Selective dopamine D2 receptor deletion from Nkx6.2 expressing cells causes impaired cognitive, motivation and anxiety phenotypes in mice.

Abnormal dopamine neurotransmission is a common trait of some psychiatric diseases, like schizophrenia or bipolar disorder. Excessive dopaminergic tone in subcortical brain regions is associated with psychotic episodes, while reduced prefrontal dopaminergic activity is associated with impaired cognitive performance and reduced motivation, among other symptoms. Inhibitory interneurons expressing the calcium binding protein parvalbumin are particularly affected in both schizophrenia and bipolar disorder, as they set a fine-tuned physiological inhibitory/excitatory balance. Parvalbumin and somatostatin interneuron subtypes, are born from the medial ganglionic eminence and require the sequential expression of specific transcription factors for their specification, such as Nkx6.2. Here, we aimed at characterizing in detail interneuron subtypes derived from Nkx6.2 expressing progenitors by the generation of an Nkx6.2 Cre transgenic mouse line. We show that Nkx6.2 specifies over a third part of the total population of cortical somatostatin interneurons, preferentially at early developmental time points, whereas at late developmental stages, Nkx6.2 expressing progenitors shift to parvalbumin interneuron specification. Dopamine D2 receptor deletion from Nkx6.2 expressing progenitors causes abnormal phenotypes restricted to cognitive, motivation and anxiety domains. Our results show that Nkx6.2 have the potential to specify both somatostatin and parvalbumin interneurons in an opposite timed program and that DRD2 expression is required in Nkx6.2 expressing progenitors to avoid impaired phenotypes commonly associated to the pathophysiology of psychiatric diseases.

Growth Hormone Action in Somatostatin Neurons Regulates Anxiety and Fear Memory.

Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and other neuropsychiatric diseases. GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of posttraumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence the development of neuropsychiatric diseases. Here, we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) caused no alterations in energy or glucose metabolism. Notably, SSTΔGHR male mice exhibited increased anxiety-like behavior in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. Conversely, GHR ablation in SST neurons did not affect memory in the novel object recognition test. Gene expression was analyzed in a micro punch comprising the central nucleus of the amygdala (CEA) and basolateral (BLA) complex. GHR ablation in SST neurons caused sex-dependent changes in the expression of factors involved in synaptic plasticity and function. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not female mice. GHR ablation in SST neurons also decreases fear memory and affects gene expression in the amygdala, although marked sex differences were observed. Our findings identified for the first time a neurochemically-defined neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases.SIGNIFICANCE STATEMENT Hormone action in the brain regulates different neurological aspects, affecting the predisposition to neuropsychiatric disorders, like depression, anxiety, and posttraumatic stress disorder. Growth hormone (GH) receptor is widely expressed in the brain, but the exact function of neuronal GH action is not fully understood. Here, we showed that mice lacking the GH receptor in a group of neurons that express the neuropeptide somatostatin exhibit increased anxiety. However, this effect is only observed in male mice. In contrast, the absence of the GH receptor in somatostatin-expressing neurons decreases fear memory, a key feature of posttraumatic stress disorder, in males and females. Thus, our study identified a specific group of neurons in which GH acts to affect the predisposition to neuropsychiatric diseases.

Effects of the Isolated and Combined Ablation of Growth Hormone and IGF-1 Receptors in Somatostatin Neurons.

