Polybioside, a Neuroactive Compound from the Venom of the Social Wasp Polybia paulista

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Tamoxifen down-regulates CaMKII messenger RNA levels in normal human breast tissue

Tamoxifen was proven to reduce the incidence of breast cancer by 49% in women at increased risk of the disease in the Breast Cancer Prevention Trial. In order to identify potential candidates to explain the preventive effect induced by tamoxifen on breast cancer, normal breast tissue obtained from 42 fibroadenoma patients, randomly assigned to receive placebo or tamoxifen, was analyzed by the reverse Northern blot and RT-PCR techniques. The cDNA fragments used on Northern blot membranes were generated by the Human Cancer Genome Project funded by the Ludwig Institute for Cancer Research and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil). Total RNA was obtained from normal breast tissue from patients with clinical, cytological and ultrasound diagnosis of fibroadenoma. After a 50-day treatment with tamoxifen (10 or 20 mg/day) or placebo, normal breast tissue adjacent to the tumor was collected during lumpectomy with local anesthesia. One differentially expressed gene, Calcium/calmodulin-dependent protein kinase II (CaMKII), was found to be down-regulated during TAM treatment. CaMKII is an ubiquitous serine/threonine protein kinase that has been implicated in the diverse effects of hormones utilizing Ca2+ as a second messenger as well as in c-fos activation. These results indicate that the down-regulation of CaMKII induced by TAM might represent alternative or additional mechanisms of the action of this drug on cell cycle control and response to hormones in normal human breast tissue.

Chronic administration of risperidone in a rat model of schizophrenia: A behavioural, morphological and molecular study

In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D2 and 5-HT2A receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects. © 2013.

Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality

The nucleus of the solitary tract (NTS) is the primary site of visceral afferents to the central nervous system. In the present study, we investigated the effects of lesions in the commissural portion of the NTS (commNTS) on the activity of vasopressinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, plasma vasopressin, arterial pressure, water intake, and sodium excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats with 15-20 days of sham or electrolytic lesion (1 mA; 10 s) of the commNTS were used. CommNTS lesions enhanced a 2 M NaCl intragastrically induced increase in the number of vasopressinergic neurons expressing c-Fos in the PVN (28 ± 1, vs. sham: 22 ± 2 c-Fos/AVP cells) and SON (26 ± 4, vs. sham: 11 ± 1 c-Fos/AVP cells), plasma vasopressin levels (21 ± 8, vs. sham: 6.6 ± 1.3 pg/ml), pressor responses (25 ± 7 mmHg, vs. sham: 7 ± 2 mmHg), water intake (17.5 ± 0.8, vs. sham: 11.2 ± 1.8 ml/2 h), and natriuresis (4.9 ± 0.8, vs. sham: 1.4 ± 0.3 meq/1 h). The pretreatment with vasopressin antagonist abolished the pressor response to intragastric 2 M NaCl in commNTS-lesioned rats (8 ± 2.4 mmHg at 10 min), suggesting that this response is dependent on vasopressin secretion. The results suggest that inhibitory mechanisms dependent on commNTS act to limit or counterbalance behavioral, hormonal, cardiovascular, and renal responses to an acute increase in plasma osmolality. © 2013 the American Physiological Society.

Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling

The cysteine proteinase inhibitor cystatin C inhibited RANKL-stimulated osteoclast formation in mouse bone marrow macrophage cultures, an effect associated with decreased mRNA expression of Acp5, Calcr, Ctsk, Mmp9, Itgb3, and Atp6i, without effect on proliferation or apoptosis. The effects were concentration dependent with half-maximal inhibition at 0.3 μM. Cystatin C also inhibited osteoclast formation when RANKL-stimulated osteoclasts were cultured on bone, leading to decreased formation of resorption pits. RANKL-stimulated cells retained characteristics of phagocytotic macrophages when cotreated with cystatin C. Three other cysteine proteinase inhibitors, cystatin D, Z-RLVG-CHN2 (IC50 0.1 μM), and E-64 (IC 50 3 μM), also inhibited osteoclast formation in RANKL-stimulated macrophages. In addition, cystatin C, Z-RLVG-CHN2, and E-64 inhibited osteoclastic differentiation of RANKL-stimulated CD14+ human monocytes. The effect by cystatin C on differentiation of bone marrow macrophages was exerted at an early stage after RANKL stimulation and was associated with early (4 h) inhibition of c-Fos expression and decreased protein and nuclear translocation of c-Fos. Subsequently, p52, p65, IκBα, and Nfatc1 mRNA were decreased. Cystatin C was internalized in osteoclast progenitors, a process requiring RANKL stimulation. These data show that cystatin C inhibits osteoclast differentiation and formation by interfering intracellularly with signaling pathways downstream RANK. © FASEB.

Insuficiência aórtica subcrônica e vias centrais relacionadas à regulação da ingestão de sódio

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Participação do grupamento catecolaminérgico A2 do núcleo do trato solitário comissural nos ajustes cardiovasculares e do equilíbrio hidroeletrolitíco induzidos por alterações da osmolaridade ou volume plasmático

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Efeito da deficiência de magnésio sobre o metabolismo do tecido ósseo

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Ajustes cardiovasculares e do equilibrio hidroeletrolítico induzidos por soluções hipertônicas em ratos com lesão do núcleo do trato solitário comissural

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Avaliação da toxicidade do dióxido de carbono no sistema nervoso de Apis mellifera (Hymenoptera, Apidae)

A concentração de dióxido de carbono (CO2) global eleva-se a cada ano, isso deve-se a um desequilíbrio entre as taxas de emissão deste gás por atividades antropogênicas e fontes naturais e a taxa que a biosfera e oceanos o removem da atmosfera. O CO2 é um importante constituinte químico do ambiente, pois este é um gás que aprisiona radiação infravermelha emitida pela superfície da Terra, contribuindo, assim, para a manutenção da temperatura global necessária a vida. As alterações na concentração de CO2 na atmosfera afetam inúmeros animais que dependem que estas estejam altamente controladas para poderem sobreviver. Em abelhas Apis mellifera valores elevados de temperatura ou níveis de CO2 dentro da colméia podem ter efeitos deletérios. Estes insetos são considerados bioindicadores naturais, pois apresentam diferenças fisiológicas conforme as condições do ambiente, sendo utilizadas na avaliação de efeitos a várias substâncias presentes no meio. Atualmente uma das técnicas utilizadas para a avaliação do efeito de estímulos externos é a utilização da marcação da proteína c-Fos através da expressão do gene c-fos, que indicam tanto a existência de atividade celular como também possibilita a identificação de áreas cerebrais determinadas. Esta proteína foi utilizada com o intuído de verificar se concentrações elevadas de gás carbônico são capazes de alterar as funções cerebrais da abelha Apis mellifera, comprometendo sua atividade de orientação e, conseqüentemente seu forrageamento. Marcações positivas à proteína Fos foram observadas nas regiões dos lobos ópticos e ocelos tanto do grupo controle quanto dos grupos Resumo Jacob, C. R. O. 9 expostos ao gás dióxido de carbono para todas as idades coletadas, estes resultados estão relacionados com a...(Resumo completo, clicar acesso eletrônico abaixo)

Hydrogen peroxide attenuates the dipsogenic, renal and pressor responses induced by cholinergic activation of the medial septal area

Cholinergic activation of the medial septal area (MSA) with carbachol produces thirst, natriuresis, antidiuresis and pressor response. In the brain, hydrogen peroxide (H2O2) modulates autonomic and behavioral responses. In the present study, we investigated the effects of the combination of carbachol and H2O2 injected into the MSA on water intake, renal excretion, cardiovascular responses and the activity of vasopressinergic and oxytocinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Furthermore, the possible modulation of carbachol responses by H2O2 acting through K+ATP channels was also investigated. Male Holtzman rats (280–320 g) with stainless steel cannulas implanted in the MSA were used. The pre-treatment with H2O2 in the MSA reduced carbachol-induced thirst (7.9 ± 1.0, vs. carbachol: 13.2 ± 2.0 ml/60 min), antidiuresis (9.6 ± 0.5, vs. carbachol: 7.0 ± 0.8 ml/120 min,), natriuresis (385 ± 36, vs. carbachol: 528 ± 46 μEq/120 min) and pressor response (33 ± 5, vs. carbachol: 47 ± 3 mmHg). Combining H2O2 and carbachol into the MSA also reduced the number of vasopressinergic neurons expressing c-Fos in the PVN (46.4 ± 11.2, vs. carbachol: 98.5 ± 5.9 c-Fos/AVP cells) and oxytocinergic neurons expressing c-Fos in the PVN (38.5 ± 16.1, vs. carbachol: 75.1 ± 8.5 c-Fos/OT cells) and in the SON (57.8 ± 10.2, vs. carbachol: 102.7 ± 7.4 c-Fos/OT cells). Glibenclamide (K+ATP channel blocker) into the MSA partially reversed H2O2 inhibitory responses. These results suggest that H2O2 acting through K+ATP channels in the MSA attenuates responses induced by cholinergic activation in the same area.

Catecholaminergic neurons in the comissural region of the nucleus of the solitary tract modulate hyperosmolality-induced responses

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Iptakalim: A Potential Antipsychotic Drug with Novel Mechanisms?

