Pedro Leão

Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: The role of glycogen-synthase-kinase-3β

Mood disorders are the most common psychiatric disorders. Although the mechanisms implicated in the genesis of mood disorders are still unclear, stress is known to predispose to depression, and recently, studies have related hippocampal neurogenesis and apoptosis to depression. In the present study we first examined the balance between cell birth-death in the hippocampus and subventricular zone (SVZ) of pre-pubertal and adult rats subjected to chronic-mild-stress (CMS). CMS led to increased corticosterone secretion and induced depressive-like symptoms (assessed in the forced-swimming test); these endocrine and behavioral effects were paralleled by decreased hippocampal, but not SVZ, cell proliferation/differentiation and by increased apoptotic rate. In order to determine if lithium, a known mood stabilizer with antidepressant properties, could prevent the stress-induced events, we analyzed the same parameters in a group of rats treated with lithium during the stress exposure period (CMS+Li) and observed that the hormonal, behavioral and cell turnover effects of CMS were abrogated in these animals. Subsequently, to search for possible pathways through which CMS and lithium influence behavior, cell fate and synaptic plasticity, we analyzed the expression of glycogen-synthase-kinase-3beta (GSK-3beta), as well as some of its downstream targets (B-cell-CLL/lymphoma2-associated athanonege (BAG-1) and synapsin-I). CMS increased GSK-3beta and decreased synapsin-I and BAG-1 expression in the hippocampus. Interestingly, co-administration of lithium precluded the CMS-induced effects in GSK-3beta, synapsin-I and BAG-1 expression. Our observation that specific inhibition of this kinase with AR-A014418 blocked the effects of CMS in depressive-like behavior and in BAG-1 and synapsin-I expression confirmed the involvement of the GSK-3beta pathway in stress-induced effects. In summary, these results reveal that lithium, by regulating the activity of GSK-3beta, prevents the deleterious effects of stress on behavior and cellular functions.

Potential programming of dopaminergic circuits by early life stress

Stress and high levels of glucocorticoids during pre- and early postnatal life seem to alter developmental programs that assure dopaminergic transmission in the mesolimbic, mesocortical, and nigrostriatal systems. The induced changes are likely to be determined by the ontogenetic state of development of these brain regions at the time of stress exposure and their stability is associated with increased lifetime susceptibility to psychiatric disorders, including drug addiction. This article is intended to serve as a starting point for future studies aimed at the attenuation or reversal of the effects of adverse early life events on dopamine-regulated behaviors.

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

Stress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.

Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content

BackgroundWhile acute effects of stress on pain are well described, those produced by chronic stress are still a matter of dispute. Previously we demonstrated that chronic unpredictable stress results in antinociception in the tail-flick test, an effect that is mediated by increased levels of corticosteroids. In the present study, we evaluated nociception in rats after chronic treatment with corticosterone (CORT) and dexamethasone (DEX) in order to discriminate the role of each type of corticosteroid receptors in antinociception.ResultsBoth experimental groups exhibited a pronounced antinociceptive effect after three weeks of treatment when compared to controls (CONT); however, at four weeks the pain threshold in CORT-treated animals returned to basal levels whereas in DEX-treated rats antinociception was maintained. In order to assess if these differences are associated with altered expression of neuropeptides involved in nociceptive transmission we evaluated the density of substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SS) and B2-γ-aminobutiric acid receptors (GABAB2) expression in the spinal dorsal horn using light density measurements and stereological techniques. After three weeks of treatment the expression of CGRP in the superficial dorsal horn was significantly decreased in both CORT and DEX groups, while GABAB2 was significantly increased; the levels of SP for both experimental groups remained unchanged at this point. At 4 weeks, CGRP and SP are reduced in DEX-treated animals and GABAB2 unchanged, but all changes were restored to CONT levels in CORT-treated animals. The expression of SS remained unaltered throughout the experimental period.ConclusionThese data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the exclusive GR activation resulted in more profound and sustained behavioural and neurochemical changes, than the one observed with a mixed ligand of corticosteroid receptors. These results might be of relevance for the pharmacological management of certain types of chronic pain, in which corticosteroids are used as adjuvant analgesics.