Hypophysiotropic somatostatin (SST) neurons in the periventricular hypothalamic area express growth hormone (GH) receptor (GHR) and are frequently considered as the key neuronal population that mediates the negative feedback loop controlling the hypothalamic-GH axis. Additionally, insulin-like growth factor-1 (IGF-1) may also act at the hypothalamic level to control pituitary GH secretion via long-loop negative feedback. However, to the best of our knowledge, no study so far has tested whether GHR or IGF-1 receptor (IGF1R) signaling specifically in SST neurons is required for the homeostatic control of GH secretion. Here we show that GHR ablation in SST neurons did not impact the negative feedback mechanisms that control pulsatile GH secretion or body growth in male and female mice. The sex difference in hepatic gene expression profile was only mildly affected by GHR ablation in SST neurons. Similarly, IGF1R ablation in SST neurons did not affect pulsatile GH secretion, body growth, or hepatic gene expression. In contrast, simultaneous ablation of both GHR and IGF1R in SST-expressing cells increased mean GH levels and pulse amplitude in male and female mice, and partially disrupted the sex differences in hepatic gene expression. Despite the increased GH secretion in double knockout mice, no alterations in body growth and serum or liver IGF-1 levels were observed. In summary, GHR and IGF1R signaling in SST neurons play a redundant role in the control of GH secretion. Furthermore, our results reveal the importance of GH/IGF-1 negative feedback mechanisms on SST neurons for the establishment of sex differences in hepatic gene expression profile.

Dentate Gyrus Somatostatin Cells are Required for Contextual Discrimination During Episodic Memory Encoding.

Memory systems ought to store and discriminate representations of similar experiences in order to efficiently guide future decisions. This problem is solved by pattern separation, implemented in the dentate gyrus (DG) by granule cells to support episodic memory formation. Pattern separation is enabled by tonic inhibitory bombardment generated by multiple GABAergic cell populations that strictly maintain low activity levels in granule cells. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the DG. Nonetheless, somatostatin cells have very low connection probability and synaptic efficacy with both granule cells and other interneuron types. Hence, the role of somatostatin cells in DG circuitry, particularly in the context of pattern separation, remains uncertain. Here, by using optogenetic stimulation and behavioral tasks in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

Differential Coupling of Adult-Born Granule Cells to Parvalbumin and Somatostatin Interneurons.

A strong GABAergic tone imposes sparse levels of activity in the dentate gyrus of the hippocampus. This balance is challenged by the addition of new granule cells (GCs) with high excitability. How developing GCs integrate within local inhibitory networks remains unknown. We used optogenetics to study synaptogenesis between new GCs and GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs). PV-INs target the soma, and synapses become mature after 6 weeks. This transition is accelerated by exposure to an enriched environment. PV-INs exert efficient control of GC spiking and participate in both feedforward and feedback loops, a mechanism that would favor lateral inhibition and sparse coding. SST-INs target the dendrites, and synapses mature after 8 weeks. Outputs from GCs onto PV-INs develop faster than those onto SST-INs. Our results reveal a long-lasting transition wherein adult-born neurons remain poorly coupled to inhibition, which might enhance activity-dependent plasticity of input and output synapses.

Basal forebrain somatostatin cells differentially regulate local gamma oscillations and functionally segregate motor and cognitive circuits.

The basal forebrain delivers extensive axonal projections to the cortical mantle regulating brain states and cognitive processing. Recent evidence has established the basal forebrain as a subcortical node of the default mode network that directionally influences cortical dynamics trough gamma oscillations, yet their synaptic origin has not been established. Here, we used optogenetic stimulation and in vivo recordings of transgenic mice to show that somatostatin neurons exert an anatomically specialized role in the coordination of subcortical gamma oscillations of the rostral basal forebrain. Indeed, the spike timing of somatostatin cells was tightly correlated with gamma oscillations in the ventral pallidum, but not in the medial septum. Consequently, optogenetic inactivation of somatostatin neurons selectively disrupted the amplitude and coupling of gamma oscillations only in the ventral pallidum. Moreover, photosupression of somatostatin cells produced specific behavioral interferences, with the ventral pallidum regulating locomotor speed and the medial septum modulating spatial working memory. Altogether, these data suggest that basal forebrain somatostatin cells can selectively synchronize local neuronal networks in the gamma band directly impinging on cortical dynamics and behavioral performance. This further supports the role of the basal forebrain as a subcortical switch commanding transitions between internally and externally oriented brain states.

