Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.500
Filtrar
1.
Curr Top Med Chem ; 19(16): 1365-1380, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553283

RESUMO

The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric disorders. Several pharmacokinetic challenges with previously identified small molecule D1R agonists have been recently overcome with the discovery and advancement of new ligands, including drug-like non-catechol D1R agonists and positive allosteric modulators. From this, several novel molecules and mechanisms have recently entered clinical studies. Here we review the major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators, highlighting their structure-activity relationships and medicinal chemistry. Recent chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also hold promise for creating pharmacotherapy for several neurological diseases.


Assuntos
Agonistas de Dopamina/farmacologia , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Receptores de Dopamina D1/agonistas , Animais , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/química , Humanos , Ligantes , Transtornos Mentais/metabolismo , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Receptores de Dopamina D1/metabolismo
3.
J Clin Pathol ; 72(11): 725-735, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31395625

RESUMO

Neurodegenerative diseases are characterised by selective dysfunction and progressive loss of synapses and neurons associated with pathologically altered proteins that deposit primarily in the human brain and spinal cord. Recent discoveries have identified a spectrum of distinct immunohistochemically and biochemically detectable proteins, which serve as a basis for protein-based disease classification. Diagnostic criteria have been updated and disease staging procedures have been proposed. These are based on novel concepts which recognise that (1) most of these proteins follow a sequential distribution pattern in the brain suggesting a seeding mechanism and cell-to-cell propagation; (2) some of the neurodegeneration-associated proteins can be detected in peripheral organs; and (3) concomitant presence of neurodegeneration-associated proteins is more the rule than the exception. These concepts, together with the fact that the clinical symptoms do not unequivocally reflect the molecular pathological background, place the neuropathological examination at the centre of requirements for an accurate diagnosis. The need for quality control in biomarker development, clinical and neuroimaging studies, and evaluation of therapy trials, as well as an increasing demand for the general public to better understand human brain disorders, underlines the importance for a renaissance of postmortem neuropathological studies at this time. This review summarises recent advances in neuropathological diagnosis and reports novel aspects of relevance for general pathological practice.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Patologia Molecular/métodos , Biomarcadores/metabolismo , Biópsia , Humanos , Imuno-Histoquímica , Sistema Nervoso/patologia , Doenças Neurodegenerativas/classificação , Doenças Neurodegenerativas/patologia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes
4.
Georgian Med News ; (291): 97-101, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31418740

RESUMO

Objective of the work is to study enalapril effect, a blocker of renin-angiotensin system, on glutathione chain of the antioxidant system of the cerebral cortex and hippocampus of rats with experimental neurodegeneration. The experiments were conducted on nonlinear laboratory albino male rats with their body weight of 0,18-0,20 kg. The model of neurodegeneration was created by means of intraperitoneally administration of scopolamine hydrochloride (Sigma, USA) during 27 days in the dose of 1 mg/kg. Since the 28th day of the experiment enalapril (Zdorovye, Ukraine) was introduced intraperitoneally in the dose of 1 mg/kg in 1 ml of physiological solution once a day during 14 days. The content of reduced glutathione in male rats with scopolamine-induced neurodegeneration after introduction of enalapril increased in the cerebral cortex 1,8 times as much, and in the hippocampus - 1,2 times. Under enalapril effect the content of sulfhydryl groups increased in the cerebral cortex and hippocampus 1,3 and 1,1 times respectively. A positive effect of enalapril was characterized by an increased activity of glutathione reductase in the cerebral cortex 1,7 times as much, and 1,6 times - in the hippocampus. Thus, enalapril improves the indices of glutathione chain of the antioxidant system of the cerebral cortex and hippocampus, which is indicative of its neuroprotective ability under conditions of scopolamine-induced damage and development of neurodegenerative processes in rats.


Assuntos
Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Enalapril/farmacologia , Glutationa/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Animais , Humanos , Masculino , Doenças Neurodegenerativas/induzido quimicamente , Ratos Wistar , Escopolamina
5.
Yakugaku Zasshi ; 139(7): 1007-1013, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31257247

RESUMO

α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a ß-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.