Iptakalim is a novel putative adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener. In the brain, iptakalim is thought to act on the neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels. Because iptakalim demonstrates an action on the regulation of dopamine and glutamate release in the forebrain regions, we examined its potential antipsychotic efficacy in several preclinical tests. First, we show that iptakalim is effective in reducing amphetamine- and phencyclidine-induced hyperlocomotion as well as selectively disrupting conditioned avoidance responding. Next, we show that combined iptakalim and amphetamine treatment produces a reduction on prepulse inhibition of acoustic startle and this combined drug effect is also found with haloperidol, but not with clozapine. Finally, we show that iptakalim and clozapine preferentially increase c-Fos expression in the medial prefrontal cortex, nucleus accumbens and lateral septal nucleus, whereas haloperidol induces a greater increase in the nucleus accumbens, the dorsolateral striatum and lateral septal nucleus. Collectively, our findings indicate that iptakalim is likely to be a potential antipsychotic drug with distinct mechanisms of action. This study also suggests that neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels may be a novel target that deserves attention for antipsychotic drug development. Future research using other sensitive tests is needed to confirm this property of iptakalim.

Moxonidine into the lateral parabrachial nucleus reduces renal and hormonal responses to cell dehydration

The deactivation of the inhibitory mechanisms with injections of moxonidine (alpha(2)-adrenoceptor/imidazoline receptor agonist) into the lateral parabrachial nucleus (LPBN) increases hypertonic NaCl intake by intra- or extracellular dehydrated rats. In the present study, we investigated the changes in the urinary sodium and volume, sodium balance, and plasma vasopressin and oxytocin in rats treated with intragastric (i.g.) 2 M NaCl load (2 ml/rat) combined with injections of moxonidine into the LPBN. Male Holtzman rats (n=5-12/group) with stainless steel cannulas implanted bilaterally into LPBN were used. Bilateral injections of moxonidine (0.5 nmol/0.2 mu l) into the LPBN decreased i.g. 2 M NaCIinduced diuresis (4.6 +/- 0.7 vs. vehicle: 7.4 +/- 0.6 ml/120 min) and natriuresis (1.65 +/- 0.29 vs. vehicle: 2.53 +/- 0.17 mEq/120 min), whereas the previous injection of the alpha(2)-adrenoceptor antagonist RX 821002 (10 nmol/0.2 mu l) into the LPBN abolished the effects of moxonidline. Moxonidine injected into the LPBN reduced i.g. 2 M NaCl-induced increase in plasma oxytocin and vasopressin (14.6 +/- 2.8 and 2.2 +/- 0.3 vs. vehicle: 25.7 +/- 7 and 4.3 +/- 0.7 pg/ml, respectively). Moxonidine injected into the LPBN combined with i.g. 2 M NaCl also increased 0.3 M NaCl intake (7.5 +/- 1.7 vs. vehicle: 0.5 +/- 0.2 mEq/2 h) and produced positive sodium balance (2.3 +/- 1.4 vs. vehicle: -1.2 +/- 0.4 mEq/2 h) in rats that had access to water and NaCl. The present results show that LPBN alpha(2)-adrenoceptor activation reduces renal and hormonal responses to intracellular dehydration and increases sodium and water intake, which facilitates sodium retention and body fluid volume expansion. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

DIFFERENTIAL INVOLVEMENT OF DORSAL RAPHE SUBNUCLEI IN THE REGULATION OF ANXIETY- AND PANIC-RELATED DEFENSIVE BEHAVIORS

A wealth of evidence indicates that the dorsal raphe nucleus (DR) is not a homogenous structure, but an aggregate of distinctive populations of neurons that may differ anatomically, neurochemically and functionally. Other findings suggest that serotonergic neurons within the mid-caudal and caudal part of the DR are involved in anxiety processing while those within the lateral wings (IwDR) and ventrolateral periaqueductal gray (vIPAG) are responsive to panic-evoking stimuli/situations. However, no study to date has directly compared the activity of 5-HT and non-5HT neurons within different subnuclei of the DR following the expression of anxiety- and panic-related defensive responses. In the present investigation, the number of doubly immunostained cells for Fos protein and tryptophan hydroxylase, a marker of serotonergic neurons, was assessed within the rat DR, median raphe nucleus (MRN) and PAG following inhibitory avoidance and escape performance in the elevated T-maze, behaviors associated with anxiety and panic, respectively. Inhibitory avoidance, but not escape, significantly increased the number of Fos-expressing serotonergic neurons within the mid-caudal part of the dorsal subnucleus, caudal and interfascicular subnuclei of the DR and in the MRN. Escape, on the other hand, caused a marked increase in the activity of non-5HT cells within the IwDR, vIPAG, dorsolateral and dorsomedial columns of the PAG. These results strongly corroborate the view that different subsets of neurons in the DR are activated by anxiety- and panic-relevant stimuli/situations, with important implications for the understanding of the pathophysiology of generalized anxiety and panic disorders. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.