Characterization and distribution of GHRH, PACAP, TRH, SST and IGF1 mRNAs in the green iguana.

The somatotropic axis (SA) regulates numerous aspects of vertebrate physiology such as development, growth, and metabolism and has influence on several tissues including neural, immune, reproductive and gastric tract. Growth hormone (GH) is a key component of SA, it is synthesized and released mainly by pituitary somatotrophs, although now it is known that virtually all tissues can express GH, which, in addition to its well-described endocrine roles, also has autocrine/paracrine/intracrine actions. In the pituitary, GH expression is regulated by several hypothalamic neuropeptides including GHRH, PACAP, TRH and SST. GH, in turn, regulates IGF1 synthesis in several target tissues, adding complexity to the system since GH effects can be exerted either directly or mediated by IGF1. In reptiles, little is known about the SA components and their functional interactions. The aim of this work was to characterize the mRNAs of the principal SA components in the green iguana and to develop the tools that allow the study of the structural and functional evolution of this system in reptiles. By employing RT-PCR and RACE, the cDNAs encoding for GHRH, PACAP, TRH, SST and IGF1 were amplified and sequenced. Results showed that these cDNAs coded for the corresponding protein precursors of 154, 170, 243, 113, and 131 amino acids, respectively. Of these, GHRH, PACAP, SST and IGF1 precursors exhibited a high structural conservation with respect to its counterparts in other vertebrates. On the other hand, iguana's TRH precursor showed 7 functional copies of mature TRH (pyr-QHP-NH2), as compared to 4 and 6 copies of TRH in avian and mammalian proTRH sequences, respectively. It was found that in addition to its primary production site (brain for GHRH, PACAP, TRH and SST, and liver for IGF1), they were also expressed in other peripheral tissues, i.e. testes and ovaries expressed all the studied mRNAs, whereas TRH and IGF1 mRNAs were observed ubiquitously in all tissues considered. These results show that the main SA components in reptiles of the Squamata Order maintain a good structural conservation among vertebrate phylogeny, and suggest important physiological interactions (endocrine, autocrine and/or paracrine) between them due to their wide peripheral tissue expression.

Early Postnatal Development of Somastostatinergic Systems in Brainstem Respiratory Network.

Somatostatin is a peptide able to stop breathing, acting in the neural network that generates and control the respiratory rhythm. In this chapter, we present data on the early postnatal development of somatostatinergic systems in the mouse brainstem and summarize evidence for their influence on the generation and control of the respiratory rhythm.

Somatostatin signaling system as an ancestral mechanism: Myoregulatory activity of an Allatostatin-C peptide in Hydra.

The coordination of physiological processes requires precise communication between cells. Cellular interactions allow cells to be functionally related, facilitating the maintaining of homeostasis. Neuropeptides functioning as intercellular signals are widely distributed in Metazoa. It is assumed that neuropeptides were the first intercellular transmitters, appearing early during the evolution. In Cnidarians, neuropeptides are mainly involved in neurotransmission, acting directly or indirectly on epithelial muscle cells, and thereby controlling coordinated movements. Allatostatins are a group of chemically unrelated neuropeptides that were originally characterized based on their ability to inhibit juvenil hormone synthesis in insects. Allatostatin-C has pleiotropic functions, acting as myoregulator in several insects. In these studies, we analyzed the myoregulatory effect of Aedes aegypti Allatostatin-C in Hydra sp., a member of the phylum Cnidaria. Allatostatin-C peptide conjugated with Qdots revealed specifically distributed cell populations that respond to the peptide in different regions of hydroids. In vivo physiological assays using Allatostatin-C showed that the peptide induced changes in shape and length in tentacles, peduncle and gastrovascular cavity. The observed changes were dose and time dependent suggesting the physiological nature of the response. Furthermore, at highest doses, Allatostatin-C induced peristaltic movements of the gastrovascular cavity resembling those that occur during feeding. In silico search of putative Allatostatin-C receptors in Cnidaria showed that genomes predict the existence of proteins of the somatostatin/Allatostatin-C receptors family. Altogether, these results suggest that Allatostatin-C has myoregulatory activity in Hydra sp, playing a role in the control of coordinated movements during feeding, indicating that Allatostatin-C/Somatostatin based signaling might be an ancestral mechanism.

Histochemical and immunohistochemical study on endocrine cells (5HT, GAS, and SST) of the gastrointestinal tract of a teleost, the characin Astyanax bimaculatus.

Endocrine cells secrete hormones through the mucosa of the gastrointestinal tract (GIT) and act on the overall regulation of digestive processes such as nutrient absorption, gut motility and intestinal blood flow. This study aimed to determine regional distribution and frequency of endocrine cells secretory of serotonin (5-HT), somatostatin (SST) and gastrin (GAS) in the GIT of a small-bodied widespread characin Astyanax bimaculatus using histological, histochemical and immunohistochemical techniques. Fragments of the stomach and gut fixed for 8h in Bouin liquid were subjected to histological processing and immunohistochemical routine. For the histological analyses, the technique of staining with hematoxylin and eosin (HE) was used, whereas for the histochemical analyses Gomori's trichrome, periodic acid+Schiff (PAS) and Alcian blue pH 2.5 (AB) were used to further immunohistochemical processing. The stomach has a mucosa lined with a simple columnar epithelium with mucus-secreting cells; the glandular region (proximal and distal portions) has folds and pits, whereas the non-glandular region has pits only. The intestinal epithelium is simple with plain cylindrical grooved and goblet cells. The anterior region has thin folds with few goblet cells, and the posterior region with thick folds and many goblet cells. The regional distribution and frequency of endocrine cells varied across regions of the GIT with the stomach showing the highest amount of immunoreactive (IR) cells. Only the 5-HT was found in the stomach (epithelia and glands) and gut regions, with comparatively higher frequency in the stomach. SST-IR cells were found in the stomach (epithelia and gastric glands) with higher frequency in the glandular region, whereas GAS-IR were found in the gastric glands only. The stomach was the only organ to have all the three types of endocrine cells, indicating that this organ is the main site of digestion of food in this species.

Effectiveness of hip muscle strengthening in patellofemoral pain syndrome patients: a systematic review

Introduction: Patellofemoral pain syndrome (PFPS) is characterized by anterior knee pain, which may limit the performance of functional activities. The influence of hip joint motion on the development of this syndrome has already been documented in the literature. In this regard, studies have investigated the effectiveness of hip muscle strengthening in patients with PFPS. Objectives: The aims of this systematic review were (1) to summarize the literature related to the effects of hip muscle strengthening on pain intensity, muscle strength, and function in individuals with PFPS and (2) to evaluate the methodological quality of the selected studies. Method: A search for randomized controlled clinical trials was conducted using the following databases: Google Scholar, MEDLINE, PEDro, LILACS, and SciELO. The selected studies had to distinguish the effects of hip muscle strengthening in a group of patients with PFPS, as compared to non-intervention or other kinds of intervention, and had to investigate the following outcomes: pain, muscle strength, and function. The methodological quality of the selected studies was analyzed by means of the PEDro scale. Results: Seven studies were selected. These studies demonstrated that hip muscle strengthening was effective in reducing pain. However, the studies disagreed regarding the treatments' ability to improve muscle strength. Improvement in functional capabilities after hip muscle strengthening was found in five studies. Conclusion: Hip muscle strengthening is effective in reducing the intensity of pain and improving functional capabilities in patients with PFPS, despite the lack of evidence for its ability to increase muscle strength. .

Relative distribution of gastrin-, CCK-8-, NPY- and CGRP-immunoreactive cells in the digestive tract of dorado (Salminus brasiliensis).

The endocrine cells (ECs) of the gastrointestinal mucosa form the largest endocrine system in the body, not only in terms of cell numbers but also in terms of the different produced substances. Data describing the association between the relative distributions of the peptide-specific ECs in relation to feeding habits can be useful tools that enable the creation of a general expected pattern of EC distribution. We aimed to investigate the distribution of ECs immunoreactive for the peptides gastrin (GAS), cholecystokinin (CCK-8), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) in different segments of the digestive tract of carnivorous fish dorado (Salminus brasiliensis) by using immunohistochemistry procedures. The distribution of endocrine cells immunoreactive for gastrin (GAS), cholecystokinin (CCK-8), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) in digestive tract of dorado S. brasiliensis was examined by immunohistochemistry. The results describe the association between the distribution of the peptide-specific endocrine cells and feeding habits in different carnivorous fish. The largest number of endocrine cells immunoreactive for GAS, CCK-8, and CGRP were found in the pyloric stomach region and the pyloric caeca. However, NPY-immunoreactive endocrine cells were markedly restricted to the midgut. The distribution pattern of endocrine cells identified in S. brasiliensis is similar to that found in other carnivorous fishes.

Specificity studies on Kallikrein-related peptidase 7 (KLK7) and effects of osmolytes and glycosaminoglycans on its peptidase activity.

KLK7 substrate specificity was evaluated by families of fluorescence resonance energy transfer (FRET) peptides derived from Abz-KLFSSK-Q-EDDnp (Abz=ortho-aminobenzoic acid and Q-EDDnp=glutaminyl-N-[2,4-dinitrophenyl] ethylenediamine), by one bead-one peptide FRET peptide library in PEGA resin, and by the FRET peptide libraries Abz-GXX-Z-XX-Q-EDDnp (Z and X are fixed and random natural amino acids, respectively). KLK7 hydrolyzed preferentially F, Y or M, and its S1' and S2' subsites showed selectivity for hydrophilic amino acids, particularly R and K. This set of specificities was confirmed by the efficient kininogenase activity of KLK7 on Abz-MISLM(↓)KRPPGFSPF(↓)RSSRI-NH2 ((↓)indicates cleavage), hydrolysis of somatostatin and substance P and inhibition by kallistatin. The peptide Abz-NLY(↓)RVE-Q-EDDnp is the best synthetic substrate so far described for KLK7 [kcat/Km=455 (mMs)(-1)] that was designed from the KLK7 substrate specificity analysis. It is noteworthy that the NLYRVE sequence is present in human semaphorin 6B. KLK7 is activated by GAGs, inhibited by neutral salts, and activated by high concentration of kosmotropic salt. Pyroglutamic acid inhibited KLK7 (Ki=33mM) and is present in skin moisturizing factor (124mM). The KLK7 specificity described here and elsewhere reflects its participation in patho-physiological events in skin, the gastrointestinal tract and central nervous system, where KLK7 is significantly expressed.

Role of high mobility group box-1 and protection of growth hormone and somatostatin in severe acute pancreatitis

In this study, we investigated the potential role of high-mobility group box 1 (HMGB1) in severe acute pancreatitis (SAP) and the effects of growth hormone (G) and somatostatin (S) in SAP rats. The rats were randomly divided into 6 groups of 20 each: sham-operated, SAP, SAP+saline, SAP+G, SAP+S and SAP+G+S. Ileum and pancreas tissues of rats in each group were evaluated histologically. HMGB1 mRNA expression was measured by reverse transcription-PCR. Levels of circulating TNF-α, IL-1, IL-6, and endotoxin were also measured. In the SAP group, interstitial congestion and edema, inflammatory cell infiltration, and interstitial hemorrhage occurred in ileum and pancreas tissues. The levels of HMGB1, TNF-α, IL-1, IL-6 and endotoxin were significantly up-regulated in the SAP group compared with those in the sham-operated group, and the 7-day survival rate was 0%. In the SAP+G and SAP+S groups, the inflammatory response of the morphological structures was alleviated, the levels of HMGB1, TNF-α, IL-1, IL-6, and endotoxin were significantly decreased compared with those in the SAP group, and the survival rate was increased. Moreover, in the SAP+G+S group, all histological scores were significantly improved and the survival rate was significantly higher compared with the SAP group. In conclusion, HMGB1 might participate in pancreas and ileum injury in SAP. Growth hormone and somatostatin might play a therapeutic role in the inflammatory response of SAP.

Role of high mobility group box-1 and protection of growth hormone and somatostatin in severe acute pancreatitis.

In this study, we investigated the potential role of high-mobility group box 1 (HMGB1) in severe acute pancreatitis (SAP) and the effects of growth hormone (G) and somatostatin (S) in SAP rats. The rats were randomly divided into 6 groups of 20 each: sham-operated, SAP, SAP+saline, SAP+G, SAP+S and SAP+G+S. Ileum and pancreas tissues of rats in each group were evaluated histologically. HMGB1 mRNA expression was measured by reverse transcription-PCR. Levels of circulating TNF-α, IL-1, IL-6, and endotoxin were also measured. In the SAP group, interstitial congestion and edema, inflammatory cell infiltration, and interstitial hemorrhage occurred in ileum and pancreas tissues. The levels of HMGB1, TNF-α, IL-1, IL-6 and endotoxin were significantly up-regulated in the SAP group compared with those in the sham-operated group, and the 7-day survival rate was 0%. In the SAP+G and SAP+S groups, the inflammatory response of the morphological structures was alleviated, the levels of HMGB1, TNF-α, IL-1, IL-6, and endotoxin were significantly decreased compared with those in the SAP group, and the survival rate was increased. Moreover, in the SAP+G+S group, all histological scores were significantly improved and the survival rate was significantly higher compared with the SAP group. In conclusion, HMGB1 might participate in pancreas and ileum injury in SAP. Growth hormone and somatostatin might play a therapeutic role in the inflammatory response of SAP.

Effect of a Denture Adhesive on the Satisfaction and Kinesiographic Parameters of Complete Denture Wearers: A Cross-Over Randomized Clinical Trial

The aim of the present study was to assess the effect of a denture adhesive (DA) on patient satisfaction and kinesiographic parameters of complete denture wearers by a cross-over study. Fifty edentulous patients received a set of new complete dentures. After an adaptation period, the participants were enrolled in the trial and randomized to receive a sequence of treatment protocols: Protocol 1- DA use during the first 15 days, followed by no DA for the next 15 days; Protocol 2- no DA during the first 15 days, followed by use of DA for the next 15 days. Outcomes were assessed after 15 days of each sequence of treatment. A questionnaire was used to assess the patients´ satisfaction. A kinesiograph was used to record mandible movements and patterns of maxillary complete denture movement during chewing. The Wilcoxon test (α=0.05) and a paired sample t-test (α=0.05) were used to compare satisfaction levels and kinesiographic data, respectively. Use of DA improved the overall level of patient satisfaction (p<0.001). The kinesiographic recordings revealed a significant increase (1.7 mm) in vertical mandible movements (p<0.001) during chewing and a lower (0.3 mm) vertical intrusion of the maxillary complete dentures (p=0.002) during chewing after using the DA. Use of DA in complete denture wearers improved the patients´ satisfaction and altered mandible movements, with increases in vertical movements during chewing and less intrusion of maxillary complete dentures.

O objetivo deste estudo foi avaliar o efeito da utilização de um adesivo para prótese na satisfação e nos parâmetros cinesiográficos em usuários de próteses totais por meio de um estudo "cross-over". Cinquenta pacientes desdentados receberam novas próteses totais bimaxilares. Após um período de adaptação, os participantes incluídos no estudo receberam uma sequência de tratamento: Protocolo 1- utilização do adesivo para prótese durante os primeiros 15 dias, seguida por não utilização do adesivo os próximos 15 dias; Protocolo 2- não utilização do adesivo durante os primeiros 15 dias; seguida por utilização do adesivo nos próximos 15 dias. Os resultados foram avaliados após 15 dias de cada sequência de tratamento. Um questionário para avaliar a satisfação dos pacientes e um cinesiógrafo para registrar os movimentos mandibulares e o padrão de movimento da prótese total maxilar durante mastigação foram utilizados. O teste de "Wilcoxon" (α=0,05) e o "t-test" de Student para amostras pareadas (α=0,05) foram utilizados para comparar o grau de satisfação dos pacientes e os dados cinesiográficos, respectivamente. O adesivo para prótese melhorou significativamente a satisfação geral dos participantes (p<0,001). Os registros cinesiográficos mostraram um aumento significativo (1,7 mm) no movimento mandibular vertical (p<0,001) e uma menor intrusão (0,3 mm) da prótese total superior (p=0,002) durante a mastigação após o uso de adesivo. O uso de adesivo para prótese melhorou a satisfação dos usuários de próteses totais e gerou um aumento no movimento mandibular vertical e uma menor intrusão da prótese total maxilar durante a mastigação.

Insulin versus glucagon crosstalk: central plus peripheral mechanisms.

Plasma glucose level depends on the peripheral intra-islet crosstalk between A cells (glucagon) + B-cells (insulin) and D-cells (somatostatin). Gastrointestinal hormones (secretin, CCK-PZ, gastrin, and serotonin) modulate the glucose- and amino acids-induced secretions of insulin and glucagon, respectively. Serotonin (5-HT) arose from the enterochromaffin cells during postprandial periods excites basal but inhibits excited B-cells. Serotonin excites adrenal glands that release adrenaline (Ad) + dopamine (DA). The former is positively correlated with hyperglycemia, whereas DA antagonizes this effect. Noradrenaline (NA) released from both sympathetic nerves and adrenal glands modulates the Ad release from this latter and excites A-cells. Thus, NA attenuates the hyperglycemic effects triggered by Ad. Dopamine released from both sources, adrenal glands and peripheral sympathetic nerves, antagonizes Ad-induced hyperglycemia plus the NA-triggered glucagon secretion. Both plasma insulin and glucagon cross the blood-brain barrier and excite A5(NA) and C1(Ad) neurons, respectively. C1 (Ad) neurons send excitatory drives to both islet A-cells and adrenal glands. Both central nervous system A5(NA) and C1(Ad) nuclei interchange inhibitory axons. Predominance of the former redounds in hyperinsulinism plus hypoglycemia, whereas the latter axis is responsible for hyperglucagonemia + hyperglycemia. In addition, the dorsal raphe serotonergic and the median raphe serotonergic nuclei interchange excitatory axons with the C1 (Ad) and the A5(NA) neurons, respectively. Hence, the former binomial axis (responsible for uncoping stress) is positively correlated with the hyperglycemic syndrome, whereas the A5(NA) + median raphe serotonergic binomial is correlated with hypoglycemia. Hence, the insulin resistance disorder should be underlain by the overactivity of both axes simultaneously. The above pathophysiological mechanisms are consistent with the successful neuropharmacological manipulations addressed to treat these neuroendocrine syndromes. Finally, one of the showiest findings derived from our research work arises from the unbalance between the DA versus 5-HT circulating parameters demonstrating that absolute predominance of the former is always paralleled by hypoglycemia (endogenous depression syndrome), whereas the opposite profile is registered in mammals affected by hyperglycemia (dysthymic depression and uncoping stress syndromes).

Anti-ulcerogenic mechanisms of the sesquiterpene lactone onopordopicrin-enriched fraction from Arctium lappa L. (Asteraceae): role of somatostatin, gastrin, and endogenous sulfhydryls and nitric oxide.

Arctium lappa L. has been used in folk medicine as a diuretic, depurative, and digestive stimulant and in dermatological conditions. The mechanisms involved in the anti-ulcerogenic activity of the sesquiterpene onopordopicrin (ONP)-enriched fraction (termed the ONP fraction), obtained from A. lappa leaves, were studied. The gastroprotective mechanism of the ONP fraction was evaluated in experimental in vivo models in rodents, mimicking this disease in humans. ONP fraction (50 mg/kg, p.o.) significantly inhibited the mucosal injury induced by ethanol/HCl solution (75%), indomethacin/bethanecol (68.9%), and stress (58.3%). When the ONP fraction was investigated in pylorus ligature, it did not induce alteration in the gastric volume but did modify the pH and total acid concentration of gastric juice. ONP fraction significantly increased serum somatostatin levels (82.1±4.1 vs. control group 12.7±4 pmol/L) and decreased serum gastrin levels (62.6±6.04 vs. control group 361.5±8.2 µU/mL). Mucus production was not significantly altered by the ONP fraction. Gastroprotection by the ONP fraction was completely inhibited by N-ethylmaleimide treatment and did not modify the effect in the animals pretreated with l-N(G)-nitroarginine methyl ester. These results suggest an antisecretory mechanism involved with the antiulcerogenic effect of the ONP fraction. However, only endogenous sulfhydryls play an important role in gastroprotection of the ONP fraction.

Hippocampal effects of neuronostatin on memory, anxiety-like behavior and food intake in rats.

A 13-amino acid peptide named neuronostatin (NST) encoded in the somatostatin pro-hormone has been recently reported. It is produced throughout the body, particularly in brain areas that have significant actions over the metabolic and autonomic regulation. The present study was performed in order to elucidate the functional role of NST on memory, anxiety-like behavior and food intake and the hippocampal participation in these effects. When the peptide was intra-hippocampally administered at 3.0 nmol/µl, it impaired memory retention in both, object recognition and step-down test. Also, this dose blocked the hippocampal long-term potentiation (LTP) generation. When NST was intra-hippocampally administered at 0.3 nmol/µl and 3.0 nmol/µl, anxiolytic effects were observed. Also, the administration in the third ventricle at the higher dose (3.0 nmol/µl) induced similar effects, and both doses reduced food intake. The main result of the present study is the relevance of the hippocampal formation in the behavioral effects induced by NST, and these effects could be associated to a reduced hippocampal synaptic plasticity.

The anti-ulcerogenic effects of Curatella americana L.

ETHNOPHARMACOLOGICAL RELEVANCE: Curatella americana L. (Dilleneaceae) is a medicinal plant very frequently cited as acting against gastrointestinal disorders in ethnopharmacological inventories of the Cerrado region of Brazil. AIM OF THE STUDY: The ethanolic extract (CEB) and infusion (BI) of Curatella americana bark were investigated for their ability to prevent and heal ulceration of the gastric mucosa. MATERIALS AND METHODS: The preventive and healing actions of Curatella americana were evaluated in experimental in vivo models in rodents that simulated this disease in human gastric mucosa. RESULTS: CEB significantly decreased the severity of gastric damage formation induced by the combination of several gastroprotective models (HCl/ethanol, indomethacin/bethanecol, absolute ethanol, stress and pylorus ligature). But, unlike CEB, the BI did not exert gastroprotective effect. The gastroprotective action of CEB involved antisecretory action, augmentation of gastric mucus (48%) and participation of endogenous sulfhydryl compounds that increase efficacy of barrier mucosa against injurious agents. CEB also presents effective healing action in chronic gastric disease (1.90+/-0.55 vs. 6.86+/-0.46 mm2)in the control) and its action mechanisms consisted of increasing the PGE2 (40%) and somatostatin levels (269%) while decreasing the gastrin level in rat plasma (79%). CONCLUSIONS: The gastroprotective effect and healing action of Curatella americana involved modulation of PGE2, somatostatin and gastrin levels, probably due to the presence of oligomeric and polymeric proanthocyanidins in the bark.