Assuntos
Doenças Neurodegenerativas/metabolismo , Agregação Patológica de Proteínas , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Callithrix , Humanos , Doença por Corpos de Lewy , Camundongos , Doenças Neurodegenerativas/etiologia , Doença de Parkinson , Fosforilação , Príons
6.
Cell Mol Life Sci ; 76(16): 3167-3191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197405

RESUMO

As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood-brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.


Assuntos
Doença de Alzheimer/patologia , Metaloproteinases da Matriz/metabolismo , Doenças Neurodegenerativas/patologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Proteínas ADAM/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
7.
Biochemistry (Mosc) ; 84(Suppl 1): S159-S192, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213201

RESUMO

In the middle of the 20th century, it was postulated that degradation of intracellular proteins is a stochastic process. More than fifty years of intense studies have finally proven that protein degradation is a very complex and tightly regulated in time and space process that plays an incredibly important role in the vast majority of metabolic pathways. Degradation of more than a half of intracellular proteins is controlled by a hierarchically aligned and evolutionarily perfect system consisting of many components, the main ones being ubiquitin ligases and proteasomes, together referred to as the ubiquitin-proteasome system (UPS). The UPS includes more than 1000 individual components, and most of them are critical for the cell functioning and survival. In addition to the well-known signaling functions of ubiquitination, such as modification of substrates for proteasomal degradation and DNA repair, polyubiquitin (polyUb) chains are involved in other important cellular processes, e.g., cell cycle regulation, immunity, protein degradation in mitochondria, and even mRNA stability. This incredible variety of ubiquitination functions is related to the ubiquitin ability to form branching chains through the ε-amino group of any of seven lysine residues in its sequence. Deubiquitination is accomplished by proteins of the deubiquitinating enzyme family. The second main component of the UPS is proteasome, a multisubunit proteinase complex that, in addition to the degradation of functionally exhausted and damaged proteins, regulates many important cellular processes through controlled degradation of substrates, for example, transcription factors and cyclins. In addition to the ubiquitin-dependent-mediated degradation, there is also ubiquitin-independent degradation, when the proteolytic signal is either an intrinsic protein sequence or shuttle molecule. Protein hydrolysis is a critically important cellular function; therefore, any abnormalities in this process lead to systemic impairments further transforming into serious diseases, such as diabetes, malignant transformation, and neurodegenerative disorders (multiple sclerosis, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease and Huntington's disease). In this review, we discuss the mechanisms that orchestrate all components of the UPS, as well as the plurality of the fine-tuning pathways of proteasomal degradation.


Assuntos
Doenças Neurodegenerativas/metabolismo , Complexo de Endopeptidases do Proteassoma , Proteólise , Ubiquitinas , Humanos , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/fisiologia , Transdução de Sinais , Ubiquitinação , Ubiquitinas/química , Ubiquitinas/fisiologia
8.
Biochemistry (Mosc) ; 84(5): 453-463, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234761

RESUMO

Amino acids undergo many covalent modifications, but only few amino acid repair enzymes have been identified. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), also known as L-isoaspartyl/D-aspartyl protein carboxyl methyltransferase (PCMT), methylates covalently modified isoaspartate (isoAsp) residues accumulated in proteins via Asn deamidation and Asp hydrolysis. This cytoplasmic reaction occurs through the formation of succinimide cyclical intermediate and generates either isoAsp or Asp from succinimide. Succinimide conversion into Asp is spontaneous, while isoAsp is restored by PIMT using S-adenosylmethionine as a methyl donor. PIMT transforms isoAsp into succinimide, thereby creating an opportunity for the later to be converted into Asp. Apart from normal cell physiology, formation of isoAsp in proteins is promoted by various stress conditions. The resulting isoAsp can form a kink or bend in the protein backbone thus making the protein conformationally and functionally distorted. Many PIMT-interacting proteins (proteins with isoAsp residues) have been reported in eukaryotes, but only few of them have been found in prokaryotes. Extensive studies in mice have shown the importance of PIMT in neurodegeneration. Detail elucidation of PIMT function can create a platform for addressing various disorders such as Alzheimer's disease and cancer.


Assuntos
Proteína D-Aspartato-L-Isoaspartato Metiltransferase/metabolismo , Animais , Ácido Aspártico/metabolismo , Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Humanos , Ácido Isoaspártico/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/química , Estrutura Quaternária de Proteína , S-Adenosilmetionina/metabolismo
10.
Cell Mol Life Sci ; 76(20): 3987-4008, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31227845

RESUMO

Polyamines (PAs) are essential organic polycations for cell viability along the whole phylogenetic scale. In mammals, they are involved in the most important physiological processes: cell proliferation and viability, nutrition, fertility, as well as nervous and immune systems. Consequently, altered polyamine metabolism is involved in a series of pathologies. Due to their pathophysiological importance, PA metabolism has evolved to be a very robust metabolic module, interconnected with the other essential metabolic modules for gene expression and cell proliferation/differentiation. Two different PA sources exist for animals: PA coming from diet and endogenous synthesis. In the first section of this work, the molecular characteristics of PAs are presented as determinant of their roles in living organisms. In a second section, the metabolic specificities of mammalian PA metabolism are reviewed, as well as some obscure aspects on it. This second section includes information on mammalian cell/tissue-dependent PA-related gene expression and information on crosstalk with the other mammalian metabolic modules. The third section presents a synthesis of the physiological processes described as modulated by PAs in humans and/or experimental animal models, the molecular bases of these regulatory mechanisms known so far, as well as the most important gaps of information, which explain why knowledge around the specific roles of PAs in human physiology is still considered a "mysterious" subject. In spite of its robustness, PA metabolism can be altered under different exogenous and/or endogenous circumstances so leading to the loss of homeostasis and, therefore, to the promotion of a pathology. The available information will be summarized in the fourth section of this review. The different sections of this review also point out the lesser-known aspects of the topic. Finally, future prospects to advance on these still obscure gaps of knowledge on the roles on PAs on human physiopathology are discussed.


Assuntos
Fertilidade/fisiologia , Gastroenteropatias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Poliaminas/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Carboxiliases/genética , Carboxiliases/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Gastroenteropatias/genética , Gastroenteropatias/fisiopatologia , Regulação da Expressão Gênica , Humanos , Hidrolases/genética , Hidrolases/metabolismo , Mamíferos , Neoplasias/genética , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas/administração & dosagem , Poliaminas/farmacologia
11.
Cell Mol Life Sci ; 76(20): 3953-3967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250034

RESUMO

The brain tissue has only a limited capacity for generating new neurons. Therefore, to treat neurological diseases, there is a need of other cell sources for brain repair. Different sources of cells have been subject of intense research over the years, including cells from primary tissue, stem cell-derived cells and reprogrammed cells. As an alternative, direct reprogramming of resident brain cells into neurons is a recent approach that could provide an attractive method for treating brain injuries or diseases as it uses the patient's own cells for generating novel neurons inside the brain. In vivo reprogramming is still in its early stages but holds great promise as an option for cell therapy. To date, both inhibitory and excitatory neurons have been obtained via in vivo reprogramming, but the precise phenotype or functionality of these cells has not been analysed in detail in most of the studies. Recent data shows that in vivo reprogrammed neurons are able to functionally mature and integrate into the existing brain circuitry, and compose interneuron phenotypes that seem to correlate to their endogenous counterparts. Interneurons are of particular importance as they are essential in physiological brain function and when disturbed lead to several neurological disorders. In this review, we describe a comprehensive overview of the existing studies involving brain repair, including in vivo reprogramming, with a focus on interneurons, along with an overview on current efforts to generate interneurons for cell therapy for a number of neurological diseases.


Assuntos
Lesões Encefálicas/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Interneurônios/citologia , Doenças Neurodegenerativas/terapia , Regeneração/fisiologia , Animais , Biomarcadores/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Transdiferenciação Celular , Reprogramação Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Injeções Intraventriculares , Interneurônios/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurogênese/genética , Transplante de Células-Tronco/métodos
12.
J Biochem ; 166(3): 213-221, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251338

