Liver-enriched antimicrobial peptide 2 (LEAP2) is a natural antagonist/inverse agonist of ghrelin receptor GHSR. Its truncated palmitoylated analog palm-LEAP2(1-14) promised anti-obesity properties because it exhibited favourable stability and an acute anorexigenic effect in our previous studies. Here we demonstrate desirable palm-LEAP2(1-14) pharmacokinetics, with significant levels of the peptide persisting in mouse blood 3 h after its subcutaneous administration. Palm-LEAP2 (1-14) reduced ghrelin-induced c-Fos immunoreactivity in arcuate nucleus and area postrema, in line with previously described silencing of ghrelin orexigenic effect. In spite of this, anti-obesity effect was not reached by two-week palm-LEAP2(1-14) treatment in mice with diet-induced obesity. Similarly, palm-LEAP2(1-14) administered simultaneously with high-fat diet feeding for 8 weeks did not protect mice from development of obesity and related biochemical changes. However, palm-LEAP2(1-14) kept its ability to attenuate liver de novo lipogenesis, and prominently lowered liver gene expression of nuclear receptors PPARG, SREBF1 and PPARA, and also expression of lipogenic and lipolytic enzymes. In our recent study, we described a high-fat diet-induced ghrelin resistance, reversible by switch to standard diet, followed by resistance to the acute anorexigenic effects of palm-LEAP2(1-14). Here we conclude that this resistance to palm-LEAP2(1-14) in obesity is probably selective and does not concern its ability to inhibit liver lipid metabolism.

• MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• ghrelin * metabolismus   MeSH
• játra * metabolismus   účinky léků   MeSH
• kationické antimikrobiální peptidy metabolismus   MeSH
• lipogeneze účinky léků   genetika   MeSH
• metabolismus lipidů * účinky léků   MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• obezita * metabolismus   MeSH
• peptidové fragmenty MeSH
• protoonkogenní proteiny c-fos metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Autism spectrum disorder (ASD) is a neurodevelopmental disorder accompanied by narrow interests, difficulties in communication and social interaction, and repetitive behavior. In addition, ASD is frequently associated with eating and feeding problems. Although the symptoms of ASD are more likely to be observed in boys, the prevalence of eating disorders is more common in females. The ingestive behavior is regulated by the integrative system of the brain, which involves both homeostatic and hedonic neural circuits. Sex differences in the physiology of food intake depend on sex hormones regulating the expression of the ASD-associated Shank genes. Shank3 mutation leads to ASD-like traits and Shank3B -/- mice have been established as an animal model to study the neurobiology of ASD. Therefore, the long-lasting neuronal activity in the central neural circuit related to the homeostatic and hedonic regulation of food intake was evaluated in both sexes of Shank3B mice, followed by the evaluation of the food intake and preference. In the Shank3B +/+ genotype, well-preserved relationships in the tonic activity within the homeostatic neural network together with the relationships between ingestion and hedonic preference were observed in males but were reduced in females. These interrelations were partially or completely lost in the mice with the Shank3B -/- genotype. A decreased hedonic preference for the sweet taste but increased total food intake was found in the Shank3B -/- mice. In the Shank3B -/- group, there were altered sex differences related to the amount of tonic cell activity in the hedonic and homeostatic neural networks, together with altered sex differences in sweet and sweet-fat solution intake. Furthermore, the Shank3B -/- females exhibited an increased intake and preference for cheese compared to the Shank3B +/+ ones. The obtained data indicate altered functional crosstalk between the central homeostatic and hedonic neural circuits involved in the regulation of food intake in ASD.

• MeSH
• homeostáza * fyziologie   MeSH
• mikrofilamentové proteiny * genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• pohlavní dimorfismus * MeSH
• poruchy autistického spektra * genetika   metabolismus   MeSH
• preference v jídle fyziologie   MeSH
• přijímání potravy * fyziologie   genetika   MeSH
• proteiny nervové tkáně * genetika   MeSH
• protoonkogenní proteiny c-fos metabolismus   biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

