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1.
Biomedicines ; 10(9)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36140378

RESUMO

Parkinson's disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons.

2.
Molecules ; 27(7)2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35408484

RESUMO

Cell culturing methods in its classical 2D approach have limitations associated with altered cell morphology, gene expression patterns, migration, cell cycle and proliferation. Moreover, high throughput drug screening is mainly performed on 2D cell cultures which are physiologically far from proper cell functions resulting in inadequate hit-compounds which subsequently fail. A shift to 3D culturing protocols could solve issues with altered cell biochemistry and signaling which would lead to a proper recapitulation of physiological conditions in test systems. Here, we examined porous ultra-high molecular weight polyethylene (UHMWPE) as an inexpensive and robust material with varying pore sizes for cell culturing. We tested and developed culturing protocols for immortalized human neuroblastoma and primary mice hippocampal cells which resulted in high rate of cell penetration within one week of cultivation. UHMWPE was additionally functionalized with gelatin, poly-L-lysine, BSA and chitosan, resulting in increased cell penetrations of the material. We have also successfully traced GFP-tagged cells which were grown on a UHMWPE sample after one week from implantation into mice brain. Our findings highlight the importance of UHMWPE use as a 3D matrix and show new possibilities arising from the use of cheap and chemically homogeneous material for studying various types of cell-surface interactions further improving cell adhesion, viability and biocompatibility.


Assuntos
Técnicas de Cultura de Células , Polietilenos , Animais , Técnicas de Cultura de Células/métodos , Células Cultivadas , Camundongos , Peso Molecular , Polietileno/química , Polietilenos/química , Porosidade
3.
J Alzheimers Dis ; 81(4): 1429-1443, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935079

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. OBJECTIVE: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. METHODS: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1-359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. RESULTS: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. CONCLUSION: We suggest that revealed EEG modifications in ΔFUS(1-359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Apomorfina/farmacologia , Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Agonistas de Dopamina/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia
4.
Neurobiol Aging ; 91: 76-87, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224067

RESUMO

The etiology and pathogenesis of Parkinson's disease (PD) are tightly linked to the gain-of-function of α-synuclein. However, gradual accumulation of α-synuclein aggregates in dopaminergic neurons of substantia nigra pars compacta (SNpc) leads to the depletion of the functional pool of soluble α-synuclein, and therefore, creates loss-of-function conditions, particularly in presynaptic terminals of these neurons. Studies of how this late-onset depletion of a protein involved in many important steps of neurotransmission contributes to PD progression and particularly, to worsening the nigrostriatal pathology at late stages of the disease are limited and obtained data, are controversial. Recently, we produced a mouse line for conditional knockout of the gene encoding α-synuclein, and here we used its tamoxifen-inducible pan-neuronal inactivation to study consequences of the adult-onset (from the age of 6 months) and late-onset (from the age of 12 months) α-synuclein depletion to the nigrostriatal system. No significant changes of animal balance/coordination, the number of dopaminergic neurons in the SNpc and the content of dopamine and its metabolites in the striatum were observed after adult-onset α-synuclein depletion, but in aging (18-month-old) late-onset depleted mice we found a significant reduction of major dopamine metabolites without changes to the content of dopamine itself. Our data suggest that this might be caused, at least partially, by reduced expression of aldehyde dehydrogenase ALDH1a1 and could lead to the accumulation of toxic intermediates of dopamine catabolism. By extrapolating our findings to a potential clinical situation, we suggest that therapeutic downregulation of α-synuclein expression in PD patients is a generally safe option as it should not cause adverse side effects on the functionality of their nigrostriatal system. However, if started in aged patients, this type of therapy might trigger slight functional changes of the nigrostriatal system with potentially unwanted additive effect to already existing pathology.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Técnicas de Inativação de Genes , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Família Aldeído Desidrogenase 1/genética , Família Aldeído Desidrogenase 1/metabolismo , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Regulação para Baixo , Expressão Gênica/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Doença de Parkinson/terapia , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Transmissão Sináptica/genética
5.
Mol Neurobiol ; 57(1): 191-199, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31515692

RESUMO

A series of new positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors based on 3,7-diazabicyclo[3.3.1]nonane scaffold have been designed, synthesized, and analyzed. In electrophysiological patch clamp studies, several compounds have demonstrated a sub-nanomolar potency. Compound 4 in in vivo tests showed anti-amnestic properties in the scopolamine-induced model of amnesia in the step-through passive avoidance or maximal electroshock experiments in rats at 0.01 mg/kg showing a significant "dose-response" advantage over memantine. Based on the analysis of the flexible docking results of PAMs, the cyclothiazide-like mechanism of binding mode was suggested as the major site for the interaction with AMPA receptors.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Receptores de AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Benzotiadiazinas/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Masculino , Ratos Wistar
6.
J Alzheimers Dis ; 70(1): 241-256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31177214

RESUMO

Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer's disease (AD). 5xFAD mice, a transgenic model of AD, are characterized by an enhanced level of amyloid-ß and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-ß transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their frequency spectra were analyzed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta-theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development.


Assuntos
Doença de Alzheimer/patologia , Apomorfina/farmacologia , Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/patologia , Mesencéfalo/patologia , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Eletroencefalografia , Masculino , Mesencéfalo/fisiopatologia , Camundongos , Camundongos Transgênicos
7.
Curr Neuropharmacol ; 17(3): 288-294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30227819

RESUMO

Alzheimer's disease (AD) is characterized by the loss of neurons. It is the most common cause of dementia in the elderly population accompanied by pathological degeneration of neurofibrillary tangles. Senile plaques are formed with beta-amyloid, hyperphosphoryled tau protein, apolipoprotein E and presenilin associated with protease activity [amyloid beta (Aß), gamma-secretase (γS)]. The molecular mechanisms of neurodegeneration include apoptosis, oxidative stress (free radical generation), inflammation, immune activation, and others. The lack of effective treatments for AD stems mainly from the incomplete understanding the causes of AD. Currently, there are several hypotheses explaining the early mechanisms of AD pathogenesis. Recent years witnessed an unprecedented research growth in the area of nanotechnology, which uses atomic, molecular and macromolecular methods to create products in microscale (nanoscale) dimensions. In this article, we have discussed the role of nanotechnology in the development and improvement of techniques for early diagnosis and effective treatment of AD. Since AD pathology is practically irreversible, applications of disease-modifying treatments could be successful only if early diagnosis of AD is available. This review highlights various possibilities for the early diagnosis and therapy of AD and investigates potential adaptation of nanoparticles-dendrimers as a class of well-defined branched polymers that are chemically synthesized with a well-defined shape, size and nanoscopic physicochemical properties reminiscent of the proteins for the treatment of neurodegenerative diseases.


Assuntos
Doença de Alzheimer/terapia , Antipsicóticos/uso terapêutico , Dendrímeros/uso terapêutico , Animais , Dendrímeros/química , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico
8.
CNS Neurol Disord Drug Targets ; 17(8): 604-607, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30047337

RESUMO

BACKGROUND: It was previously shown that inactivation of gamma-synuclein which is a small soluble neuronal protein affects psycho-emotional status and cognitive abilities in knock-out mice. OBJECTIVE: Determine the role of gamma-synuclein inactivation on memory performance in aging animals. METHOD: We used the passive avoidance test and acute amphetamine administration in aging gammasynuclein knock-out mice. RESULTS: As a result, we found moderate aging-unlinked deficit of dopaminergic neurotransmitter system of gamma-synuclein knock-out mice. At the same time, the evidence of progressive synaptic vesicle trafficking machinery impairment was obtained. CONCLUSION: Therefore most likely these dysfunctions are associated with a reduction in the highefficient learning performance in tests that require intact working memory.


Assuntos
Envelhecimento/genética , Dopamina/metabolismo , Transtornos da Memória/genética , Memória de Curto Prazo/fisiologia , gama-Sinucleína/deficiência , Anfetamina/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , gama-Sinucleína/genética
9.
Neurogenetics ; 19(3): 189-204, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29982879

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS (fused in sarcoma) and TDP-43, implicated in RNA metabolism. Herein, we performed a comprehensive analysis of the in vivo model of FUS-mediated proteinopathy (ΔFUS(1-359) mice). First, we used the Noldus CatWalk system and confocal microscopy to determine the time of onset of the first clinical symptoms and the appearance of FUS-positive inclusions in the cytoplasm of neuronal cells. Second, we applied RNA-seq to evaluate changes in the gene expression profile encompassing the pre-symptomatic and the symptomatic stages of disease progression in motor neurons and the surrounding microglia of the spinal cord. The resulting data show that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and the molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). After this time, the pathological process develops very rapidly, resulting in the formation of massive FUS-positive inclusions accompanied by a transcriptional "burst" in the spinal cord cells. Specifically, it manifests in activation of a pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that the highly reproducible course of the pathological process, as well as the described accompanying features, makes ΔFUS(1-359) mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Modelos Animais de Doenças , Camundongos Transgênicos , Proteína FUS de Ligação a RNA/genética , Animais , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Camundongos , Neurônios Motores/fisiologia , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/patologia , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/patologia
10.
Med Res Rev ; 37(5): 1186-1225, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28084618

RESUMO

Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity¼ database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents") - these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ensaios Clínicos como Assunto , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Descoberta de Drogas , Humanos
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