Role of p21 and oxidative stress on renal tubular resistance after acute ischaemic injury

Background. Subsequent ischaemic episodes may induce renal resistance. P21 is a cell cycle inhibitor that may be induced by oxygen-free radicals and may have a protective effect in ischaemic acute kidney injury (AKI). This study aimed at evaluating the role of oxidative stress and p21 on tubular resistance in a model of acquired resistance after renal ischaemia and in isolated renal tubules. Methods. Wistar rats were divided into: Group 1-sham; Group 2-sham operated and after 2 days submitted to 45-min ischaemia; and Group 3-45-min ischaemia followed after 2 days by a second 45-min ischaemia. Plasma urea was evaluated on Days 0, 2 and 4. Serum creatinine, creatinine clearance and oxidants (thiobarbituric acid-reactive substances) were determined 48 h after the second procedure (Day 4). Histology, immunohistochemistry for lymphocytes (CD3), macrophages (ED1), proliferation (PCNA) and apoptosis (TUNEL) were also evaluated. Rat proximal tubules (PTs) were isolated by collagenase digestion and Percoll gradient from control rats and rats previously subjected to 35 min of ischaemia. PTs were submitted to 15-min hypoxia followed by 45-min reoxygenation. Cell injury was assessed by lactate dehydrogenase release and hydroperoxide production (xylenol orange). Results. Ischaemia induced AKI in Group 2 and 3 rats. Subsequent ischaemia did not aggravate renal injury, demonstrating renal resistance (Group 3). Renal function recovery was similar in Group 2 and 3. Plasma and urine oxidants were similar among in Group 2 and 3. Histology disclosed acute tubular necrosis in Group 2 and 3. Lymphocyte infiltrates were similar among all groups whereas macrophages infiltrate was greater in Group 3. Cell proliferation was greater in Group 2 compared with Group 3. Apoptosis was similar in groups 2 and 3. The p21 expression was increased only in Group 3 whereas it was similar in groups 1 and 2. PTs from the ischaemia group were sensitive to hypoxia but resistant to reoxygenation injury which was followed by lower hydroperoxide production compared to control PT. Conclusion. Renal resistance induced by ischaemia was associated with cell mechanism mediators involving oxidative stress and increased p21 expression.

Management of acromegaly in Latin America: expert panel recommendations

Although there are international guidelines orienting physicians on how to manage patients with acromegaly, such guidelines should be adapted for use in distinct regions of the world. A panel of neuroendocrinologists convened in Mexico City in August of 2007 to discuss specific considerations in Latin America. Of major discussion was the laboratory evaluation of acromegaly, which requires the use of appropriate tests and the adoption of local institutional standards. As a general rule to ensure diagnosis, the patient`s GH level during an oral glucose tolerance test and IGF-1 level should be evaluated. Furthermore, to guide treatment decisions, both GH and IGF-1 assessments are required. The treatment of patients with acromegaly in Latin America is influenced by local issues of cost, availability and expertise of pituitary neurosurgeons, which should dictate therapeutic choices. Such treatment has undergone profound changes because of the introduction of effective medical interventions that may be used after surgical debulking or as first-line medical therapy in selected cases. Surgical resection remains the mainstay of therapy for small pituitary adenomas (microadenomas), potentially resectable macroadenomas and invasive adenomas causing visual defects. Radiotherapy may be indicated in selected cases when no disease control is achieved despite optimal surgical debulking and medical therapy, when there is no access to somatostatin analogues, or when local issues of cost preclude other therapies. Since not all the diagnostic tools and treatment options are available in all Latin American countries, physicians need to adapt their clinical management decisions to the available local resources and therapeutic options.

Patient Characteristics as Predictors of Image Quality and Diagnostic Accuracy of MDCT Compared With Conventional Coronary Angiography for Detecting Coronary Artery Stenoses: CORE-64 Multicenter International Trial

OBJECTIVE. The purpose of the study was to investigate patient characteristics associated with image quality and their impact on the diagnostic accuracy of MDCT for the detection of coronary artery stenosis. MATERIALS AND METHODS. Two hundred ninety-one patients with a coronary artery calcification (CAC) score of <= 600 Agatston units (214 men and 77 women; mean age, 59.3 +/- 10.0 years [SD]) were analyzed. An overall image quality score was derived using an ordinal scale. The accuracy of quantitative MDCT to detect significant (>= 50%) stenoses was assessed using quantitative coronary angiography (QCA) per patient and per vessel using a modified 19-segment model. The effect of CAC, obesity, heart rate, and heart rate variability on image quality and accuracy were evaluated by multiple logistic regression. Image quality and accuracy were further analyzed in subgroups of significant predictor variables. Diagnostic analysis was determined for image quality strata using receiver operating characteristic (ROC) curves. RESULTS. Increasing body mass index (BMI) (odds ratio [OR] = 0.89, p < 0.001), increasing heart rate (OR = 0.90, p < 0.001), and the presence of breathing artifact (OR = 4.97, p = 0.001) were associated with poorer image quality whereas sex, CAC score, and heart rate variability were not. Compared with examinations of white patients, studies of black patients had significantly poorer image quality (OR = 0.58, p = 0.04). At a vessel level, CAC score (10 Agatston units) (OR = 1.03, p = 0.012) and patient age (OR = 1.02, p = 0.04) were significantly associated with the diagnostic accuracy of quantitative MDCT compared with QCA. A trend was observed in differences in the areas under the ROC curves across image quality strata at the vessel level (p = 0.08). CONCLUSION. Image quality is significantly associated with patient ethnicity, BMI, mean scan heart rate, and the presence of breathing artifact but not with CAC score at a patient level. At a vessel level, CAC score and age were associated with reduced diagnostic accuracy.

Comorbid major depression in obsessive-compulsive disorder patients

Although major depressive disorder (MDD) has been consistently considered the most frequent complication of obsessive-compulsive disorder (OCD), little is known about the clinical characteristics of patients with both disorders. This study assessed 815 Brazilian OCD patients using a comprehensive psychiatric evaluation. Clinical and demographic variables, including OCD symptom dimensions, were compared among OCD patients with and without MDD. Our findings showed that prevalence rates of current MDD (32%) and lifetime MDD (67.5%) were similar for both sexes in this study. In addition, patients with comorbid MDD had higher severity scores of OCD symptoms. There was no preferential association of MDD with any particular OCD symptom dimension. This study supports the notion that depressed OCD patients present more severe general psychopathology. (C) 2011 Elsevier Inc. All rights reserved.

Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress

Systemic administration of cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, attenuates the cardiovascular and behavioral responses to restraint stress. Although the brain structures related to CBD effects are not entirely known, they could involve brainstem structures responsible for cardiovascular control. Therefore, to investigate this possibility the present study verified the effects of CBD (15.30 and 60 nmol) injected into the cisterna magna on the autonomic and behavioral changes induced by acute restraint stress. During exposure to restraint stress (1 h) there was a significant increase in mean arterial pressure (MAP) and heart rate (HR). Also, 24 h later the animals showed a decreased percentage of entries onto the open arms of the elevated plus-maze. These effects were attenuated by CBD (30 nmol). The drug had no effect on MAP and HR baseline values. These results indicate that intracisternal administration of CBD can attenuate autonomic responses to stress. However, since CBD decreased the anxiogenic consequences of restraint stress, it is possible that the drug is also acting on forebrain structures. (C) 2011 Elsevier Inc. All rights reserved.

Cardiovascular effects of acetylcholine microinjection into the ventrolateral and dorsal periaqueductal gray of rats

In the present study, we describe the cardiovascular effects of local acetylcholine (Ach) microinjection into both the ventrolateral (vlPAG) and dorsal (dPAG) periaqueductal gray areas of anesthetized rats and the possible local receptors involved with these responses. Microinjection of Ach (9, 27, 45 or 81 nmol/50 nL) into the vlPAG caused dose-related depressor responses. These hypotensive responses were blocked by local pretreatment with increasing doses of the nonselective muscarinic antagonist atropine (1, 3 or 9 nmol/50 nL). The microinjection of Ach into the dPAG caused no significant cardiovascular responses in anesthetized rats. In conclusion, the present findings suggest that a cholinergic system present in the vlPAG, but not in the dPAG, is involved with cardiovascular system control. Moreover, these cardiovascular responses evoked by Ach are mediated by muscarinic receptors. (C) 2010 Elsevier B.V. All rights reserved.

Paraventricular nucleus modulates autonomic and neuroendocrine responses to acute restraint stress in rats

The paraventricular nucleus of the hypothalamus (PVN) has been implicated in several aspects of neuroendocrine and cardiovascular control The PVN contains parvocellular neurons that release the corticotrophin release ha mone (CRH) under stress situations In addition this brain area is connected to several limbic structures implicated in defensive behavioral control as well to forebrain and brainst m structures involved in cardiovascular control Acute restraint is an unavoidable stress situation that evokes corticosterone release as well as marked autonomic changes the latter characterized by elevated mean arterial pressure (MAP) intense heart rate (HR) Increases and decrease in the tail temperature We report the effect of PVN inhibition on MAP and HR responses corticosterone plasma levels and tail temperature response during acute restraint in rats Bilateral microinjection of the nonspecific synaptic blocker CoCl(2) (1 mM/100 nL) into the PVN reduced the pressor response it inhibited the increase in plasma corticosterone concentration as well as the fall in tail temperature associated with acute restraint stress Moreover bilateral microinjection of CoCl(2) into areas surrounding the PVN did not affect the blood pressure hormonal and tail vasoconstriction responses to restraint stress The present results show that a local PVN neurotransmission is involved in the neural pathway that controls autonomic and neuroendocrine responses which are associated with the exposure to acute restraint stress (C) 2010 Elsevier B V All rights reservi.d

Cannabinoid CB(1) receptors in the medial prefrontal cortex modulate the expression of contextual fear conditioning

The ventral portion of the medial prefrontal cortex (vMPFC) has been related to the expression of contextual fear conditioning. This study investigated the possible involvement of CB(1) receptors in this aversive response. Male Wistar rats were submitted to a contextual aversive conditioning session and 48 h later re-exposed to the aversive context in which freezing and cardiovascular responses (increase of arterial pressure and heart rate) were recorded. The expression of CB(1) receptor-mRNA in the vMPFC was also measured using real time-PCR. In the first experiment intra-vMPFC administration of the CB(1) receptor agonist anandamide (AEA, 5 pmol/200 nl) or the AEA transport inhibitor AM404 (50 pmol/200 nl) prior to re-exposure to the aversive context attenuated the fear-conditioned responses. These effects were prevented by local pretreatment with the CB(1) receptor antagonist AM251 (100 pmol/200 nl). Using the same conditioning protocol in another animal group, we observed that CB(1) receptor mRNA expression increased in the vMPFC 48 h after the conditioning session. Although AM251 did not cause any effect by itself in the first experiment, this drug facilitated freezing and cardiovascular responses when the conditioning session employed a lesser aversive condition. These results indicated that facilitation of cannabinoid-mediated neurotransmission in the vMPFC by local CB(1) receptor activation attenuates the expression of contextual fear responses. Together they suggest that local endocannabinoid-mediated neurotransmission in the vMPFC can modulate these responses.

Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT(1A) receptors

Cannabidiol (CBD) is a non-psychotomimetic constituent of the Cannabis sativa plant that inhibits behavioral and cardiovascular responses to aversive situations. facilitating 5-HT(1A)-mediated neurotransmission. Previous results from our group suggest that the bed nucleus of the stria terminalis (BNST) may be involved in CBD`s anti-aversive effects. To investigate whether the cardiovascular effects of the CBD could involve a direct drug effect on the BNST, we evaluated the effects of CBD microinjection into this structure on baroreflex activity. We also verified whether these effects were mediated by the activation of 5-HT(1A) receptors. Bilateral microinjection of CBD (60 nmol/100 nL) into the BNST increased the bradycardiac response to arterial pressure increases. However, no changes were observed in tachycardiac responses evoked by arterial pressure decreases. Pretreatment of the BNST with the selective 5-HT(1A) receptor antagonist WAY100635 (0.37 nmol/100 nL) prevented CBD effects on the baroreflex activity. Moreover, microinjection of the 5-HT(1A) receptor agonist 8-OH-DPAT (4 nmol/100 nL) caused effects that were similar to those observed after the microinjection of CBD, which were also blocked by pretreatment with WAY100635. In conclusion, the present studies show that the microinjection of CBD into the BNST has a facilitatory influence on the baroreflex response to blood pressure increases, acting through the activation of 5-HT(1A) receptors. (C) 2010 Elsevier Ltd. All rights reserved.

N-Methyl-D-aspartate glutamate receptors in the hypothalamic paraventricular nucleus modulate cardiac component of the baroreflex in unanesthetized rats

In the present study, we investigated the role played by the hypothalamic paraventricular nucleus (PVN) in the modulation of cardiac baroreflex activity in unanesthetized rats. Bilateral microinjections of the nonselective neurotransmission blocker CoCl(2) into the PVN decreased the reflex bradycardic response evoked by blood pressure increases, but had no effect on reflex tachycardia evoked by blood pressure decreases. Bilateral microinjections of the selective NMDA glutamate receptor antagonist LY235959 into the PVN caused effects that were similar to those observed after microinjections of CoCl(2), decreasing reflex bradycardia without affecting tachycardic response. The microinjection of the selective non-NMDA glutamate receptor antagonist NBQX into the PVN did not affect the baroreflex activity. Also, the microinjection of L-glutamate into the PVN increased the reflex bradycardia, an effect opposed to that observed after PVN treatment with CoCl(2) or LY235959, and this effect of L-glutamate was blocked by PVN pretreatment with LY235959. LY235959 injected into the PVN after iv. treatment with the selective beta(1)-adrenoceptor antagonist atenolol still decreased the reflex bradycardia. Taken together, our results suggest a facilitatory influence of the PVN on the bradycardic response of the baroreflex through activation of local NMDA glutamate receptors and a modulation of the cardiac parasympathetic activity. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors

Cannabidiol (CBD) is a major nonpsychotomimetic component of Cannabis sativa that has been shown to have an anxiolytic effect in human and animal models. Earlier studies suggest that these effects involve facilitation of serotonin, a neurotransmitter that has also been related to obsessive-compulsive disorder. On the basis of this evidence, this study investigated the effects of CBD in C57BL/6J mice submitted to the marble-burying test (MBT), an animal model proposed to reflect compulsive behaviour. CBD (15, 30 and 60 mg/kg) induced a significant decrease in the number of buried marbles compared with controls (34, 41 and 48%, respectively). A similar, although larger, decrease was also found after the serotonin selective reuptake inhibitor paroxetine (10 mg/kg, 77% decrease) and the benzodiazepine diazepam (2.5 mg/kg, 84% decrease). The effect of CBD (30 mg/kg) was still significant after 7 days of daily repeated administration, whereas the effect of diazepam disappeared. Pretreatment with WAY100635 (3 mg/kg), a 5HT1A receptor antagonist, prevented the effects of paroxetine but failed to alter those of CBD. These latter effects, however, were prevented by pretreatment with the CB1 receptor antagonist AM251 (1 mg/kg). These results indicated that CBD and paroxetine decrease the number of buried marbles in the MBT through distinct pharmacological mechanisms. They also suggest a potential role of drugs acting on the cannabinoid system in modulating compulsive behaviour. Behavioural Pharmacology 21: 353-358 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Panicolytic-like effect of BDNF in the rat dorsal periaqueductal grey matter: the role of 5-HT and GABA

A wealth of evidence suggests a role for brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the aetiology of depression and in the mode of action of antidepressant drugs. Less clear is the involvement of this neurotrophin in other stress-related pathologies such as anxiety disorders. The dorsal periaqueductal grey matter (DPAG), a midbrain area rich in BDNF and TrkB receptor mRNAs and proteins, has been considered a key structure in the pathophysiology of panic disorder. In this study we investigated the effect of intra-DPAG injection of BDNF in a proposed animal model of panic: the escape response evoked by the electrical stimulation of the same midbrain area. To this end, the intensity of electrical current that needed to be applied to DPAG to evoke escape behaviour was measured before and after microinjection of BDNF. We also assessed whether 5-HT- or GABA-related mechanisms may account for the putative behavioural/autonomic effects of the neurotrophin. BDNF (0.05, 0.1, 0.2 ng) dose-dependently inhibited escape performance, suggesting a panicolytic-like effect. Local microinjection of K252a, an antagonist of TrkB receptors, or bicuculline, a GABA(A) receptor antagonist, blocked this effect. Intra-DPAG administration of WAY-100635 or ketanserin, respectively 5-HT(1A) and 5-HT(2A/2c) receptor antagonists, did not alter BDNF`s effects on escape. Bicuculline also blocked the inhibitory effect of BDNF on mean arterial pressure increase caused by electrical stimulation of DPAG. Therefore, in the DPAG, BDNF-TrkB signalling interacts with the GABAergic system to cause a panicolytic-like effect.

Involvement of the lateral septal area in the expression of fear conditioning to context

Considering the evidence that the lateral septal area (LSA) modulates defensive responses, the aim of the present study is to verify if this structure is also involved in contextual fear conditioning responses. Neurotransmission in the LSA was reversibly inhibited by bilateral microinjections of cobalt chloride (CoCl(2), 1 mM) 10 min before or after conditioning or 10 min before re-exposure to the aversively conditioned chamber. Only those animals that received CoCl(2) before re-exposure showed a decrease in both cardiovascular and behavioral conditioned responses. These results suggest that the LSA participates in the expression, but not acquisition or consolidation, of contextual fear conditioning.

Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats

Rationale: Systemic administration of cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is able to attenuate cardiovascular and behavioral (freezing) changes induced by re-exposure to a context that had been previously paired with footshocks. The brain sites mediating this effect, however, remain unknown. The medial prefrontal cortex (mPFC) has been related to contextual fear conditioning. Objectives: (1) To verify, using c-Fos immunocytochemistry, if the mPFC is involved in the attenuation of contextual fear induced by systemic administration of CBD; (2) to investigate if direct microinjections of CBD into mPFC regions would also attenuate contextual fear. Results: Confirming previous results systemic administration of CBD (10 mg/kg) decreased contextual fear and associated c-Fos expression in the prefrontal cortex (prelimbic and infralimbic regions). The drug also attenuated c-Fos expression in the bed nucleus of the stria terminalis (BNST). Direct CBD (30 nmol) microinjection into the PL prefrontal cortex reduced freezing induced by re-exposure to the aversively conditioned context. In the infralimbic (IL) prefrontal cortex, however, CBD (30 nmol) produced an opposite result, increasing the expression of contextual fear conditioning. This result was confirmed by an additional experiment where the conditioning session was performed under a less aversive protocol. Conclusion: These results suggest that the PL prefrontal cortex may be involved in the attenuation of contextual fear induced by systemic injection of CBD. They also support the proposition that the IL and PL play opposite roles in fear conditioning. A possible involvement of the BNST in CBD effects needs to be further investigated. (C) 2009 Elsevier B.V. All rights reserved.

The bed nucleus of the stria terminalis modulates exercise-evoked cardiovascular responses in rats

Dynamic exercise evokes sustained cardiovascular changes, which are characterized by blood pressure and heart rate (HR) increases. Although it is well accepted that there is a central nervous system (CNS) mediation of cardiovascular adjustments during dynamic exercise, information on the role of specific CNS structures is limited. The bed nucleus of the stria terminalis (BST) is a forebrain structure known to be involved in central cardiovascular control. Based on this, we tested the hypothesis that BST modulates HR and mean arterial pressure (MAP) responses evoked when rats are submitted to dynamic exercise. Male Wistar rats were tested at three levels of exercise (0.4, 0.8 and 1 km h-1) on a rodent treadmill before and after BST treatment with CoCl(2), a non-selective neurotransmission blocker. Bilateral microinjection of CoCl(2) (1 nmol in 100 nl artificial cerebrospinal fluid) into the BST reduced the pressor response to exercise at 0.4 km h-1 as well as the tachycardic responses evoked by exercise at 0.4, 0.8 and 1 km h-1. The BST treatment with CoCl(2) did not affect baseline MAP or HR, suggesting a lack of tonic BST influence on cardiovascular parameters at rest. Moreover, BST treatment with CoCl(2) did not affect motor performance in the open-field test, which indicates that effects of BST inhibition on cardiovascular responses to dynamic exercise are not due to changes in motor activity. The present results suggest that local neurotransmission in the BST modulates exercise-related cardiovascular adjustments. Data indicate that BST facilitates pressor and tachycardic responses evoked by dynamic exercise in rats.