RATIONALE: Alcohol can disrupt conditioned sexual inhibition (CSI) established by first-order conditioning in male rats. CSI can also be induced using second-order conditioning, during which male rats are trained to associate a neutral odor with a nonreceptive female. As a result, when given access to two receptive females (one scented and one unscented) during a copulatory preference test, they display CSI toward the scented female. OBJECTIVE: The present study examined the effect of low-to-moderate doses of alcohol on CSI and brain activation following exposure to alcohol and the olfactory cue alone. METHODS: Sexually-naïve Long-Evans rats received alternate conditioning sessions with unscented receptive or scented (almond extract) non-receptive females. Following the conditioning phase, males were injected with saline, alcohol 0.5 g/kg or 1 g/kg, 45 min before a copulatory test with two receptive females, with one bearing the olfactory cue. Fos activation was later assessed, following exposure to alcohol and the olfactory cue alone, in several brain regions involved in the expression and regulation of male sexual behavior. RESULTS: While males in the saline group displayed sexual avoidance towards the scented female, those injected with alcohol before the copulatory test, regardless of the dose, copulated indiscriminately with both females. Subsequent exposure to alcohol and the olfactory cue alone induced different Fos expression between groups in several brain regions. CONCLUSIONS: Low to moderate doses of alcohol disrupt conditioned sexual inhibition in male rats and induce a differential pattern of neural activation, particularly in regions involved in the expression and regulation of sexual behavior.

• MeSH
• ethanol * farmakologie   aplikace a dávkování   MeSH
• inhibice (psychologie) MeSH
• krysa rodu rattus MeSH
• látky tlumící činnost CNS farmakologie   aplikace a dávkování   MeSH
• mozek účinky léků   metabolismus   MeSH
• podmiňování (psychologie) účinky léků   MeSH
• podněty MeSH
• potkani Long-Evans * MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• sexuální chování zvířat * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Prolactin-releasing peptide (PrRP) has been proposed to mediate the central satiating effects of cholecystokinin (CCK) through the vagal CCK1 receptor. PrRP acts as an endogenous ligand of G protein-coupled receptor 10 (GPR10), which is expressed at the highest levels in brain areas related to food intake regulation, e.g., the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS). The NTS and PVN are also significantly activated after peripheral CCK administration. The aim of this study was to determine whether the endogenous PrRP neuronal system in the brain is involved in the central anorexigenic effect of the peripherally administered CCK agonist JMV236 or the CCK1 antagonist devazepide and whether the CCK system is involved in the central anorexigenic effect of the peripherally applied lipidized PrRP analog palm-PrRP31 in fasted lean mice. The effect of devazepide and JMV236 on the anorexigenic effects of palm-PrRP31 as well as devazepide combined with JMV236 and palm-PrRP31 on food intake and Fos cell activation in the PVN and caudal NTS was examined. Our results suggest that the anorexigenic effect of JMV236 is accompanied by activation of PrRP neurons of the NTS in a CCK1 receptor-dependent manner. Moreover, while the anorexigenic effect of palm-PrRP31 was not affected by JMV236, it was partially attenuated by devazepide in fasted mice. The present findings indicate that the exogenously influenced CCK system may be involved in the central anorexigenic effect of peripherally applied palm-PrRP31, which possibly indicates some interaction between the CCK and PrRP neuronal systems.

• MeSH
• anorektika aplikace a dávkování   MeSH
• antagonisté hormonů aplikace a dávkování   MeSH
• chemokiny CC účinky léků   metabolismus   MeSH
• cholecystokinin metabolismus   MeSH
• devazepid aplikace a dávkování   MeSH
• hormon uvolňující prolaktin aplikace a dávkování   analogy a deriváty   MeSH
• injekce intraperitoneální MeSH
• injekce subkutánní MeSH
• myši inbrední C57BL MeSH
• nucleus paraventricularis hypothalami účinky léků   metabolismus   MeSH
• nucleus solitarius účinky léků   metabolismus   MeSH
• omezení příjmu potravy MeSH
• peptidové fragmenty aplikace a dávkování   MeSH
• přijímání potravy účinky léků   MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• signální transdukce MeSH
• sinkalid aplikace a dávkování   analogy a deriváty   MeSH
• stravovací zvyklosti účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

