Characterization of a Parkinson's disease rat model using an upgraded paraquat exposure paradigm.

Animal models of human diseases are crucial experimental tools to investigate the mechanisms involved in disease pathogenesis and to develop new therapies. In spite of the numerous animal models currently available that reproduce several neuropathological features of Parkinson disease (PD), it is challenging to have one that consistently recapitulates human PD conditions in both motor behaviors and biochemical pathological outcomes. Given that, we have implemented a new paradigm to expose rats to a chronic low dose of paraquat (PQ), using osmotic minipumps and characterized the developed pathologic features over time. The PQ exposure paradigm used lead to a rodent model of PD depicting progressive nigrostriatal dopaminergic neurodegeneration, characterized by a 41% significant loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc), a significant decrease of 18% and 40% of dopamine levels in striatum at week 5 and 8, respectively, and a significant 1.5-fold decrease in motor performance. We observed a significant increase of microglia activation state, sustained levels of α-synucleinopathy and increased oxidative stress markers in the SNpc. In summary, this is an explorative study that allowed to characterize an improved PQ-based rat model that recapitulates cardinal features of PD and may represent an attractive tool to investigate several mechanisms underlying the various aspects of PD pathogenesis as well as for the validation of the efficacy of new therapeutic approaches that targets different mechanisms involved in PD neurodegeneration.

GPER activation is effective in protecting against inflammation-induced nigral dopaminergic loss and motor function impairment.

Increasing evidence suggest that excessive inflammatory responses from overactivated microglia play a critical role in Parkinson's disease (PD), contributing to, or exacerbating, nigral dopaminergic (DA) degeneration. Recent results from our group and others demonstrated that selective activation of G protein-coupled estrogen receptor (GPER) with the agonist G1 can protect DA neurons from 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxins. However, it is not known whether modulation of microglial responses is one of the mechanisms by which G1 exerts its DA neuroprotective effects. We analyzed, in the N9 microglial cell line, the effect of G1 on microglial activation induced by lipopolysaccharide (LPS) exposure. The results revealed that G1 significantly decrease phagocytic activity, expression of inducible nitric oxide synthase (iNOS) and release of nitric oxide (NO) induced by LPS. To determine the relevance of this anti-inflammatory effect to the protection of nigral DA cells, the effect of G1 was analyzed in male mice injected unilaterally in the substantia nigra (SN) with LPS. Although G1 treatment did not decrease LPS-induced increase of ionized calcium binding adaptor molecule 1 (iba-1) positive cells it significantly reduced interleukin-1beta (IL-1ß), cluster of differentiation 68 (CD68) and iNOS mRNA levels, and totally inhibited nigral DA cell loss and, as a consequence, protected the motor function. In summary, our findings demonstrated that the G1 agonist is able to modulate microglial responses and to protect DA neurons and motor functions against a lesion induced by an inflammatory insult. Since G1 lacks the feminizing effects associated with agonists of the classical estrogen receptors (ERs), the use of G1 to selectively activate the GPER may be a promising strategy for the development of new therapeutics for the treatment of PD and other neuroinflammatory diseases.

GPER: A new tool to protect dopaminergic neurons?

Parkinson's disease (PD) is characterized by a selective degeneration of nigrostriatal dopaminergic pathway. Epidemiological studies revealed a male predominance of the disease that has been attributed to the female steroid hormones, mainly the estrogen. Estrogen neuroprotective effects have been shown in several studies, however the mechanisms responsible by these effects are still unclear. Previous data from our group revealed that glial cell line-derived neurotrophic factor (GDNF) is crucial to the dopaminergic protection provided by 17ß-estradiol, and also suggest that the intracellular estrogen receptors (ERs) are not required for that neuroprotective effects. The present study aimed to investigate the contribution of the G protein-coupled ER (GPER) activation in estrogen-mediated dopaminergic neuroprotection against an insult induced by 1-methyl-4-phenylpyridinium (MPP(+)), and whether GPER neuroprotective effects involve the regulation of GDNF expression. Using primary mesencephalic cultures, we found that GPER activation protects dopaminergic neurons from MPP(+) toxicity in an extent similar to the promoted by a 17ß-estradiol. Moreover, GPER activation promotes an increase in GDNF levels. Both, GDNF antibody neutralization or RNA interference-mediated GDNF knockdown prevented the GPER-mediated dopaminergic protection verified in mesencephalic cultures challenged with MPP(+). Overall, these results revealed that G1, a selective agonist of GPER, is able to protect dopaminergic neurons and that GDNF overexpression is a key feature to GPER induced the neuroprotective effects.

Assessing the efficacy of the 'Bicho De 7 Cabeças' B-learning school-based program in enhancing mental health literacy and reducing stigma.

The prevalence of mental disorders in adolescents has a considerable impact on daily life, restricting tasks and diminishing overall quality of life while potentially leading to stigmatization. This study aims to measure the impact of a mental health literacy intervention program, called "Bicho de 7 Cabeças" project, in b-learning format, on the increase of knowledge and the decrease of stigma in young people from Póvoa de Varzim, in Portugal. A quasi-experimental study was conducted, from November 2022 to May 2023, involving an experimental group ("Bicho de 7 Cabeças" protocol) and an active control group (informational brochures), utilizing a pre-test/post-test design. Mental Health Literacy Measure-MHLM, Mental Health Promoting Knowledge Scale-MHPK-10, Mental Illness Knowledge Schedule-MAKS, Reported and Intended Behaviour Scale-RIBS, and Community Attitudes toward People with Mental Illness-CAMI were used. A total of 504 young students from the 9th grade enroll in this study, with a mean age around 14 years old. There is a significant difference between stigma (p <.001) and knowledge (p <.001) scores at baseline and follow-up. The results of this study shows that interventions aimed at young people for the promotion of mental health literacy and stigma reduction are needed and more initiatives should be implemented in schools to address these problems.

DESI-MSI-based technique to unravel spatial distribution of COMT inhibitor Tolcapone.

Ascertaining compound exposure and its spatial distribution are essential steps in the drug development process. Desorption electrospray ionization mass spectrometry (DESI-MSI) is a label-free imaging technique capable of simultaneously identify and visualize the distribution of a diverse range of biomolecules. In this study, DESI-MSI was employed to investigate spatial distribution of tolcapone in rat liver and brain coronal - frontal and striatal -sections after a single oral administration of 100 mg/Kg of tolcapone, brain-penetrant compound. Tolcapone was evenly distributed in liver tissue sections whereas in the brain it showed differential distribution across brain regions analyzed, being mainly located in the olfactory bulb, basal forebrain region, striatum, and pre-frontal cortex (PFC; cingulate, prelimbic and infralimbic area). Tolcapone concentration in tissues was compared using DESI-MSI and liquid-chromatography mass spectrometry (LC-MS/MS). DESI-MSI technique showed a higher specificity on detecting tolcapone in liver sections while in the brain samples DESI-MSI did not allow a feasible quantification. Indeed, DESI-MSI is a qualitative technique that allows to observe heterogeneity on distribution but more challenging regarding accurate measurements. Overall, tolcapone was successfully localized in liver and brain tissue sections using DESI-MSI, highlighting the added value that this technique could provide in assisting tissue-specific drug distribution studies.

Endogenous GDNF Is Unable to Halt Dopaminergic Injury Triggered by Microglial Activation.

Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson's disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses. However, in vivo, the control of neuroinflammation is more complex as it depends on the interaction between different types of cells other than microglia and astrocytes. Whether neurons may interfere in the astrocyte-microglia crosstalk, affecting the control of microglial reactivity exerted by astrocytes, is unclear. Therefore, the present work aimed to disclose if the control of microglial responses mediated by astrocyte-derived factors, including GDNF, could be affected by the crosstalk with neurons, impacting GDNF's ability to protect dopaminergic neurons exposed to a pro-inflammatory environment. Also, we aimed to disclose if the protection of dopaminergic neurons by GDNF involves the modulation of microglial cells. Our results show that the neuroprotective effect of GDNF was mediated, at least in part, by a direct action on microglial cells through the GDNF family receptor α-1. However, this protective effect seems to be impaired by other mediators released in response to the neuron-astrocyte crosstalk since neuron-astrocyte secretome, in contrast to astrocytes secretome, was unable to protect dopaminergic neurons from the injury triggered by lipopolysaccharide-activated microglia. Supplementation with exogenous GDNF was needed to afford protection of dopaminergic neurons exposed to the inflammatory environment. In conclusion, our results revealed that dopaminergic protective effects promoted by GDNF involve the control of microglial reactivity. However, endogenous GDNF is insufficient to confer dopaminergic neuron protection against an inflammatory insult. This reinforces the importance of further developing new therapeutic strategies aiming at providing GDNF or enhancing its expression in the brain regions affected by Parkinson's disease.

Mental Health Literacy and Stigma in a Municipality in the North of Portugal: A Cross-Sectional Study.

Portugal has Europe's second-highest prevalence of psychiatric illnesses, and this is the reason why mental health literacy (MHL) and stigma should be addressed. This study aimed to investigate the mental health literacy and stigma levels among different groups of people from Póvoa de Varzim, a municipality in the north of Portugal. Students, retired people, and professionals (education, social, and healthcare fields) were recruited using a convenience sample from June to November 2022. Participants' MHL levels were evaluated using the Mental Health Promoting Knowledge Scale (MHPK), Mental Health Literacy Measure (MHLM) and Mental Health Knowledge Schedule (MAKS). Stigma levels were evaluated using Community Attitudes towards Mental Illness (CAMI) and the Reported and Intended Behaviour Scale (RIBS). A total of 928 questionnaires were filed. The respondents included 65.70% of women, a mean age of 43.63 (±26.71) years and 9.87 (±4.39) years of school education. MHL increased with age, education level and was higher in women (p < 0.001). A higher level of MHL was seen in health professionals (p < 0.001). Findings revealed that older people stigmatized people with mental illness more (p < 0.001), and the female gender stigmatize less (p < 0.001). In addition, results showed that stigma decreased with higher mental health literacy (r between 0.11 and 0.38; p < 0.001). To conclude, specific campaigns that promote mental health literacy should be tailored to specific profiles within this population to address those that have more stigma.

Antimicrobial peptide-grafted PLGA-PEG nanoparticles to fight bacterial wound infections.

Wound infection treatment with antimicrobial peptides (AMPs) is still not a reality, due to the loss of activity in vivo. Unlike the conventional strategy of encapsulating AMPs on nanoparticles (NPs) leaving activity dependent on the release profile, this work explores AMP grafting to poly(D,L-lactide-co-glycolide)-polyethylene glycol NPs (PLGA-PEG NPs), whereby AMP exposition, infection targeting and immediate action are promoted. NPs are functionalized with MSI-78(4-20), an equipotent and more selective derivative of MSI-78, grafted through a thiol-maleimide (Mal) Michael addition. NPs with different ratios of PLGA-PEG/PLGA-PEG-Mal are produced and characterized, with 40%PLGA-PEG-Mal presenting the best colloidal properties and higher amounts of AMP grafted as shown by surface charge (+8.6 ± 1.8 mV) and AMP quantification (326 µg mL-1, corresponding to 16.3 µg of AMP per mg of polymer). NPs maintain the activity of the free AMP with a minimal inhibitory concentration (MIC) of 8-16 µg mL-1 against Pseudomonas aeruginosa, and 16-32 µg mL-1 against Staphylococcus aureus. Moreover, AMP grafting accelerates killing kinetics, from 1-2 h to 15 min for P. aeruginosa and from 6-8 h to 0.5-1 h for S. aureus. NP activity in a simulated wound fluid is maintained for S. aureus and decreases slightly for P. aeruginosa. Furthermore, NPs do not demonstrate signs of cytotoxicity at MIC concentrations. Overall, this promising formulation helps unleash the full potential of AMPs for the management of wound infections.

The therapeutic benefit of upgrade to cardiac resynchronization therapy in patients with pacing-induced cardiomyopathy.

Background: Pacing-induced cardiomyopathy (PICM) is an important cause of heart failure in patients with a right ventricular pacing burden. Recent evidence suggests that an upgrade to cardiac resynchronization therapy (CRT) may confer benefit in PICM. Objective: To assess the extent and identify predictors of improvement following upgrade to CRT in patients with PICM. Methods: We retrospectively analyzed 43 patients undergoing CRT upgrade for PICM over the 10-year period of 2011 to 2021 at our center. All patients with PICM who underwent device upgrade from a dual- or single-chamber ventricular pacemaker to CRT were included. PICM was defined as a decrease of ≥10% in left ventricular ejection fraction (LVEF), resulting in an LVEF <50% among patients with ≥20% Right ventricular pacing burden without an alternative cause for cardiomyopathy. Results: LVEF significantly improved from 28.7% preupgrade to 44.3% post-CRT upgrade (P < .01). Of 37 patients with severe LV dysfunction, 34 (91.9%) improved to an LVEF >35% and 13 (35.1%) improved to an LVEF >50%. The LV end-diastolic diameter decreased from 5.9 cm preupgrade to 5.4 cm postupgrade (P < .01). Using linear regression, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use was associated with significant LVEF improvement (+7.21%, P = .05). We observed a low rate of complications, and 1 in 4 CRT upgrades required venoplasty (n = 10 of 43, 23.3%). Conclusion: We provide further evidence for the benefit of CRT upgrade in the management of patients with PICM.

Astrocyte-derived GDNF is a potent inhibitor of microglial activation.

Neuroinflammation is recognized as a major factor in Parkinson's disease (PD) pathogenesis and increasing evidence propose that microglia is the main source of inflammation contributing to the dopaminergic degeneration observed in PD. Several studies suggest that astrocytes could act as physiological regulators preventing excessive microglia responses. However, little is known regarding how astrocytes modulate microglial activation. In the present study, using Zymosan A-stimulated midbrain microglia cultures, we showed that astrocytes secrete factors capable of modulating microglial activation, namely its phagocytic activity and the production of reactive oxygen species since both parameters were highly diminished in cells incubated with astrocytes conditioned media (ACM). Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF) and brain-derived neurotrophic factor (BDNF), known to have a neuroprotective role in the nigrostriatal system, are among the candidates to be astrocyte-secreted molecules involved in the modulation of microglial activation. The effect of ACM on Zymosan A-induced microglial activation was abolished when the GDNF present in the ACM was abrogated using a specific antibody, but not when ACM was neutralized with anti-CDNF, anti-BDNF or with a heat-inactivated GDNF antibody. In addition, media conditioned by astrocytes silenced for GDNF were not able to prevent microglial activation, whereas supplementation of non-conditioned media with GDNF prevented the activation of microglia evoked by Zymosan A. Taken together, these results indicate that astrocyte-derived GDNF plays a major contribution to the control of midbrain microglial activation, suggesting that GDNF can protect from neurodegeneration through the inhibition of neuroinflammation.

The Antidiabetic Effect of Grape Pomace Polysaccharide-Polyphenol Complexes.

Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic metabolic diseases of the 21st century. Nevertheless, its prevalence might be attenuated by taking advantage of bioactive compounds commonly found in fruits and vegetables. This work is focused on the recovery of polyphenols and polysaccharide-polyphenol conjugates from grape pomace for T2DM management and prevention. Bioactives were extracted by solid-liquid extraction and by pressurized hot water extraction (PHWE). Polyphenolic fraction recovered by PHWE showed the highest value for total phenolic content (427 µg GAE.mg-1), mainly anthocyanins and proanthocyanidins, and higher antioxidant activity compared to the fraction recovered by solid-liquid extraction. Polysaccharide-polyphenol conjugates comprehended pectic polysaccharides to which approximately 108 µg GAE of phenolic compounds (per mg fraction) were estimated to be bound. Polyphenols and polysaccharide-polyphenol conjugates exhibited distinct antidiabetic effects, depending on the extraction methodologies employed. Extracts were particularly relevant in the inhibition of a-glucosidase activity, with free polyphenols showing an IC50 of 0.47 µg.mL-1 while conjugates showed an IC50 of 2.7, 4.0 and 5.2 µg.mL-1 (solid-liquid extraction, PHWE at 95 and 120 °C, respectively). Antiglycation effect was more pronounced for free polyphenols recovered by PHWE, while the attenuation of glucose uptake by Caco-2 monolayers was more efficient for conjugates obtained by PHWE. The antidiabetic effect of grape pomace bioactives opens new opportunities for the exploitation of these agri-food wastes in food nutrition, the next step towards reaching a circular economy in grape products.

Microglia of rat ventral midbrain recovers its resting state over time in vitro: let microglia rest before work.

Cortical or total brain cultures of microglia are commonly used as a model to study the inflammatory processes in Parkinson's disease. Here we characterize microglia cultures from rat ventral midbrain and evaluate their response to zymosan A. We used specific markers of microglia and evaluated the morphology, the phagocytic activity and reactive oxygen species (ROS) levels of the cells. During the first 10 days in vitro (DIV), cultures presented predominantly cells with a round morphology, expressing CD68 and with high phagocytic activity and ROS production. After 13 DIV, this tendency was reversed, with cultures showing higher number of ramified cells and fewer CD68(+) cells along with lower phagocytic and ROS production capability, suggesting that microglia must be kept in vitro for at least 13 days to recover its resting state. The exposure of cultures with less than 10 DIV to zymosan A significantly decreased cell viability. Exposure of cultures with 13 DIV to zymosan A (0.05, 0.5, or 5 microg/ml) increased the total cell number, the percentage of CD68(+) cells, and the phagocytic activity. Concentrations of zymosan A higher than 5 microg/ml were also effective in activating microglia but significantly decreased the number of viable cells. In summary, microglial cells remain in the activated state for several days after the isolation process and, thus, stimulation of microglia recently isolated can compromise interpretation of the results. However, upon 13 DIV, cells achieve properties of nonactivated microglia and present a characteristic response to a proinflammatory agent.

Acute salt loading induces sympathetic nervous system overdrive in mice lacking salt-inducible kinase 1 (SIK1).

Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice. Here, we further addressed the possible early mechanisms that may relate to the observed rise in BP in mice lacking SIK1. SIK1 knockout (sik1-/-) and wild-type (sik1+/+) littermate mice were challenged with either a high-salt (8% NaCl) or control (0.3% NaCl) diet for 7 days. Systolic BP was significantly increased in sik1-/- mice after 7 days of high-salt diet as compared with sik1+/+ mice and to sik1-/- counterparts on a control diet. The renin-angiotensin-aldosterone system and the sympathetic nervous system were assayed to investigate possible causes for the increase in BP in sik1-/- mice fed a 7-day high-salt diet. Although no differences in serum renin and angiotensin II levels were observed, a reduction in aldosterone serum levels was observed in mice fed a high-salt diet. Urinary L-DOPA and noradrenaline levels were significantly increased in sik1-/- mice fed a high-salt diet as compared with sik1-/- mice on a control diet. Similarly, the activity of dopamine ß-hydroxylase (DßH), the enzyme that converts dopamine to noradrenaline, was significantly increased in the adrenal glands of sik1-/- mice on a high-salt intake compared with sik1+/+ and sik1-/- mice on a control diet. Treatment with etamicastat (50 mg/kg/day), a peripheral reversible DßH inhibitor, administered prior to high-salt diet, completely prevented the systolic BP increase in sik1-/- mice. In conclusion, SIK1 activity is necessary to prevent the development of salt-induced high blood pressure and associated SNS overactivity.

Role of Neurotrophic Factors in Parkinson's Disease.

Parkinson's disease is an age-associated progressive neurodegenerative disorder that has gained crescent social and economic impact due to the aging of the western society. All current therapies are symptomatic and fail to reverse or halt the progression of dopaminergic neurons loss. The discovery of the capability of neurotrophic factors to protect these neurons lead numerous research groups to focus their efforts in developing therapies aiming at promoting the control of Parkinson´s disease through the delivery of neurotrophic factors to the brain or by boosting their endogenous levels. Both strategies were successful in inducing protection of dopaminergic neurons and motor recovery in preclinical models of the disease. Contrariwise, very limited success was obtained in clinical studies, where glial cell line-derived neurotrophic factor and neurturin were the neurotrophic factors of choice for Parkinson's disease therapy. These drawbacks motivate the development of novel forms of delivery or the modification of the injected molecules aiming at providing a more stable and effective administration with improved diffusion in the target tissue, and without the immune responses observed in the earliest clinical studies. Although promising results were obtained with some of these new approaches performed in experimental models of the disease, they were not yet tested in human studies. In this review, we present the current knowledge on neurotrophic factors and their role in Parkinson's disease, focusing on the strategies that have been developed to increase their levels in target areas of the brain to achieve protection of dopaminergic neurons and motor behaviour recovery.

Sellar plasmacytoma presenting with symptoms of anterior pituitary dysfunction.

Sellar plasmacytomas are rare and the differential diagnosis with non-functioning pituitary adenomas might be difficult because of clinical and radiological resemblance. They usually present with neurological signs and intact anterior pituitary function. Some may already have or eventually progress to multiple myeloma. We describe a case associated with extensive anterior pituitary involvement, which is a rare form of presentation. A 68-year-old man was referred to our Endocrinology outpatient clinic due to gynecomastia, reduced libido and sexual impotence. Physical examination, breast ultrasound and mammography confirmed bilateral gynecomastia. Blood tests revealed slight hyperprolactinemia, low testosterone levels, low cortisol levels and central hypothyroidism. Sellar MRI showed a heterogeneous sellar mass (56 × 60 × 61 mm), initially suspected as an invasive macroadenoma. After correcting the pituitary deficits with hydrocortisone and levothyroxine, the patient underwent transsphenoidal surgery. Histological examination revealed a plasmacytoma and multiple myeloma was ruled out. The patient was unsuccessfully treated with radiation therapy (no tumor shrinkage). Myeloma ultimately developed, with several other similar lesions in different locations. The patient was started on chemotherapy, had a bone marrow transplant and is now stable (progression free) on lenalidomide and dexamethasone. The presenting symptoms and panhypopituitarism persisted, requiring chronic replacement treatment with levothyroxine, hydrocortisone and testosterone. LEARNING POINTS: Plasmacytomas, although rare, are a possible type of sellar masses, which have a completely different treatment approach, so it is important to make the correct diagnosis.Usually, they present with neurological signs and symptoms and a well-preserved pituitary function, but our case shows that anterior pituitary function can be severely compromised.Making a more extensive evaluation (clinical and biochemical) might provide some clues to this diagnosis.

Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson's Disease.

The use of dopamine replacement therapies (DRT) in the treatment of Parkinson's disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.

[Practical guidelines for peer support programmes for mental health problems]. / Directrices prácticas para programas de apoyo entre personas con enfermedad mental.

INTRODUCTION: This study aims to determine the guiding principles for the implementation of peer support programmes in Portugal. MATERIAL AND METHODS: The study was divided in 2 phases. In the first phase a systematic review of 112 papers indexed in ISI and EBSCO databases (2001 to 2012) was conducted. In the second phase clinicians, researchers, and people with psychiatric disabilities were invited to take part in a two-round online survey based on the Delphi process to rate the importance of statements generated from the systematic review. Data were analysed with NVivo 9 and SPSS 19. RESULTS: During the Delphi round 72 experts were contacted, 44 participated in the second round. A consensus was achieved on major statements, with 84% of the sentences obtaining a consensus and 8 key recommendations covering goals of peer support, selection of peer supporters, training and accreditation, role of mental health professionals, role of peer supporters, access to peer supporters, looking after peer supporters, and programme evaluation were based on these statements. CONCLUSIONS: Use of peer support for mental health problems is still underexplored and surrounded by some controversy and ambiguity. However, its organization and proper monitoring appears to enhance the quality of life and social inclusion of people with mental illness. This highlights the importance of conducting studies that increase our knowledge of these programmes and determining guidelines for their implementation. This national consensus may be used as a starting point for the design and implementation of peer support programmes in mental health organizations.

Behavioral characterization of the 6-hydroxidopamine model of Parkinson's disease and pharmacological rescuing of non-motor deficits.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative condition that is characterized by motor symptoms as a result of dopaminergic degeneration, particularly in the mesostriatal pathway. However, in recent years, a greater number of clinical studies have focused on the emergence of non-motor symptoms in PD patients, as a consequence of damage on the mesolimbic and mesocortical dopaminergic networks, and on their significant impact on the quality of life of PD patients. Herein, we performed a thorough behavioral analysis including motor, emotional and cognitive dimensions, of the unilateral medial forebrain bundle (MFB) 6-hydroxidopamine (6-OHDA)-lesioned model of PD, and further addressed the impact of pharmacological interventions with levodopa and antidepressants on mood dimensions. RESULTS: Based on apomorphine-induced turning behaviour and degree of dopaminergic degeneration, animals submitted to MFB lesions were subdivided in complete and incomplete lesion groups. Importantly, this division also translated into a different severity of motor and exploratory impairments and depressive-like symptoms; in contrast, no deficits in anxiety-like and cognitive behaviors were found in MFB-lesioned animals. Subsequently, we found that the exploratory and the anhedonic behavioural alterations of MFB-lesioned rats can be partially improved with the administration of both levodopa or the antidepressant bupropion, but not paroxetine. CONCLUSIONS: Our results suggest that this model is a relevant tool to study the pathophysiology of motor and non-motor symptoms of PD. In addition, the present data shows that pharmacological interventions modulating dopaminergic transmission are also relevant to revert the non-motor behavioral deficits found in the disease.

Excitotoxic lesions in the central nucleus of the amygdala attenuate stress-induced anxiety behavior.

The extended amygdala, composed by the amygdaloid nuclei and the bed nucleus of the stria terminalis (BNST), plays a critical role in anxiety behavior. In particular, the link between the central nucleus of the amygdala (CeA) and the BNST seems to be critical to the formation of anxiety-like behavior. Chronic unpredictable stress (CUS) exposure is recognized as a validated animal model of anxiety and is known to trigger significant morphofunctional changes in the extended amygdala. Quite surprisingly, no study has ever analyzed the role of the CeA in the onset of stress-induced anxiety and fear conditioning behaviors; thus, in the present study we induced a bilateral excitotoxic lesion in the CeA of rats that were subsequently exposed to a chronic stress protocol. Data shows that the lesion in the CeA induces different results in anxiety and fear-behaviors. More specifically, lesioned animals display attenuation of the stress response and of stress-induced anxiety-like behavior measured in the elevated-plus maze (EPM) when compared with stressed animals with sham lesions. This attenuation was paralleled by a decrease of stress-induced corticosterone levels. In contrast, we did not observe any significant effect of the lesion in the acoustic startle paradigm. As expected, lesion of the CeA precluded the appearance of fear behavior in a fear-potentiated startle paradigm in both non-stressed and stressed rats. These results confirm the implication of the CeA in fear conditioning behavior and unravel the relevance of this brain region in the regulation of the HPA axis activity and in the onset of anxiety behavior triggered by stress.