress sensitivity as assessed by semi-quantitation of the neuronal activity marker c-Fos may also be influenced by age. Here, we aimed at investigating the HPA activity and c-Fos immunoreactivity 2 h after the beginning of a single 60 min acute restraint stress in eight age groups of male Wistar rats. We hypothesized that the function of the HPA axis (i.e., pPVN c-Fos and blood corticosterone (CORT) level), the neuronal activity of nine stress-related limbic areas (i.e., magnocellular PVN (mPVN), medial (MeA), central (CeA), basolateral nuclei of the amygdala, the oval (ovBNST), dorsolateral (dlBNST), dorsomedial (dmBNST), ventral and fusiform (fuBNST) divisions of the bed nucleus of the stria terminalis (BNST)), and two brainstem stress centers such as the centrally projecting Edinger-Westphal nucleus (cpEW) and dorsal raphe nucleus (DR) show age dependency in their c-Fos response. The somatosensory barrel cortex area (S1) was evaluated to test whether the age dependency is specific for stress-centers. Our results indicate that the stress-induced rise in blood CORT titer was lower in young age reflecting relatively low HPA activity. All 12 stress-related brain areas showed c-Fos response that peaked at 2 months of age. The magnitude of c-Fos immunoreactivity correlated negatively with age in seven regions (MeA, CeA, ovBNST, dlBNST, dmBNST, fuBNST and pPVN). Unexpectedly, the CeA, ovBNST and cpEW showed a considerable basal c-Fos expression in 1-month-old rats which decreased with age. The S1 showed a U-shaped age-related dynamics in contrast to the decline observed in stress centers. We conclude that the age- and brain area dependent dynamics in stress-induced neuronal activity pattern may contribute to the age dependance of the stress reactivity. Further studies are in progress to determine the neurochemical identity of neurons showing age-dependent basal and/or stress-induced c-Fos expression

Az iszkémiás és posztiszkémiás vaszkuláris és kardiorespiratorikus károsodások tanulmányozása = Investigation of apparent injury in the vascular and cardiorespiratory system due to ischemia and reperfusion

((1) A szívhipertrófiát irányító GATA-4 transzkripciós faktort a mitogén-aktiválta protein kinázok (p38, ERK) aktiválják mechanikai feszítés során. (2) Kamrai falfeszülés az endogén endothelin-1 és az angiotenzin II révén váltja ki a BNP expressziójának fokozódását. (3) Az endogén ouabain-szerű anyag szerepet játszik az ANP bal kamrai génexpressziójának szabályozásában. (4) A nukleáris faktor-kappaB transzkripciós faktor gátlása kivédi a bal kamrai remodellinget annak előrehaladott fázisában. (5) A szívizom-kontraktilitás szabályozásában döntő szerepet játszanak a mitogén aktiválta protein kinázok. (6) Viabilitás, coronária occlusios idő okozta bal kamra funkció változás vizsgálata MRI-vel. Az occlusios idő 45 és 90 perc között változtatvan proporcionálisan rontotta a bal kamra funkciót, mely mögött okként az arányos infarctus méret áll. (7) Humán mitrokondriumok nem termelnek relevans mennyiségű nitrogén oxidot iszkémiás szívbetegekben. (8) A flavonoid szupplementáció előnyös hatású krónikus obstruktív tüdőbetegségben. (9) Invazív módon validáltuk az artériás stifness meghatározására szolgáló non-invazív Arteriográf készüléket. (10) Jellemeztük a szérum asszimmetrikus dimetil-arginin változását katéteres revascularizatios eljáráson átesett betegeknél. (11) A poli-ADP-ribóz polimeráz enzim gátlása javítja a bal kamrai funkciót akut és krónikus experimentális szívelégtelenségben. (12) A szívritmus variabilitás vizsgálatára hatékony elemző rendszert fejlesztettünk ki. | (1) Our results suggest that the prohypertrophic transcription factor GATA-4 is activated by mitogen-activated protein kinases (p38, ERK) in response to mechanical stretch. (2) Stretch-induced activation of B-type natriuretic peptid gene expression is regulated by endogenous endothelin-1 and angiotensin II. (3) Adrenal-derived endogenous ouabain-like compound is involved in the activation of atrial natriuretic peptide in the left ventricle. (4) Inhibition of nuclear factor kappa-B attenuates severe left ventricular remodeling. (5) Mitogen-activated protein kinases play pivotal role in the regulation of myocardial contractility. (6) MRI study of LV function: dependence on coronary occlusion time and viability. Occlusion time between 45 and 60 minutes induced larger infarct and consequent heart failure proportionally. (7) Human heart mitochondria do not produce physiologically relevant quantities of nitric oxide. (8) Dietary flavonoids are beneficial in chronic obstructive pulmonary disease. (9) A new, oscillometric, portable device for measuring augmentation index and aortic pulse wave velocity (Areteriograph) has been validated invasively. (10) The response of asymetric dimethylarginine levels to stent placement has been characterized in patients with coronary heart disease. (11) Inhibition of poly(ADP-ribose) polymerase improves cardiac function in acute and chronic heart failure. (12) A data analysis system has been developed for analysis of heart rate variability

A diabeteses cardialis autonóm neuropathia diagnosztikája = Diagnosis of diabetic cardiac autonomic neuropathy

Absztrakt: A cardialis autonóm neuropathia (CAN) az 1-es és 2-es típusú diabetes mellitus gyakori szövődménye, melyet a cardiovascularis rendszer autonóm szabályozásának zavaraként definiálnak. A CAN szoros összefüggést mutat a halálozási adatokkal, és bizonyos vizsgálatok szerint a vascularis szövődmények, köztük a stroke, a koszorúér-betegség és a szívinfarktus okozta halálozással is. Korai stádiumban a CAN tünetmentes lehet, majd a betegség előrehaladtával megjelennek a klinikai tünetek is. A tünetmentes periódusban a cardiovascularis reflextesztek segítségével azonosítható, melyek prognosztikai értékkel is bírnak. A tünetek megjelenését követően az autonóm működési zavar a nyugalmi tachycardia, csökkent fizikai terhelhetőség, ortosztatikus hipotónia, syncope, intraoperatív cardiovascularis instabilitás, néma szívizominfarktus vagy ischaemia okozta megnövekedett halálozás alapján diagnosztizálható. Bár a CAN nagyon gyakori és előrehaladott esetekben súlyos diabeteses szövődmény, gyakran nem kerül felismerésre. Mivel a betegség korai stádiumában a cardiovascularis denerváció részlegesen visszafordítható, vagy progressziója lelassítható, a legújabb irányelvek határozottan ajánlják a CAN szűrését diabeteses betegekben. Az alábbiakban összefoglaljuk a diabeteses CAN szűrésére alkalmas diagnosztikai lehetőségeket. Orv Hetil. 2019; 160(35): 1366–1375. | Abstract: Cardiac autonomic neuropathy (CAN) is a common complication in type 1 and 2 diabetes and is defined as the impairment of autonomic control of the cardiovascular system. CAN is strongly associated with increased mortality, and in some studies with morbidity of vascular complications, such as stroke, coronary artery disease and myocardial infarction. At the early stages, CAN can be subclinical and it becomes clinically evident as the disease progresses. Subclinically, the disease is defined by cardiovascular reflex testing, which may have prognostic implications. Clinically, the impairment in autonomic function is associated with resting tachycardia, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, silent myocardial infarction and ischemia, and increased mortality. Although very common and serious, CAN is a frequently overlooked complication of diabetes. Because the progression of cardiovascular denervation is partly reversible or can be slowed down in the early stages of the disease, recent guidelines strongly recommend screening for CAN in patients with diabetes. In this review we summarize the diagnostic tools suggested in the screening for diabetic CAN. Orv Hetil. 2019; 160(35): 1366–1375

A diabeteses cardialis autonóm neuropathia diagnosztikája

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Effects of Postnatal Enriched Environment in a Model of Parkinson’s Disease in Adult Rats

Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund's adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4-/- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains

Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates

Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat

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