The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses

RationaleSeveral human and experimental studies have shown that early life adverse events can shape physical and mental health in adulthood. Stress or elevated levels of glucocorticoids (GCs) during critical periods of development seem to contribute for the appearance of neurospyschiatric conditions such as anxiety and depression, albeit the underlying mechanisms remain to be fully elucidated.ObjectivesThe aim of the present study was to determine the long-term effect of prenatal exposure to dexamethasone- DEX (synthetic GC widely used in clinics) in fear and anxious behavior and identify the neurochemical, morphological and molecular correlates.ResultsPrenatal exposure to DEX triggers a hyperanxious phenotype and altered fear behavior in adulthood. These behavioral traits were correlated with increased volume of the bed nucleus of the stria terminalis (BNST), particularly the anteromedial subdivision which presented increased dendritic length; in parallel, we found an increased expression of synapsin and NCAM in the BNST of these animals. Remarkably, DEX effects were opposite in the amygdala, as this region presented reduced volume due to significant dendritic atrophy. Albeit no differences were found in dopamine and its metabolite levels in the BNST, this neurotransmitter was substantially reduced in the amygdala, which also presented an up-regulation of dopamine receptor 2.ConclusionsAltogether, our results show that in utero DEX exposure can modulate anxiety and fear behavior in parallel with significant morphological, neurochemical and molecular changes; importantly, GCs seem to differentially affect distinct brain regions involved in this type of behaviors.

Giant recurrent retroperitoneal liposarcoma initially presenting as inguinal hernia: Review of literature.

INTRODUCTION Liposarcomas comprise around 15% of soft tissue tumors. These tumors of mesodermal origin arise as single tumors, present one histologic type and diverse locations (including the retroperitoneum). Diagnosis of liposarcomas of retroperitoneum is difficult because of this unspecific presentation and in 50-100% of the cases there is recurrence from residual tissue. PRESENTATION OF CASE An 86 year old male patient was admitted in 1996 due to a right and voluminous inguinal hernia. During the herniaplasty, a right paratesticular tumor was isolated and removed. The histologic exam revealed a well-differentiated liposarcoma. A CT scan was performed and a large abdominal mass was detected. The patient underwent a laparotomy and an incomplete resection of the tumor was achieved. After the surgery the patient remained asymptomatic during a long period. Nine years later, the patient underwent another laparotomy with partial removal of the giant recurrent retroperitoneal liposarcoma. CONCLUSION The purpose of this publication is to report the recurrence of giant retroperitoneal liposarcoma, which is an unusual presentation in surgery today. Furthermore, we would like to emphasize the long-term survival of this patient despite partial resection and the possibility of performing a re-resection in this type of cases.

Programming Effects of Antenatal Corticosteroids Exposure in Male Sexual Behavior