RESUMO

Central nervous system (CNS)-related disorders, including neurodegenerative diseases, are common but difficult to treat. As effective medical interventions are limited, those diseases will likely continue adversely affecting people's health. There is evidence that the hyperactivation of innate immunity is a hallmark of most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases. In mammalian and fly CNS, the presence of noninfectious ligands, including danger-associated molecular patterns, is recognized by (micro)glial cells, inducing the expression of proinflammatory cytokines. Such inflammation may contribute to the onset and progression of neurodegenerative states. Studies using fruit flies have shed light on the types of signals, receptors and cells responsible for inducing the inflammation that leads to neurodegeneration. Researchers are using fly models to assess the mechanisms of sterile inflammation in the brain and its link to progressive neurodegeneration. Given the similarity of its physiological system and biochemical function to those of mammals, especially in activating and regulating innate immune signalling, Drosophila can be a versatile model system for studying the mechanisms and biological significance of sterile inflammatory responses in the pathogenesis of neurodegenerative diseases. Such knowledge would greatly facilitate the quest for a novel effective treatment for neurodegenerative diseases.


Assuntos
Modelos Animais de Doenças , Drosophila , Inflamação/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Drosophila/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia
13.
Cell Mol Life Sci ; 76(16): 3051-3053, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175371

RESUMO

This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of the central nervous system. The collection covers a wide range of situations in which matrix metalloproteinases, adamalysins and meprins are regulated and in turn regulate substrates or signalling pathways involved in: nervous system development, learning and memory, neuroinflammation, degeneration and repair after traumatic and ischemic injury or neurodegenerative mechanisms underlying retinopathies, psychiatric and neurodegenerative disorders. The authors also argue that these proteinases can be considered in some cases as biomarkers or potential therapeutic targets for diseases of the nervous system. Overall, metalloproteinases are placed among the key factors that can help us better understand the cellular and molecular processes that govern neuropathophysiology and implement the strategies that result from this knowledge to open up much-needed treatment opportunities.


Assuntos
Sistema Nervoso Central/metabolismo , Metaloproteases/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Inibidores Teciduais de Metaloproteinases/metabolismo
14.
Dokl Biochem Biophys ; 485(1): 141-144, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201636

RESUMO

It was established that in neurodegeneration models in the human neuron-like cell line SH-SY5Y, amide derivatives of arachidonic and docosahexaenoic acids were inactive in experiments with MPP+ and CoCl2 but protected from H2O2. The protective activity of neurolipins decreased in the series DHA-DA > AA-SER ≥ AA-GLY > AA-GABA ≥ AA-EA and was manifested starting from a concentration of 0.5 nM.


Assuntos
Amidas , Ácidos Graxos , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores , Transdução de Sinais/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Linhagem Celular , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Humanos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia
15.
Int J Mol Sci ; 20(9)2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060234

RESUMO

In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease.


Assuntos
Neuroimunomodulação , Plasticidade Neuronal , Animais , Autofagia , Biomarcadores , Suscetibilidade a Doenças , Metabolismo Energético , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Mediadores da Inflamação/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Transmissão Sináptica
16.
Cell Mol Life Sci ; 76(17): 3301-3310, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31073743

RESUMO

The channel kinase (chanzyme) transient receptor potential melastatin-like 7 (TRPM7) has a unique dual protein structure composed of an ion channel with an α-kinase domain on its C-terminus. In the nervous system, under physiological conditions, TRPM7 contributes to critical neurobiological processes ranging from synaptic transmission to cognitive functions. Following certain pathological triggers, TRPM7 mediates neurotoxicity, neuro-injuries, and neuronal death. Here, we summarize the current knowledge of TRPM7 functions in neuronal systems in health and disease. The molecular mechanisms by which this chanzyme might regulate synaptic and cognitive functions are discussed. We also discuss the lack of knowledge regarding the molecular mechanisms responsible for turning TRPM7 into "a vicious tool" that mediates neuronal death following certain pathological triggers. Some synthetic and natural pharmacological modulators of the TRPM7 channel and its α-kinase are reviewed. We suggest that based on current knowledge, we should reshape our thinking regarding the implications of TRPM7 in neurological and neurodegenerative disorders. Moreover, we propose a paradigm shift concerning the targeting of TRPM7 as a therapeutic approach for treating certain neurological diseases. We agree that TRPM7 overexpression or overactivation may mediate neurodegenerative processes following certain triggers. However, TRPM7 dysfunction and/or downregulation might also be among the pathological changes leading to neurodegeneration. Consequently, further investigations are required before we decide whether blocking or activating the chanzyme is the correct therapeutic approach to treat certain neurological and/or neurodegenerative diseases.


Assuntos
Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/patologia , Canais de Cátion TRPM/metabolismo , Humanos , Magnésio/metabolismo , Doenças Neurodegenerativas/metabolismo , Plasticidade Neuronal , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/genética , Zinco/metabolismo
17.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052285

RESUMO

Neuronal subpopulations display differential vulnerabilities to disease, but the factors that determine their susceptibility are poorly understood. Toxic increases in intracellular calcium are a key factor in several neurodegenerative processes, with calcium-binding proteins providing an important first line of defense through their ability to buffer incoming calcium, allowing the neuron to quickly achieve homeostasis. Since neurons expressing different calcium-binding proteins have been reported to be differentially susceptible to degeneration, it can be hypothesized that rather than just serving as markers of different neuronal subpopulations, they might actually be a key determinant of survival. In this review, we will summarize some of the evidence that expression of the EF-hand calcium-binding proteins, calbindin, calretinin and parvalbumin, may influence the susceptibility of distinct neuronal subpopulations to disease processes.


Assuntos
Calbindinas/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Calbindinas/genética , Humanos , Neurônios/metabolismo
18.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075835

RESUMO

Neuronal calcium (Ca2+) influx has long been ascribed mainly to voltage-gated Ca2+ channels and glutamate receptor channels. Recent research has shown that it is also complemented by stromal interaction molecule (STIM) protein-mediated store-operated Ca2+ entry (SOCE). SOCE is described as Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The present review summarizes recent studies that indicate a relationship between neuronal SOCE that is mediated by STIM1 and STIM2 proteins and glutamate receptors under both physiological and pathological conditions, such as neurodegenerative disorders. We present evidence that the dysregulation of neuronal SOCE and glutamate receptor activity are hallmarks of acute neurodegenerative diseases (e.g., traumatic brain injury and cerebral ischemia) and chronic neurodegenerative diseases (e.g., Alzheimer's disease and Huntington's disease). Emerging evidence indicates a role for STIM proteins and glutamate receptors in neuronal physiology and pathology, making them potential therapeutic targets.


Assuntos
Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Receptores de Glutamato/metabolismo , Animais , Ácido Glutâmico/metabolismo , Humanos , Modelos Biológicos , Molécula 1 de Interação Estromal/metabolismo
19.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096608

RESUMO

Increasing numbers of individuals suffer from neurodegenerative diseases, which are characterized by progressive loss of neurons. Oxidative stress, in particular, the overproduction of Reactive Oxygen Species (ROS), play an important role in the development of these diseases, as evidenced by the detection of products of lipid, protein and DNA oxidation in vivo. Even if they participate in cell signaling and metabolism regulation, ROS are also formidable weapons against most of the biological materials because of their intrinsic nature. By nature too, neurons are particularly sensitive to oxidation because of their high polyunsaturated fatty acid content, weak antioxidant defense and high oxygen consumption. Thus, the overproduction of ROS in neurons appears as particularly deleterious and the mechanisms involved in oxidative degradation of biomolecules are numerous and complexes. This review highlights the production and regulation of ROS, their chemical properties, both from kinetic and thermodynamic points of view, the links between them, and their implication in neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Ácidos Graxos/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Cinética , NADPH Oxidases , Oxirredução , Estresse Oxidativo , Transdução de Sinais , Superóxido Dismutase , Superóxidos/metabolismo , Termodinâmica
20.
Biomed Res Int ; 2019: 8748253, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080832

RESUMO

Aging is related to a number of functional and morphological changes leading to progressive decline of the biological functions of an organism. Reactive Oxygen Species (ROS), released by several endogenous and exogenous processes, may cause important oxidative damage to DNA, proteins, and lipids, leading to important cellular dysfunctions. The imbalance between ROS production and antioxidant defenses brings to oxidative stress conditions and, related to accumulation of ROS, aging-associated diseases. The purpose of this review is to provide an overview of the most relevant data reported in literature on the natural compounds, mainly phytochemicals, with antioxidant activity and their potential protective effects on age-related diseases such as metabolic syndrome, diabetes, cardiovascular disease, cancer, neurodegenerative disease, and chronic inflammation, and possibly lower side effects, when compared to other drugs.


Assuntos
Envelhecimento/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Envelhecimento/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA