Avaliação da resposta neurogénica à ativação do recetor de estradiol acoplado à proteína G (GPER)

Estradiol is a steroid hormone that plays an important trophic and protective role in the adult brain, being essential not only to maintaining normal brain functions but also to protect the brain against neural injuries. There is an increasing number of studies that evidence the neuroprotective effect of estradiol, namely through the activation of the G protein-coupled estrogen receptor (GPER). However, it is not known if this protective effect involve a pro-neurogenic action of this receptor. Therefore, the aim of this study was to evaluate whether GPER activation triggers a neurogenic response in the subventricular zone (SVZ), a neurogenic niche. We confirmed the presence of GPER both in neural stem cell (NSC) cultures from SVZ and in the cells present in the borders of the lateral ventricles of mice brain, where SVZ is located. We analyse the effects evoked by GPER activation in vitro, using G1, the GPER specific agonist. GPER activation promoted a significant increase in the expression levels of the receptor as well as an increase of NSC differentiation into mature neurons and glial cells, assessed by the number of Ki67+/Neuronal nuclei (NeuN+) and Ki67+/Glial fibrillary acidic protein (GFAP+)- positive cells, respectively. Contrariwise, GPER activation did not increase neuroblast (Ki67+/ Doublecortin (DCX+)) or glial (Ki67+/DCX-) proliferation in vitro, in contrast estradiol significantly promoted neural cell proliferation. The in vivo analysis of GPER activation showed that G1 per se was able to increase neural proliferation in the mice SVZ. Taken together, the results showed that GPER activation effectively promote neurogenesis in the SVZ and has potential to be used as a neurogenic therapeutic agent.O estradiol pertence ao grupo das hormonas esteroides e desempenha um papel importante, sendo essencial não só na manutenção das funções normais do cérebro, mas também na proteção contra lesões neurais. São cada vez mais os estudos que evidenciam o efeito neuroprotetor do estradiol, nomeadamente através da ativação do recetor de estrogénio acoplado à proteína G (GPER). No entanto, não se sabe se esses efeitos neuroprotetores envolvem uma ação pró-neurogénica deste recetor. Assim, o objetivo deste estudo foi avaliar se a ativação do GPER é capaz de desencadear uma resposta neurogénica na região subventricular (SVZ). Foi confirmada a presença do GPER em culturas de células estaminais neurais (NSC) isoladas a partir da SVZ, assim como em fatias de SVZ obtidas de murganhos. A estimulação de culturas de NSC derivadas de SVZ com agonistas do GPER (G1) desencadeou um aumento significativo dos níveis de expressão do recetor bem como um aumento da diferenciação de NSC em neurónios e células da glia, avaliadas através do número de células positivas para Ki67+/ Neuronal nuclei (NeuN+) e Ki67+/ Glial fibrillary acidic protein (GFAP+), respetivamente. Pelo contrário, a ativação seletiva do GPER não aumentou o número de neuroblastos (Ki67+/ Doublecortin (DCX+)) ou células da glia (Ki67+/DCX-) proliferativos, diferindo do efeito mediado pelo estradiol, o qual aumentou significativamente a proliferação de células neurais. A injeção subcutânea de murganhos com G1 (190µg/Kg) e intraperitoneal com Bromodeoxiuridina (BrdU) mostrou que o G1, per se, aumenta a proliferação neural na SVZ de murganhos. Em conjunto, os nossos resultados sugerem que a ativação do GPER promove a neurogénese na SVZ, apresentando elevado potencial para ser utilizado como uma estratégia regeneradora

Clinical diagnostic criteria have a high impact on the frequency of dementia in late-stage Parkinson's disease

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: Cognitive impairment is a potential late feature of Parkinson's disease (PD). However, studies in patients with late-stage PD are lacking due to the particular characteristics of this population.Objectives: To evaluate the frequency of dementia in late-stage PD patients and to assess the impact of using different diagnostic criteria.Methods: We conducted a cross-sectional study to estimate the frequency of dementia in late-stage PD patients using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria as the primary outcome. We also applied other diagnostic criteria [MDS (Level I), DSM-IV, and DSM-5 criteria] to determine their applicability and impact on dementia frequency.Results: 93 participants with a mean age of 75.8 years (SD 6.8) and 16.5 years (SD 7.5) of disease duration were included. 64.3% were classified as demented using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria. We observed a high discrepancy on the frequency of dementia depending on the criteria applied [6.2% with MDS (Level I), 58.8% with DSM-IV, and 72.0% with DSM-5 criteria].Conclusions: We found a frequency of dementia below what was observed in similar populations. The particular characteristics of our sample may have contributed as protective factors for late-stage dementia. Dementia frequency varied depending on the criteria used mainly due to the presence of major depression.info:eu-repo/semantics/publishedVersio

High frequency of psychosis in late-stage Parkinsońs disease.

BACKGROUND: Psychosis is a frequent non-motor symptom in Parkinson's disease (PD). Estimates of the frequency of Parkinsońs disease psychosis (PDP) vary widely. Knowledge about the frequency and phenomenology of psychosis in late-stage (LS) PD patients is limited.This study aimed to determine the frequency of psychosis in LSPD patients through clinical diagnostic interview (CDI) (gold standard), according to NINDS/NIMH diagnostic criteria for PDP. The secondary objectives were to characterize the phenomenology, to test selected instruments and assess their adequacy in comparison to CDI, and to assess the psychiatric comorbidities. METHODS: A cross-sectional study including LSPD patients (patients with ≥ 7 years from symptoms onset and Hoehn and Yahr scale score > 3 or a Schwab and England scale score < 50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Each patient was interviewed by a psychiatrist who performed a CDI. RESULTS: 92 LSPD patients were included. 55.4% experienced psychotic symptoms according to NINDS/NIMH diagnostic criteria for PDP. Hallucinations were present in 94.1% and delusions in 29.4% of the psychotic patients. Visual hallucinations were the most common (88.23%) psychotic symptom. 72.5% of LSPD patients with psychotic symptoms had at least one comorbid psychiatric diagnosis. Lower frequency of psychosis was found when the assessment was performed only through selected instruments rather than CDI. CONCLUSIONS: A high frequency (55.4%) of psychotic symptoms and comorbid psychiatric (72.5%) diagnosis were found in LSPD patients. The use of CDI, in addition to structured scales may increase the sensitivity of detecting psychotic symptoms

Profile of cognitive impairment in late‐stage Parkinson's disease

© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Introduction: The profile of cognitive impairment associated with the late stages of Parkinson's disease (LSPD) is rarely reported. Its characterization is necessary to better understand the cognitive changes that occur as the disease progresses and to better contribute to its management. Methods: In this cross-sectional study, we characterized the cognitive profile of LSPD patients using the comprehensive assessment methodology proposed by the International Parkinson and Movement Disorders Society Task Force. The association of clinical and demographic variables with dementia diagnosis was also investigated using binary logistic regression analysis. Results: Eighty-four LSPD patients were included (age 75.4 ± 6.9; disease duration 16.9 ± 7.5). Fifty-four (64.3%) were classified as demented and presented a global impairment cognitive profile. In the nondemented group (N = 30), 25 (83.3%) LSPD patients met the diagnostic criteria for mild cognitive impairment, mostly with multiple domain impairment (96.0%) and a heterogeneous profile. Memory was the most frequent and severely impaired cognitive domain in both groups. Disease disability, orientation, complex order comprehension, verbal learning, and visuoconstructive abilities were significantly associated with dementia diagnosis (p < .05). Conclusions: Cognitive impairment in multiple domains was common in LSPD patients. The most frequent and prominent deficits were in the memory domain, with a strong interference from attention impairment. Disease disability, orientation, complex order comprehension, verbal learning, and visuoconstructive abilities proved to be important determinants for dementia diagnosis.This work was supported by a doctoral fellowship (SFRH/BD/139853/2018) from Fundação para a Ciência e Tecnologia, Portugal, which was assigned to Catarina Severiano e Sousa.info:eu-repo/semantics/publishedVersio

Response of non-motor symptoms to levodopa in late-stage Parkinson's disease: results of a levodopa challenge test

Article under a CC-BY-NC-ND license - https://creativecommons.org/licenses/by-nc-nd/4.0/"BACKGROUND: Non-motor symptoms (NMS) are extremely common among late-stage Parkinson's disease (LSPD) patients. Levodopa (L-dopa) responsiveness seems to decrease with disease progression but its effect on NMS in LSPD still needs to be investigated. OBJECTIVE: To assess the response of blood pressure (BP), pain, fatigue and anxiety to L-dopa in LSPD patients. METHODS: 20 LSPD patients, defined as Schwab and England ADL Scale 3 (MED ON) and 22 PD patients treated with subthalamic deep brain stimulation (advanced PD group) underwent an L-dopa challenge. BP and orthostatic hypotension (OH) assessment, a visual analogue scale (VAS) for pain and fatigue and the Strait Trait Anxiety (STAI) were evaluated before and after the L-dopa challenge. RESULTS: Systolic BP dropped significantly after L-dopa intake (p < 0.05) in LSPD patients, while there was no change in pain, fatigue or anxiety. L-dopa significantly improved (p < 0.05) pain and anxiety in the advanced PD group, whereas it had no effect on BP or fatigue. L-dopa-related adverse effects (AEs), namely OH and sleepiness, were more common among LSPD patients. 40% and 65% of LSPD patients were not able to fill out the VAS and the STAI, respectively, while measurement of orthostatic BP was not possible in four LSPD patients. CONCLUSIONS: This exploratory study concludes that some non-motor variables in LSPD do not benefit from the acute action of L-dopa while it can still induce disabling AEs. There is a need for assessment tools of NMS adapted to these disabled LSPD patients."info:eu-repo/semantics/publishedVersio

Motivos de exclusão para a cirurgia de estimulação cerebral profunda na doença de Parkinson

Abstract de comunicação apresentada no Congresso SPDMov 2022 - Parkinsonismos Atípicos: Clássicos e Atípicos. Luso, 1-2 Abril 2022N/

Rheology, spectroscopy and performance: all together towards drug product optimization

Tese de mestrado, Engenharia Farmacêutica, 2021, Universidade de Lisboa, Faculdade de Farmácia.A compressão direta é uma estratégia desejada na indústria farmacêutica, pois reduz o número de operações unitárias, o tempo de operação e aumenta a produtividade. No entanto, problemas com o escoamento e compressibilidade resultam na produção de comprimidos com propriedades fora das especificações. Este trabalho teve como objetivo o desenvolvimento de uma mistura de excipientes adequada para uso em formulações de compressão direta contendo elevadas frações de materiais com baixo escoamento. Foi proposta uma mistura quaternária composta por dois diluentes [lactose monohidratada (LAC) e celulose microcristalina (MCC)], um deslizante [sílica coloidal (CS)] e um lubrificante [estearato de magnésio (MgSt)]. Em primeiro lugar, avaliou-se o tempo ótimo de mistura de cada diluente com o lubrificante, de forma a evitar problemas de sobre-mistura. Em seguida, diferentes frações de CS e rácios de LAC:MCC foram analisadas e comparados. Posteriormente, dois compostos com baixo escoamento (hidroxipropilmetilcelulose obtida por secagem por atomização - HPMC SD - e indometacina - IND) foram adicionados à mistura para avaliar o impacto no seu escoamento e compressibilidade. HPMC SD e IND foram incorporados em formulações contendo diferentes rácios de LAC e MCC e com frações constantes de CS e MgSt, a 20% e 50% para as diferentes formulações. Devido ao comportamento diferente da energia de superfície de ambas as substâncias, o impacto dos fenómenos de superfície nas propriedades reológicas foi também avaliado. Os resultados indicaram que o escoamento de HPMC SD e IND melhorou significativamente, sendo este aumento mais evidente para formulações de HPMC SD. Este comportamento foi justificado com base na diferente morfologia das partículas e no comportamento de deposição do deslizante na superfície das partículas de ambos os materiais. A partir da energia específica (SE), comportamentos contrários foram obtidos para os dois compostos devido à diferente afinidade do MgSt para cobrir HPMC SD e IND. Usando uma análise de componentes principais, foi possível correlacionar a energia superficial das partículas com o comportamento reológico e com as características dos comprimidos. Por último, foi desenvolvido um modelo preditivo, utilizando uma regressão de mínimos quadrados parciais para antecipar a compressibilidade das misturas e reduzir o número de testes necessários. Em resumo, o trabalho permitiu o desenvolvimento de uma mistura quaternária possuindo um bom escoamento e compressibilidade que poderia ser usada para incorporar elevadas frações de materiais com baixo escoamento. Adicionalmente, foi possível correlacionar os fenómenos de superfície das partículas com as propriedades reológicas e o desempenho dos comprimidos.Direct compression of tablets is a desired technology used in the pharmaceutical industry as it reduces the number of unit operations, the time of operation and increases the overall productivity. However, flowability and compressibility related problems may result in the manufacture of tablets with properties out of specifications. This work aimed at the development of a blend of excipients suitable to be used in direct compression formulations containing high fractions of materials with poor flowability. A quaternary mixture composed by two diluents [lactose monohydrate (LAC) and microcrystalline cellulose (MCC)], one glidant [colloidal silica (CS)] and one lubricant [magnesium stearate (MgSt)] was proposed. Firstly, it was evaluated the blending time of each diluent with the lubricant, in order to avoid over-mixing problems. Then, different fractions of CS and LAC:MCC ratios were analyzed and compared. Thus, two poor flowable materials (spray-dried hydroxypropyl methylcellulose - HPMC SD – and indomethacin - IND) were added to the quaternary blend in order to evaluate the impact on their flowability and compressibility. HPMC SD and IND were incorporated in formulations containing different ratios of LAC and MCC and fixed contents of CS and MgSt, at 20% and 50% to the different formulations. Due to the different surface energy behavior of both substances, the impact of surface phenomena on the rheological properties of blends was also assessed. Finally, tablets were produced and characterized. Results indicated that the flowability of HPMC SD and IND improved significantly, being more evident for HPMC SD formulations. This behavior was justified based on the different particle morphology and the deposition behavior of the glidant on the surface of both materials’ particles. From specific energy (SE), contrary behaviors were obtained for the two compounds due to the different affinity of MgSt to cover HPMC SD and IND. Using a principal component analysis, it was possible to correlate the surface energy of particles in blends with their rheological behavior and with the performance of tablets. Lastly, a predictive model was developed, using a partial least square regression to anticipate the compressibility of blends and thus to reduce the number of tests required. In summary, the work conducted allowed the development of a quaternary mixture possessing good flowability and compressibility which could be suitably used to incorporate high fractions of poor flowable materials. Furthermore, it was possible to correlate the surface phenomena of particles with rheological measurements and the performance of tablets.Com o patrocínio da Empresa Hovione Farmaciencia SA

Pimavanserin for the treatment of Parkinson’s disease psychosis

© 2016 Informa UK Limited, trading as Taylor & Francis GroupIntroduction: Parkinson´s disease (PD) is a synucleinopathy that affects millions of people worldwide and leads to progressive disability. Psychosis is highly prevalent in PD patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP. Areas covered: A MEDLINE literature search, publicly available information provided by ACADIA Pharmaceuticals, and expert opinion were used for this review. A review of PDP, its current treatment and limitations is followed by the rationale for development of pimavanserin. The mechanism of action, preclinical data, pharmacokinetics, pharmacodynamics, and clinical data supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also describe the potential benefits of pimavanserin in other contexts such as schizophrenia and sleep disorders. Expert opinion: Pimavanserin is an antipsychotic with a unique mechanism of action (5-HT2A receptor inverse agonist) and no measurable dopaminergic activity; it has been demonstrated to be efficacious, well tolerated and safe for the treatment of PDP. The development of pimavanserin as an antipsychotic represents a major breakthrough in the pharmacotherapy of psychotic symptoms associated with PD.info:eu-repo/semantics/publishedVersio

Boletín meteorológico diario: Número 267 - 1980 Septiembre 23

Introduction: A growing body of evidence suggests that bipolar disorder (BD) is a progressive disease according to clinical, biochemical and neuroimaging findings. This study reviewed the literature on the relationship between specific biomarkers and BD stages. Methods: A comprehensive literature search of MEDLINE and PubMed was conducted to identify studies in English and Portuguese using the keywords biomarker, neurotrophic factors, inflammation, oxidative stress, neuroprogression and staging models cross-referenced with bipolar disorder. Results: Morphometric studies of patients with BD found neuroanatomic abnormalities, such as ventricular enlargement, grey matter loss in the hippocampus and cerebellum, volume decreases in the prefrontal cortex and variations in the size of the amygdala. Other studies demonstrated that serum concentrations of neurotrophic factors, inflammatory mediators and oxidative stress may be used as BD biomarkers. Conclusions: The analysis of neurobiological changes associated with BD progression and activity may confirm the existence of BD biomarkers, which may be then included in staging models that will lead to improvements in treatment algorithms and more effective, individually tailored treatment regimens. Biomarkers may also be used to define early interventions to control disease progression.Introdução: Níveis crescentes de evidência sugerem que o transtorno bipolar (TB) exibe um caráter progressivo, em nível tanto clínico, quanto bioquímico e neuroimagiológico. Este estudo revisa a literatura existente sobre a relação entre biomarcadores específicos e estágios do TB. Métodos: Uma busca extensa da literatura nas bases de dados MEDLINE e PubMed foi conduzida para identificar estudos publicados em inglês e em português utilizando as palavraschave biomarker (biomarcador), neurotrophic factors (fatores neurotróficos), inflammation (inflamação), oxidative stress (estresse oxidativo), neuroprogression (neuroprogressão) e staging models (modelos de estadiamento), em referência cruzada com o termo bipolar disorder (transtorno bipolar). Resultados: Estudos morfométricos em doentes bipolares mostraram a existência de alterações neuroanatômicas, tais como o alargamento dos ventrículos, a perda de substância cinzenta no hipocampo e no cerebelo, a diminuição do volume de determinadas áreas do córtex pré-frontal e variações no tamanho da amígdala. Além disso, outros estudos apontam para a potencialidade do uso dos valores séricos dos fatores neurotróficos, de mediadores inflamatórios e de estresse oxidativo como biomarcadores do TB. Conclusões: O conhecimento das alterações neurobiológicas, associadas à progressão e atividade do TB, é fundamental para a identificação de biomarcadores. A incorporação de biomarcadores nos modelos de estadiamento do TB poderá permitir um aperfeiçoamento dos algoritmos terapêuticos, possibilitando a elaboração de esquemas de tratamento mais personalizados e eficazes, com destaque para a importância da intervenção precoce na atenuação da progressão da doença