INTRODUCTION Brain regions implicated in sexual behavior begin to differentiate in the last trimester of gestation. Antenatal therapy with corticosteroids is often used in clinical practice during this period to accelerate lung maturation in preterm-risk pregnancies. Clinical and animal studies highlighted major behavioral impairments induced later in life by these treatments, especially when synthetic corticosteroids are used. AIM To evaluate the implications of acute prenatal treatment with natural vs. synthetic corticosteroids on adult male rat sexual behavior and its neurochemical correlates. METHODS Twelve pregnant Wistar rats were injected with dexamethasone (DEX-1 mg/kg), corticosterone (CORT-25 mg/kg), or saline on late gestation (pregnancy days 18 and 19). Following this brief exposure to corticosteroids, we assessed the sexual behavior of the adult male progeny and subsequently associated these behaviors with the levels of catecholamines and mRNA of dopamine and androgen receptors (AR) in brain regions relevant for sexual behavior. MAIN OUTCOME MEASURES Sexual behavior of adult male offspring was assessed by exposure to receptive females. This was associated with serum testosterone levels and levels of catecholamines (determined by high-performance liquid chromatography) and dopamine and AR mRNA expression (real-time polymerase chain reaction [PCR]) in brain regions implicated in sexual behavior. RESULTS Prenatal DEX exposure resulted in a decreased number and increased mounts and intromissions latencies in adulthood. These findings were associated with decreased levels of serum testosterone and increased hypothalamic expression of AR mRNA. DEX animals also displayed lower dopamine levels and higher dopamine receptor mRNA expression both in hypothalamus and nucleus accumbens (NAcc). The milder phenotype of CORT animals was associated only with decreased dopamine levels in NAcc. CONCLUSION Antenatal corticotherapy programs adult male sexual behavior through changes in specific neuronal and endocrine mediators. Importantly, equipotent doses of CORT trigger less detrimental consequences than DEX, emphasizing the differential impact of activation of the different corticosteroid receptors.

Webifying the computerized execution of Clinical Practice Guidelines

The means through which Clinical Practice Guidelines are disseminated and become accessible are a crucial factor in their later adoption by health care professionals. Making these guidelines available in Clinical Decision Support Systems renders their application more personal and thus acceptable at the moment of care. Web technologies may play an important role in increasing the reach and dissemination of guidelines, but this promise remains largely unfulfilled. There is a need for a guideline computer model that can accommodate a wide variety of medical knowledge along with a platform for its execution that can be easily used in mobile devices. This work presents the CompGuide framework, a web-based and service-oriented platform for the execution of Computer-Interpretable Guidelines. Its architecture comprises different modules whose interaction enables the interpretation of clinical tasks and the verification of clinical constraints and temporal restrictions of guidelines represented in OWL. It allows remote guideline execution with data centralization, more suitable for a work environment where physicians are mobile and not bound to a machine. The solution presented in this paper encompasses a computer-interpretable guideline model, a web-based framework for guideline execution and an Application Programming Interface for the development of other guideline execution systems.

Prenatal cocaine exposure accelerates morphological changes and transient expression of tyrosine hydroxylase in the cochlea of developing rats.

Prenatal cocaine exposure causes alterations in auditory brainstem response in children and experimental animals and has adverse effects on auditory information processing and language skills in children. These effects may result from lesions in the cochlea since this organ is particularly sensitive to chemical insults during the development. We have thus studied here the effect of prenatal cocaine exposure on the maturation of the rat cochlea using the transient non-catecholaminergic expression of tyrosine hydroxylase in spiral ganglion neurons as an index of cochlear maturation and morphometry to evaluate the maturation of primary auditory neurons and the organ of Corti. We showed that prenatal cocaine exposure accelerated the cochlear maturation. In the basal coil of cochleas from PND8 cocaine-treated pups, the Köllikers organ had disappeared, the tunnel of Corti was opened, and the stria vascularis no longer contained undifferentiated marginal cells. The maximum expression of tyrosine hydroxylase in type I primary auditory neurons occurred at PND8 instead of PND12 in pair-fed controls. On the other hand, the prenatal cocaine exposure had no effect on the width and height of the organ of Corti, spiral ganglion volume and number and size of primary auditory neurons. In conclusion, our data suggest that prenatal cocaine exposure, though not lethal to primary auditory neurons, accelerates aspects of the cochlear sensorineural maturation. This accelerated cochlear maturation in cocaine-treated rat pups could cause auditory dysfunctions by desynchronizing the development of the whole auditory pathway.

Doctor, How Much Weight Will I Lose?-a New Individualized Predictive Model for Weight Loss.

Bariatric surgery is an effective treatment for weight loss, but the patient’s ability to reach a sustained weight loss depends upon several technical and individual factors. Creating an easy model that adapts bariatric surgery’s weight loss goals for each patient is very important for pre-surgery and follow-up evaluations.