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State of Art in Non-Clinical Models for Neurodegenerative Diseases

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A special issue of Behavioral Sciences (ISSN 2076-328X).

Deadline for manuscript submissions: closed (30 November 2017) | Viewed by 75823

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Special Issue Editors

Dr. Caridad Ivette Fernandez Verdecia

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Guest Editor

International Center of Neurological Restoration (CIREN), Basic Division, La Habana, Cuba
Interests: Translational processes in neurodegenerative diseases, particularly, Alzheimer disease and mild cognitive impairment and age-related cognitive disabilities; evaluation of new drugs/nonconventional therapies and life style modifiers to restore neurodisabilities and improve quality of life; neurological restoration as a multifactorial therapeutic approach
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Dr. Tangui Maurice

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Guest Editor

INSERM UMR-S1198, University of Montpellier, CEDEX 5, 34095 Montpellier, France
Interests: sigma-1 receptor; neuroprotection; neurodegenerative diseases; Alzheimer; butyrylcholinesterase; learning and memory; brain plasticity; animal behavior
Special Issues, Collections and Topics in MDPI journals

Dr. Isaac G. Onyango

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Guest Editor

Gencia Biotech Corporation, 706 Suite B Forest St. Charlottesville, VA 22903, USA
Interests: signal transduction; growth factors; cell death mechanisms and modulation of mitochondrial biogenesis in human aging and metabolic diseases

Special Issue Information

Dear Colleagues:

The International Congress “Non-Clinical Models for Neurodegenerative Diseases” (21–24 June, 2017, in Laguna Azul Hotel, in Varadero, Cuba) together with cutting-edge information on molecular mechanisms and non-clinical models, will cover a sequence that goes from basic science to clinical proof of concept. The workshop on challenges and requirements for translational medicine (bench to bedside) completes the aim of beginning the walk within a multidisciplinary environment as a way of reducing the “valley of death” in neurodegenerative diseases.

Main Objectives:

• Identifying cutting edge advances in molecular mechanisms of neurodegeneration and development of non-clinical models for these diseases
• Promoting the exchange of experiences, presentation and discussion of results from basic research to clinical proof of concept.
• Contributing to incorporate harmonized criteria for Laboratory Animal Science, Animal Welfare and Quality Assurance in the care and use of experimental animals, experimental design and interpretation of results.
• Promoting networking and collaborative projects between Cuba and other countries

Dr. Caridad Ivette Fernandez Verdecia
Dr. Tangui Maurice
Dr. Isaac G. Onyango
Guest Editors

Manuscript Submission Information

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Keywords

Neurodegenerative diseases
Nonclinical models
Translational medicine
Care and use of experimental animals

Published Papers (12 papers)

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Research

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13 pages, 1977 KiB

Open AccessFeature PaperArticle

by Dasha Fuentes, Nidia Fernández, Yenela García, Teidy García, Ana Ruth Morales and Roberto Menéndez

Behav. Sci. 2018, 8(3), 33; https://doi.org/10.3390/bs8030033 - 03 Mar 2018

Cited by 32 | Viewed by 5745

Abstract

The knockout mouse model, B6.129P2-Apoe^tm1Unc is homozygotic for the Apolipoprotein E (ApoE) deletion; thus, it is capable of developing hyperlipidemia and atherosclerosis but ApoE is also a lipid-transport protein abundantly expressed in most neurons in the central nervous system, so these animals could also be models of neurodegenerative diseases. The aim of this study was to determine age-related changes in spontaneous behavior and in learning and memory of Apolipoprotein E knockout mice. Spontaneous behavioral measurements included sleeping pattern, motor coordination and balance by rotarod and open field activity, whereas learning and memory tests included forced alternation in Y-maze, novel object recognition and passive avoidance conditioning. Significant behavioral differences between aged knockout mice and age-matched wild type strain, C57Bl/6 were found in all the behavioral tests, except for the rotarod test. Genetically’ modified mice exhibited less huddling contact during sleeping, decreased locomotor activity in novel environments and in learning and memory deficits. These results are consistent with the cognitive impairment and memory loss seen as the earliest clinical symptoms in neurodegenerative disorders such as Alzheimer’s disease. The ApoE knockout mice might therefore be an appropriate model for studying the underlying mechanisms involved in behavioral changes caused by neurodegenerative diseases as well as for evaluating new therapies for these pathologies. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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11 pages, 2272 KiB

Open AccessFeature PaperArticle

Neuroprotective Effects of neuroEPO Using an In Vitro Model of Stroke

by Garzón Fernando, Rodríguez Yamila, García Julio Cesar and Rama Ramón

Behav. Sci. 2018, 8(2), 26; https://doi.org/10.3390/bs8020026 - 13 Feb 2018

Cited by 23 | Viewed by 5724

Abstract

Erythropoietin (EPO) is a glycoprotein initially identified as a hormone synthesized and secreted by the kidney that regulates erythropoiesis. EPO, and a group of its derivatives, are being evaluated as possible neuroprotective agents in cerebral ischemia. The objective of this study, using an in vitro model, was to determine how neuroEPO—which is a variant of EPO with a low sialic acid content—protects neurons from the toxic action of glutamate. Primary neuronal cultures were obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a medium containing 100 µM glutamate for 15 min. After this time, a new medium containing 100 ng of neuroEPO/mL was added. Morphological cell change was assessed by phase-contrast microscopy. Oxidative stress was analysed by measuring antioxidant and oxidant activity. After 24 h, the treatment with 100 ng of neuroEPO/mL showed a significant (p < 0.01) decrease in mortality, compared to cells treated with glutamate alone. neuroEPO treatment decreased mortality and tended to reproduce the morphological characteristics of the control. The oxidative stress induced by glutamate is reduced after neuroEPO treatment. These results confirm that neuroEPO has a protective effect against neuronal damage induced by excitotoxicity, improving antioxidant activity in the neuron, and protecting it from oxidative stress. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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13 pages, 3142 KiB

Open AccessFeature PaperArticle

Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion

by Lisette Blanco-Lezcano, Esteban Alberti-Amador, Mei-Li Díaz-Hung, María Elena González-Fraguela, Bárbara Estupiñán-Díaz, Teresa Serrano-Sánchez, Liliana Francis-Turner, Javier Jiménez-Martín, Yamilé Vega-Hurtado and Isabel Fernández-Jiménez

Behav. Sci. 2018, 8(2), 20; https://doi.org/10.3390/bs8020020 - 01 Feb 2018

Cited by 6 | Viewed by 5202

Abstract

Background: The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson’s disease (PD). Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. Methods: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats. Results: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01). DAT mRNA expression showed a significant decrease (p < 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. Conclusions: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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10 pages, 2007 KiB

Open AccessArticle

Comparison of the Response of Male BALB/c and C57BL/6 Mice in Behavioral Tasks to Evaluate Cognitive Function

by Yenela Garcia and Nashelly Esquivel

Behav. Sci. 2018, 8(1), 14; https://doi.org/10.3390/bs8010014 - 18 Jan 2018

Cited by 17 | Viewed by 9232

Abstract

To evaluate several cognitive parameters during the execution of behavioral tasks assessing cognitive function in laboratory animals, the parameters are reported within a range. This situation entails that each laboratory must establish the conditions under which the behavioral task to evaluate the cognitive function can be carried out. C57BL/6 and BALB/c inbred strains are used more often in behavioral studies relating to anxiety, stress, fear and cognitive function. The aim of this work was to compare the behavioral response of mice of the strains BALB/c and C57BL/6 to evaluate memory and learning as cognitive functions. Young male mice, 7–8 weeks of age, from each strain were used. Y maze, object recognition and passive avoidance tasks were performed. Both strains of mice showed differences in the response to the passive avoidance and Y maze task. This study advances knowledge about the baseline behavior of laboratory mice strains and their response during the experimental procedures, which are due to the treatment, genetic influence, procedural differences, genetic background variance, or any combination of these elements. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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1148 KiB

Open AccessArticle

Effectiveness of a Computer-Based Training Program of Attention and Memory in Patients with Acquired Brain Damage

by Elizabeth Fernandez, Jorge A. Bergado Rosado, Daymi Rodriguez Perez, Sonia Salazar Santana, Maydane Torres Aguilar and Maria Luisa Bringas

Behav. Sci. 2018, 8(1), 4; https://doi.org/10.3390/bs8010004 - 30 Dec 2017

Cited by 15 | Viewed by 8249

Abstract

Many training programs have been designed using modern software to restore the impaired cognitive functions in patients with acquired brain damage (ABD). The objective of this study was to evaluate the effectiveness of a computer-based training program of attention and memory in patients with ABD, using a two-armed parallel group design, where the experimental group (n = 50) received cognitive stimulation using RehaCom software, and the control group (n = 30) received the standard cognitive stimulation (non-computerized) for eight weeks. In order to assess the possible cognitive changes after the treatment, a post-pre experimental design was employed using the following neuropsychological tests: Wechsler Memory Scale (WMS) and Trail Making test A and B. The effectiveness of the training procedure was statistically significant (p < 0.05) when it established the comparison between the performance in these scales, before and after the training period, in each patient and between the two groups. The training group had statistically significant (p < 0.001) changes in focused attention (Trail A), two subtests (digit span and logical memory), and the overall score of WMS. Finally, we discuss the advantages of computerized training rehabilitation and further directions of this line of work. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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Review

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14 pages, 330 KiB

Open AccessReview

What We Know About the Brain Structure–Function Relationship

by Karla Batista-García-Ramó and Caridad Ivette Fernández-Verdecia

Behav. Sci. 2018, 8(4), 39; https://doi.org/10.3390/bs8040039 - 18 Apr 2018

Cited by 79 | Viewed by 9956

Abstract

How the human brain works is still a question, as is its implication with brain architecture: the non-trivial structure–function relationship. The main hypothesis is that the anatomic architecture conditions, but does not determine, the neural network dynamic. The functional connectivity cannot be explained only considering the anatomical substrate. This involves complex and controversial aspects of the neuroscience field and that the methods and methodologies to obtain structural and functional connectivity are not always rigorously applied. The goal of the present article is to discuss about the progress made to elucidate the structure–function relationship of the Central Nervous System, particularly at the brain level, based on results from human and animal studies. The current novel systems and neuroimaging techniques with high resolutive physio-structural capacity have brought about the development of an integral framework of different structural and morphometric tools such as image processing, computational modeling and graph theory. Different laboratories have contributed with in vivo, in vitro and computational/mathematical models to study the intrinsic neural activity patterns based on anatomical connections. We conclude that multi-modal techniques of neuroimaging are required such as an improvement on methodologies for obtaining structural and functional connectivity. Even though simulations of the intrinsic neural activity based on anatomical connectivity can reproduce much of the observed patterns of empirical functional connectivity, future models should be multifactorial to elucidate multi-scale relationships and to infer disorder mechanisms. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

17 pages, 2081 KiB

Open AccessReview

C-Phycocyanin and Phycocyanobilin as Remyelination Therapies for Enhancing Recovery in Multiple Sclerosis and Ischemic Stroke: A Preclinical Perspective

by Giselle Pentón-Rol, Javier Marín-Prida and Viviana Falcón-Cama

Behav. Sci. 2018, 8(1), 15; https://doi.org/10.3390/bs8010015 - 18 Jan 2018

Cited by 30 | Viewed by 8522

Abstract

Myelin loss has a crucial impact on behavior disabilities associated to Multiple Sclerosis (MS) and Ischemic Stroke (IS). Although several MS therapies are approved, none of them promote remyelination in patients, limiting their ability for chronic recovery. With no available therapeutic options, enhanced demyelination in stroke survivors is correlated with a poorer behavioral recovery. Here, we show the experimental findings of our group and others supporting the remyelinating effects of C-Phycocyanin (C-PC), the main biliprotein of Spirulina platensis and its linked tetrapyrrole Phycocyanobilin (PCB), in models of these illnesses. C-PC promoted white matter regeneration in rats and mice affected by experimental autoimmune encephalomyelitis. Electron microscopy analysis in cerebral cortex from ischemic rats revealed a potent remyelinating action of PCB treatment after stroke. Among others biological processes, we discussed the role of regulatory T cell induction, the control of oxidative stress and pro-inflammatory mediators, gene expression modulation and COX-2 inhibition as potential mechanisms involved in the C-PC and PCB effects on the recruitment, differentiation and maturation of oligodendrocyte precursor cells in demyelinated lesions. The assembled evidence supports the implementation of clinical trials to demonstrate the recovery effects of C-PC and PCB in these diseases. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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Other

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7 pages, 191 KiB

Open AccessFeature PaperConference Report

Non-Clinical Contribution to Clinical Trials during Lead Optimization Phase

by Lázara Martínez Muñoz

Behav. Sci. 2018, 8(1), 17; https://doi.org/10.3390/bs8010017 - 24 Jan 2018

Viewed by 4265

Abstract

This manuscript comments on guidelines related to requirements for clinical trials for new drugs and the importance of considering regulatory criteria in the planning phase, in order to enhance the utility of data generated in basic research. Suggestions are made for optimizing regulatory [...] Read more.

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

11 pages, 219 KiB

Open AccessFeature PaperConference Report

Report on the Symposium “Molecular Mechanisms Involved in Neurodegeneration”

by Giselle Pentón-Rol and Majel Cervantes-Llanos

Behav. Sci. 2018, 8(1), 16; https://doi.org/10.3390/bs8010016 - 18 Jan 2018

Cited by 9 | Viewed by 4578

Abstract

The prevalence of neurodegenerative diseases is currently a major concern in public health because of the lack of neuroprotective and neuroregenerative drugs. The symposium on Molecular Mechanisms Involved in Neurodegeneration held in Varadero, Cuba, updated the participants on the basic mechanisms of neurodegeneration, on the different approaches for drug discovery, and on early research results on therapeutic approaches for the treatment of neurodegenerative diseases. Alzheimer’s disease and in silico research were covered by many of the presentations in the symposium, under the umbrella of the “State of the Art of Non-clinical Models for Neurodegenerative Diseases” International Congress, held from 20 to 24 June 2017. This paper summarizes the highlights of the symposium. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

212 KiB

Open AccessPerspective

Non-Clinical Models for Neurodegenerative Diseases: Therapeutic Approach and Drug Validation in Animal Models

by Caridad Ivette Fernandez, Jessica López and Lázara Martinez

Behav. Sci. 2017, 7(4), 82; https://doi.org/10.3390/bs7040082 - 07 Dec 2017

Cited by 3 | Viewed by 4980

Abstract

In 2016, 19.8% of the Cuban population was aged 60 or over. As a result, age-associated degenerative diseases and other diseases have become priority targets from a prophylactic, diagnostic and therapeutic perspective. As a result, the Cuban biomedical scientific community has addressed its basic, preclinical and epidemiological research in order to rise up to the challenge. A firm step in this direction has been the international congress “State of the art in non-clinical models for neurodegenerative diseases” which has brought together preclinical and clinical researchers, technicians and regulatory staff members from different countries to review the state of the art in neurodegenerations, find unifying ideas, objectives and collaborations or partnership. The objective is to expose the perspectives of new biotechnological products from Cuba and other countries from the diagnostic, therapeutic and neuroprotective point of view. It is crucial, therefore, that the irreplaceable role of laboratory animals in achieving these objectives is understood but they must be used in rational, adequate and ethical manner. We expose the current development trends in this field, being of common interest to the work directed to the search for potential drugs, diagnostic tools and the promotion of changes in lifestyle as a preventive projection. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

135 KiB

Open AccessOpinion

Creating a World-Class Program through Training and Certification

by Ann Turner

Behav. Sci. 2017, 7(4), 78; https://doi.org/10.3390/bs7040078 - 16 Nov 2017

Cited by 1 | Viewed by 4407

Abstract

The animal research field has gotten more sophisticated with the use of genetically engineered animals, biohazardous agents, and advanced technologies. Trained and competent personnel are a cornerstone of any animal care and use program. Individual career success is a combination of education, experience, continuing competence, professional development, and personal commitment. Integration of training and certification into programs demonstrate institutional commitment to quality research and enhance the program by providing staff with knowledge and training to address problems and situation that arise and to perform their job in a professional and effective manner. Professional development programs offered through the American Association for Laboratory Animal Science—including the AALAS Learning Library and the AALAS certification process—will be presented. Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

146 KiB

Open AccessFeature PaperPerspective

Perspectives on the Role of Professional Laboratory Animal Science Associations

by Ann Tourigny Turner, Ekaterina Botovchenco Rivera and Cynthia Pekow

Behav. Sci. 2017, 7(4), 73; https://doi.org/10.3390/bs7040073 - 23 Oct 2017

Viewed by 4270

Abstract

The three authors of this letter had the honor and pleasure of being invited to the international meeting “Laboratory Animal Science, Moving Forward Together: State of the Art in Non-Clinical Models for Neurodegenerative Diseases”, held in Varadero, Cuba, 21–24 June 2017.[...] Full article

(This article belongs to the Special Issue State of Art in Non-Clinical Models for Neurodegenerative Diseases)

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