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State-of-the-Art Neurobiology and Neurologic Disease in Portugal

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 27752

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Dr. Cristina Carvalho

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Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal
Interests: Alzheimer’s disease; mitochondrial dysfunction; cell (dys)metabolism; type 2 diabetes
Special Issues, Collections and Topics in MDPI journals

Dr. Sónia Catarina Correia

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Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
Interests: Alzheimer’s disease; mitochondria; brain tolerance; hypoxia
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Dr. Susana Cardoso

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Guest Editor

Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
Interests: diabetes; Alzheimer’s disease; mental disorders; mitochondria; oxidative stress; uncoupling proteins; brain metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic non-communicable neurologic diseases, known to affect the central and the peripheral nervous system, represent the leading cause of disability and the second-leading cause of mortality worldwide.

Portugal has a long reputation in the study of neurological and behavioral disorders. Going back to the pioneer work of Egas Moniz, the developer of cerebral angiography and one of the founders of modern psychosurgery, to the renowned neuroscientist António Damásio, who pursued the understanding of the boundaries between the mind and the brain, currently, there are several Portuguese physicians and researchers committed to improving the neurocognitive and neuropsychological profile of the individual in different contexts and phases of life.

Importantly, the natural history of neurobiology and neurologic diseases in Portugal is marked by the occurrence of two rare hereditary disorders, the transthyretin familial amyloid polyneuropathy with endemic populations predominantly in the north of Portugal and Machado–Joseph disease with a high prevalence in the islands of Azores.

This Special Issue is intended to honor the pioneering achievements made by Portuguese physicians in the neurology field and to present the scientific developments in epidemiology, diagnosis, and treatment of neurologic diseases in Portugal.

Dr. Cristina Carvalho
Dr. Sónia Catarina Correia
Dr. Susana Cardoso
Guest Editors

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Research

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12 pages, 3569 KiB

Open AccessArticle

Learning the Biochemical Basis of Axonal Guidance: Using Caenorhabditis elegans as a Model

by Andreia Teixeira-Castro, João Carlos Sousa, Cármen Vieira, Joana Pereira-Sousa, Daniela Vilasboas-Campos, Fernanda Marques, Perpétua Pinto-do-Ó and Patrícia Maciel

Biomedicines 2023, 11(6), 1731; https://doi.org/10.3390/biomedicines11061731 - 16 Jun 2023

Viewed by 1468

Abstract

Aim: Experimental models are a powerful aid in visualizing molecular phenomena. This work reports how the worm Caenorhabditis elegans (C. elegans) can be effectively explored for students to learn how molecular cues dramatically condition axonal guidance and define nervous system structure and behavior at the organism level. Summary of work: A loosely oriented observational activity preceded detailed discussions on molecules implied in axonal migration. C. elegans mutants were used to introduce second-year medical students to the deleterious effects of gene malfunctioning in neuron response to extracellular biochemical cues and to establish links between molecular function, nervous system structure, and animal behavior. Students observed C. elegans cultures and associated animal behavior alterations with the lack of function of specific axon guidance molecules (the soluble cue netrin/UNC-6 or two receptors, DCC/UNC-40 and UNC-5H). Microscopical observations of these strains, in combination with pan-neuronal GFP expression, allowed optimal visualization of severely affected neurons. Once the list of mutated genes in each strain was displayed, students could also relate abnormal patterns in axon migration/ventral and dorsal nerve cord neuron formation in C. elegans with mutated molecular components homologous to those in humans. Summary of results: Students rated the importance and effectiveness of the activity very highly. Ninety-three percent found it helpful to grasp human axonal migration, and all students were surprised with the power of the model in helping to visualize the phenomenon. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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22 pages, 8310 KiB

Open AccessArticle

Repurposed Edaravone, Metformin, and Perampanel as a Potential Treatment for Hypoxia–Ischemia Encephalopathy: An In Vitro Study

by Daniela Silva, Ruben Rocha, Ana Salomé Correia, Bárbara Mota, Maria Dulce Madeira, Nuno Vale and Armando Cardoso

Biomedicines 2022, 10(12), 3043; https://doi.org/10.3390/biomedicines10123043 - 25 Nov 2022

Cited by 7 | Viewed by 1664

Abstract

Hypoxia–ischemia encephalopathy results from the interruption of oxygen delivery and blood flow to the brain. In the developing brain, it can lead to a brain injury, which is associated with high mortality rates and comorbidities. The hippocampus is one of the brain regions that may be affected by hypoxia–ischemia with consequences on cognition. Unfortunately, clinically approved therapeutics are still scarce and limited. Therefore, in this study, we aimed to test three repurposed drugs with good pharmacological properties to evaluate if they can revert, or at least attenuate, the deleterious effects of hypoxia–ischemia in an in vitro model. Edaravone, perampanel, and metformin are used for the treatment of stroke and amyotrophic lateral sclerosis, some forms of epileptic status, and diabetes type 2, respectively. Through cell viability assays, morphology analysis, and detection of reactive oxygen species (ROS) production, in two different cell lines (HT-22 and SH-SY5Y), we found that edaravone and low concentrations of perampanel are able to attenuate cell damage induced by hypoxia and oxygen-glucose deprivation. Metformin did not attenuate hypoxic-induced events, at least in the initial phase. Among these repurposed drugs, edaravone emerged as the most efficient in the attenuation of events induced by hypoxia–ischemia, and the safest, since it did not exhibit significant cytotoxicity, even in high concentrations, and induced a decrease in ROS. Our results also reinforce the view that ROS and overexcitation play an important role in the pathophysiology of hypoxia–ischemia brain injury. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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14 pages, 1645 KiB

Open AccessArticle

Clinical Application of Pharmacokinetics to Appraise Adherence to Levetiracetam in Portuguese Epileptic Patients

by Rui Silva, Joana Bicker, Anabela Almeida, Andreia Carona, Ana Silva, Francisco Sales, Isabel Santana, Amílcar Falcão and Ana Fortuna

Biomedicines 2022, 10(9), 2127; https://doi.org/10.3390/biomedicines10092127 - 30 Aug 2022

Cited by 1 | Viewed by 1592

Abstract

Adherence to antiseizure drug treatment determines its effectiveness and safety, and consequently affects patients’ quality of life. Herein, we assessed adherence to levetiracetam in Portuguese patients with refractory epilepsy (n = 115), with resort to a pharmacokinetic drug monitoring approach. The pharmacokinetic parameters of levetiracetam in each patient were determined in steady-state while admitted to the hospital. Then, adherence was assessed by comparing the plasma concentration of the drug observed on the first day of hospitalization with the predicted plasma concentration, considering previously determined pharmacokinetic parameters. The rate of adherence was assessed according to gender, age, diagnosis, and antiseizure drug regimen. Among 115 enrolled patients, 49 (42.6%) were identified as non-adherent, 30 (26.1%) classified as under-consumers, and 19 (16.5%) as over-consumers. A relationship between adherence, daily dose and plasma concentrations was herein reported for the first time. Adherent patients received higher daily doses of levetiracetam [2500 (2000–3000) mg] than non-adherent over-consumers [1500 (1000–2000) mg] and non-adherent under-consumers [2000 (1500–3000) mg]. Higher average steady-state plasma concentrations of levetiracetam were found in non-adherent under-consumers [27.28 (15.33–36.36) mg/L], followed by adherent patients [22.05 (16.62–29.81) mg/L] and non-adherent over-consumers [17.50 (10.69–24.37) mg/L]. This study demonstrates that adherence (or lack thereof) influences the plasma concentrations of levetiracetam in steady-state and its pharmacological effects. Moreover, it emphasizes the importance of educating patients to encourage adherence to therapy. Otherwise, the risk of developing toxic and subtherapeutic concentrations is undeniable, compromising the therapeutic effect and safety of treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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17 pages, 3699 KiB

Open AccessArticle

Generation and Characterization of Novel iPSC Lines from a Portuguese Family Bearing Heterozygous and Homozygous GRN Mutations

by Ana Rafaela Oliveira, Solange Martins, Giuseppe Cammarata, Mariana Martins, Ana Maria Cardoso, Maria Rosário Almeida, Maria do Carmo Macário, Isabel Santana, João Peça and Ana Luísa Cardoso

Biomedicines 2022, 10(8), 1905; https://doi.org/10.3390/biomedicines10081905 - 6 Aug 2022

Cited by 1 | Viewed by 2142

Abstract

Mutations in granulin (GRN) have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, GRN mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous GRN mutation. hiPSCs were reprogrammed from human dermal fibroblasts by episomal nucleofection of the Yamanaka factors. The new generated lines were positive for pluripotency markers, could be further differentiated to cells expressing all trilineage markers, and presented a normal karyotype. They were also capable of differentiating into 3D brain organoids and presented a significant decrease in progranulin protein levels. Hence, these cell lines constitute suitable new tools to elucidate the pathophysiological mechanisms associated with the GRN mutations in the context of FTLD. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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24 pages, 22490 KiB

Open AccessArticle

Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D₂ and Serotonin 1A and 2A Receptors in C. elegans

by Ana Jalles, Cármen Vieira, Joana Pereira-Sousa, Daniela Vilasboas-Campos, Ana Francisca Mota, Sara Vasconcelos, Bruna Ferreira-Lomba, Marta Daniela Costa, Jorge Diogo Da Silva, Patrícia Maciel and Andreia Teixeira-Castro

Biomedicines 2022, 10(2), 370; https://doi.org/10.3390/biomedicines10020370 - 3 Feb 2022

Cited by 5 | Viewed by 3170

Abstract

The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D₂-like and serotonin 5-HT_1A and 5-HT_2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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27 pages, 14269 KiB

Open AccessArticle

Profiling Microglia in a Mouse Model of Machado–Joseph Disease

by Ana Bela Campos, Sara Duarte-Silva, Bruno Fernandes, Sofia Pereira das Neves, Fernanda Marques, Andreia Teixeira-Castro, Andreia Neves-Carvalho, Daniela Monteiro-Fernandes, Camila Cabral Portugal, Renato Socodato, Teresa Summavielle, António Francisco Ambrósio, João Bettencourt Relvas and Patrícia Maciel

Biomedicines 2022, 10(2), 237; https://doi.org/10.3390/biomedicines10020237 - 23 Jan 2022

Cited by 5 | Viewed by 4109

Abstract

Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado–Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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19 pages, 3025 KiB

Open AccessArticle

Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3

by Joana Sofia Correia, Andreia Neves-Carvalho, Bárbara Mendes-Pinheiro, Joel Pires, Fábio Gabriel Teixeira, Rui Lima, Susana Monteiro, Nuno André Silva, Carina Soares-Cunha, Sofia Cravino Serra, Sara Duarte-Silva, Andreia Teixeira-Castro, António José Salgado and Patrícia Maciel

Biomedicines 2021, 9(12), 1754; https://doi.org/10.3390/biomedicines9121754 - 24 Nov 2021

Cited by 6 | Viewed by 2796

Abstract

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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Review

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16 pages, 2013 KiB

Open AccessReview

The Homogeneous Azorean Machado-Joseph Disease Cohort: Characterization and Contributions to Advances in Research

by Manuela Lima, Mafalda Raposo, Ana Ferreira, Ana Rosa Vieira Melo, Sara Pavão, Filipa Medeiros, Luís Teves, Carlos Gonzalez, João Lemos, Paula Pires, Pedro Lopes, David Valverde, José Gonzalez, Teresa Kay and João Vasconcelos

Biomedicines 2023, 11(2), 247; https://doi.org/10.3390/biomedicines11020247 - 18 Jan 2023

Cited by 1 | Viewed by 2302

Abstract

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia worldwide. MJD is characterized by late-onset progressive cerebellar ataxia associated with variable clinical findings, including pyramidal signs and a dystonic-rigid extrapyramidal syndrome. In the Portuguese archipelago of the Azores, the worldwide population cluster for this disorder (prevalence of 39 in 100,000 inhabitants), a cohort of MJD mutation carriers belonging to extensively studied pedigrees has been followed since the late 1990s. Studies of the homogeneous Azorean MJD cohort have been contributing crucial information to the natural history of this disease as well as allowing the identification of novel molecular biomarkers. Moreover, as interventional studies for this globally rare and yet untreatable disease are emerging, this cohort should be even more important for the recruitment of trial participants. In this paper, we profile the Azorean cohort of MJD carriers, constituted at baseline by 20 pre-ataxic carriers and 52 patients, which currently integrates the European spinocerebellar ataxia type 3/Machado-Joseph disease Initiative (ESMI), a large European longitudinal MJD cohort. Moreover, we summarize the main studies based on this cohort and highlight the contributions made to advances in MJD research. Knowledge of the profile of the Azorean MJD cohort is not only important in the context of emergent interventional trials but is also pertinent for the implementation of adequate interventional measures, constituting relevant information for Lay Associations and providing data to guide healthcare decision makers. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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23 pages, 3600 KiB

Open AccessReview

Ischemic Stroke, Lessons from the Past towards Effective Preclinical Models

by Beatriz Amado, Lúcia Melo, Raquel Pinto, Andrea Lobo, Pedro Barros and João R. Gomes

Biomedicines 2022, 10(10), 2561; https://doi.org/10.3390/biomedicines10102561 - 13 Oct 2022

Cited by 4 | Viewed by 7147

Abstract

Ischemic stroke is a leading cause of death worldwide, mainly in western countries. So far, approved therapies rely on reperfusion of the affected brain area, by intravenous thrombolysis or mechanical thrombectomy. The last approach constitutes a breakthrough in the field, by extending the therapeutic window to 16–24 h after stroke onset and reducing stroke mortality. The combination of pharmacological brain-protective strategies with reperfusion is the future of stroke therapy, aiming to reduce brain cell death and decrease patients’ disabilities. Recently, a brain-protective drug—nerinetide—reduced brain infarct and stroke mortality, and improved patients’ functional outcomes in clinical trials. The success of new therapies relies on bringing preclinical studies and clinical practice close together, by including a functional outcome assessment similar to clinical reality. In this review, we focused on recent upgrades of in vitro and in vivo stroke models for more accurate and effective evaluation of therapeutic strategies: from spheroids to organoids, in vitro models that include all brain cell types and allow high throughput drug screening, to advancements in in vivo preclinical mouse stroke models to mimic the clinical reality in surgical procedures, postsurgical care, and functional assessment. Full article

(This article belongs to the Special Issue State-of-the-Art Neurobiology and Neurologic Disease in Portugal)

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