As with other drugs or pharmaceuticals, opioids differ in their rewarding or analgesic effects depending on when they are applied. In the previous study, we have demonstrated the day/night difference in the sensitivity of the major circadian clock in the suprachiasmatic nucleus to a low dose of morphine, and showed the bidirectional effect of morphine on pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus depending on the time of administration. The main aim of this study was to identify other brain structures that respond differently to morphine depending on the time of its administration. Using immunohistochemistry, we identified 44 structures that show time-of-day specific changes in c-Fos level and activity of ERK1/2 and GSK3β kinases in response to a single dose of 1 mg/kg morphine. Furthermore, comparison among control groups revealed the differences in the spontaneous levels of all markers with a generally higher level during the night, that is, in the active phase of the day. We thus provide further evidence for diurnal variations in the activity of brain regions outside the suprachiasmatic nucleus indicated by the temporal changes in the molecular substrate. We suggest that these changes are responsible for generating diurnal variation in the reward behavior or analgesic effect of opioid administration.

• MeSH
• cirkadiánní rytmus fyziologie   MeSH
• kinasa glykogensynthasy 3beta metabolismus   MeSH
• krysa rodu rattus MeSH
• MAP kinasový signální systém fyziologie   MeSH
• morfin farmakologie   MeSH
• mozek účinky léků   metabolismus   MeSH
• opioidní analgetika farmakologie   MeSH
• potkani Wistar MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Previous studies indicate that hypothalamic prolactin-releasing peptide (PrRP), signaling via GPR10 and neuropeptide FF2 receptor, is involved in energy homeostasis, stress responses, and cardiovascular regulation. Energy homeostasis depends on the balance between food intake regulation and energy expenditure, in which the hypothalamus plays a key role. The lipidization of PrRP31 with palmitoyl acid allows it to produce its anorexigenic effect after repeated peripheral administration and to reduce body weight and improve metabolic parameters in diet-induced obese (DIO) mice. The aim of this study was to reveal the transient and long-lasting changes in neuronal activity via c-Fos and FosB immunohistochemistry in brain nuclei related to food intake regulation and energy homeostasis during the first days of treatment with a newly designed lipidized analog of PrRP31 (palm11-PrRP31) with promising antiobesity effects. The data revealed that the anorexigenic effect of repeated application of palm11-PrRP31 was associated with delayed but gradually significantly reduced cumulative food intake in mice as well as with a significant reduction in their body weight. Moreover, while the repeated application of palm11-PrRP31 was associated with a significant reduction in acute cell activity in the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS) compare to its acute treatment, both acute and long-lasting cell activity in the dorsomedial hypothalamic nucleus (DMN) were increased. The data indicate that DMN neurons might be tonically activated after repeated administration of lipidized PrRP analogs that may be associated with the process of long-term adaptation to modified energy homeostasis.

• MeSH
• energetický metabolismus MeSH
• hormon uvolňující prolaktin metabolismus   farmakologie   MeSH
• hypothalamus účinky léků   metabolismus   MeSH
• lipidy farmakologie   MeSH
• myši inbrední C57BL MeSH
• neurony metabolismus   MeSH
• nucleus dorsomedialis hypothalami účinky léků   metabolismus   MeSH
• obezita farmakoterapie   MeSH
• přijímání potravy účinky léků   MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.

• MeSH
• abnormální reflex MeSH
• aspirační pneumonie chemicky indukované   patofyziologie   chirurgie   MeSH
• ezofágus inervace   MeSH
• kapilární permeabilita MeSH
• kyselina chlorovodíková * MeSH
• medulla oblongata metabolismus   patofyziologie   MeSH
• morčata MeSH
• neurogenní zánět chemicky indukované   patofyziologie   chirurgie   MeSH
• plíce inervace   metabolismus   MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• substance P metabolismus   MeSH
• vagotomie * MeSH
• zvířata MeSH
• Check Tag
• morčata MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Transient receptor potential vanilloid type 1 (TRPV1) receptors are important in the development of different pathological chronic pain states. Here we examined the role of spinal cord TRPV1 receptors in the mechanisms leading to activation of dorsal horn neurons after paclitaxel (PAC) treatment. PAC is a widely used chemotherapeutic drug that often leads to development of painful neuropathy. Immunohistochemical analysis of c-Fos protein expression in dorsal horn neurons was used as a marker of neuronal activation. Rat spinal cord slices were processed for in vitro incubation with PAC (100 nM) and TRPV1 receptor antagonists (SB366791 and AMG9810; 10 microM). PAC treatment induced significant upregulation of c-Fos nuclear expression in superficial dorsal horn neurons that was diminished by TRPV1 receptor antagonists pre-incubation. These results further substantiated the role of spinal TRPV1 receptors in the development of paclitaxel-induced neuropathic pain and contribute to better understanding of the pathological mechanisms involved.

• MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   MeSH
• exprese genu MeSH
• fytogenní protinádorové látky farmakologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   fyziologie   MeSH
• krysa rodu rattus MeSH
• paclitaxel farmakologie   MeSH
• potkani Wistar MeSH
• protoonkogenní proteiny c-fos agonisté   biosyntéza   genetika   MeSH
• zadní rohy míšní účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated by their peptide character. In order to overcome this unfavorable fact, we have applied the lipidization of neuropeptide prolactin-releasing peptide (PrRP), whose strong anorexigenic effect was demonstrated. A palmitoylated analog of human PrRP (h palm-PrRP31) was injected in free-fed Wistar rats by three routes: subcutaneous (s.c.), intraperitoneal (i.p) (both 5 mg/kg) and intravenous (i.v.) (from 0.01 to 0.5 mg/kg). We found a circulating compound in the blood after all three applications with the highest concentration after i.v. administration. This corresponds to the effect on food intake, which was also strongest after i.v. injection. Moreover, this is in agreement with the fact that the expression of c-Fos in specific brain regions involved in food intake regulation was also highest after intravenous application. Pharmacokinetic data are further supported by results obtained from dynamic light scattering and CD spectroscopy. Human palm-PrRP31 analog showed a strong tendency to micellize, and formation of aggregates suggested lower availability after i.p. or s.c. application. We have demonstrated that palm-PrRP influenced food intake even in free fed rats. Not surprisingly, the maximal effect was achieved after the intravenous application even though two orders of magnitude lower dose was used compared to both two other applications. We believe that palm-PrRP could have a potential as an antiobesity drug when its s.c. application would be improved.

• MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• energetický příjem účinky léků   MeSH
• hormon uvolňující prolaktin aplikace a dávkování   analogy a deriváty   metabolismus   farmakokinetika   MeSH
• křečci praví MeSH
• krysa rodu rattus MeSH
• látky proti obezitě aplikace a dávkování   metabolismus   farmakokinetika   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• neurony účinky léků   metabolismus   MeSH
• obezita farmakoterapie   MeSH
• peptidové fragmenty aplikace a dávkování   metabolismus   farmakokinetika   MeSH
• preklinické hodnocení léčiv MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• receptory spřažené s G-proteiny metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In the present study, adult Long-Evans rats were exposed either to natural conspecific aversive 22-kHz vocalizations or to artificial call-like stimuli with comparable frequency-temporal features, followed by c-Fos immunohistochemistry. The natural 22-kHz vocalizations was either played from a recording or produced by a foot-shocked animal located nearby (live vocalizations). In comparison with controls (non-exposed animals), c-Fos immunoreactivity was significantly increased in the inferior colliculus (IC), auditory cortex (AC), periaqueductal grey (PAG), basolateral amygdala (BA), and hippocampus (Hip) of rats exposed to either live or recorded 22-kHz natural vocalizations. Exposure to live natural vocalizations of the foot-shocked animal resulted in a similar pattern of c-Fos activity, as did exposure to the playback of the natural vocalizations. In contrast to this, foot-shocked rats (emitting the 22-kHz vocalizations) had the c-Fos positivity increased markedly in the PAG and only slightly in the AC. The expression of c-Fos also increased in the IC, AC, and in the PAG in animals exposed to the artificial call-like stimuli, when compared to controls; however, the increase was much less pronounced. In this case, c-Fos expression was not increased in the hippocampus or basolateral amygdala. Interestingly, almost no c-Fos expression was found in the medial nucleus of the geniculate body in any of the experimental groups. These findings suggest that differences exist between the processing of important natural conspecific vocalizations and artificial call-like stimuli with similar frequency-temporal features, and moreover they suggest the specific role of individual brain structures in the processing of such calls.

• MeSH
• akustická stimulace MeSH
• krysa rodu rattus MeSH
• limbický systém metabolismus   účinky záření   MeSH
• mapování mozku MeSH
• potkani Long-Evans MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• sluchové korové centrum metabolismus   účinky záření   MeSH
• vokalizace zvířat * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH