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1.
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
2.
Int J Mol Sci ; 20(6)2019 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-30884895

RESUMO

There are many downstream targets of mitogen-activated protein kinase (MAPK) signalling that are involved in neuronal development, cellular differentiation, cell migration, cancer, cardiovascular dysfunction and inflammation via their functions in promoting apoptosis and cell motility and regulating various cytokines. It has been reported that cyclic AMP response element-binding protein (CREB) is phosphorylated and activated by cyclic AMP signalling and calcium/calmodulin kinase. Recent evidence also points to CREB phosphorylation by the MAPK signalling pathway. However, the specific roles of CREB phosphorylation in MAPK signalling have not yet been reviewed in detail. Here, we describe the recent advances in the study of this MAPK-CREB signalling axis in human diseases. Overall, the crosstalk between extracellular signal-related kinase (ERK) 1/2 and p38 MAPK signalling has been shown to regulate various physiological functions, including central nervous system, cardiac fibrosis, alcoholic cardiac fibrosis, osteoclast differentiation, mucin production in the airway, vascular smooth muscle cell migration, steroidogenesis and asthmatic inflammation. In this review, we focus on ERK1/2 and/or p38 MAPK-dependent CREB activation associated with various diseases to provide insights for basic and clinical researchers.


Assuntos
Sistema Cardiovascular/metabolismo , Sistema Nervoso Central/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases , Mucinas/metabolismo , Osteoclastos/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Diferenciação Celular , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Osteoclastos/citologia , Fosforilação
3.
Methods Mol Biol ; 1929: 701-728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30710306

RESUMO

In recent decades a significant scientific effort has focused on projects regarding the use of neurobiomarkers in perinatal medicine with a view to understanding the mechanisms that interfere with physiological patterns of brain development and lead to ominous effects in several human diseases. Numerous potential neurobiomarkers have been proposed for use in monitoring high-risk fetuses and newborns, including markers of oxidative stress, neuroproteins, and vasoactive agents. Nonetheless, the use of these markers in clinical practice remains a matter of debate. Recently, the calcium-binding S100B protein has been proposed as being an ideal neurobiomarker, thanks to its simple availability and easy reproducibility, to the possibility of detecting it noninvasively in biological fluids with good reproducibility, and to the possibility of a longitudinal evaluation in relation to reference curves. The present chapter contains an overview of the most significant studies on the assessment of S100B in different biological fluids as a trophic factor and/or marker of brain damage in high-risk fetuses and newborns.


Assuntos
Biomarcadores/metabolismo , Doenças do Sistema Nervoso Central/diagnóstico , Sistema Nervoso Central/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Doenças do Sistema Nervoso Central/metabolismo , Testes Diagnósticos de Rotina , Feminino , Humanos , Imunoensaio , Recém-Nascido , Estresse Oxidativo , Gravidez , Prognóstico , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/urina
4.
Methods Mol Biol ; 1941: 225-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30707437

RESUMO

Immune-mediated inflammation of the brain has been recognized for more than 50 years, although the initial descriptions were mainly thought to be secondary to an underlying neoplasm. Some of these paraneoplastic encephalitides express serum antibodies, but these were not thought to be pathogenic but instead have a T-cell-mediated pathophysiology. Over the last two decades, several pathogenic antibodies against neuronal surface antigens have been described in autoimmune encephalitis, which are amenable to immunotherapy. Several of these antibodies are directed against glutamate receptors (GluRs). NMDAR encephalitis (NMDARE) is the most common of these antibodies, and patients often present with psychosis, hallucinations, and reduced consciousness. Patients often progress on to develop confusion, seizures, movement disorders, autonomic instability, and respiratory depression. Although initially described as exclusively occurring secondary to ovarian teratoma (and later other tumors), non-paraneoplastic forms are increasingly common, and other triggers like viral infections are now well recognized. AMPAR encephalitis is relatively less common than NMDARE but is more likely to paraneoplastic. AMPAR antibodies typically cause limbic encephalitis, with patients presenting with confusion, disorientation, memory loss, and often seizures. The syndromes associated with the metabotropic receptor antibodies are much rarer and often can be paraneoplastic-mGluR1 (cerebellar degeneration) and mGluR5 (Ophelia syndrome) being the ones described in literature.With the advance in molecular biology techniques, it is now possible to detect these antibodies using cell-based assays with high sensitivity and specificity, especially when coupled with brain tissue immunohistochemistry and binding to live cell-based neurons. The rapid and reliable identification of these antibodies aids in the timely treatment (either in the form of identifying/removing the underlying tumor or instituting immunomodulatory therapy) and has significantly improved clinical outcome in this otherwise devastating group of conditions.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doenças do Sistema Nervoso Central/imunologia , Receptores de AMPA/imunologia , Receptores de Glutamato/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Autoanticorpos/metabolismo , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/terapia , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/terapia , Humanos , Testes Imunológicos/métodos , Imunoterapia
5.
Biomed Res Int ; 2019: 8361858, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809547

RESUMO

Monoamine oxidases (MAOs) regulate local levels of neurotransmitters such as dopamine, norepinephrine, and serotonin and thus have been targeted by drugs for the treatment of certain CNS disorders. However, recent studies have shown that these enzymes are upregulated with age in nervous and cardiac tissues and may be involved in degeneration of these tissues, since their metabolic mechanism releases hydrogen peroxide leading to oxidative stress. Thus, targeting these enzymes may be a potential anti-aging strategy. The purpose of this study was to compare the MAO inhibition and selectivity of selected dietary phenolic compounds, using a previously validated assay that would avoid interference from the compounds. Kynuramine metabolism by human recombinant MAO-A and MAO-B leads to formation of 4-hydroxyquinoline, with Vmax values of 10.2±0.2 and 7.35±0.69 nmol/mg/min, respectively, and Km values of 23.1±0.8 µM and 18.0±2.3 µM, respectively. For oral dosing and interactions with the gastrointestinal tract, curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone were tested at their highest expected luminal concentrations from an oral dose. Each of these significantly inhibited both enzymes except for zingerone, which only inhibited MAO-A. The IC50 values were determined, and selectivity indices (MAO-A/MAO-B IC50 ratios) were calculated. Resveratrol and isoeugenol were selective for MAO-A, with IC50 values of 0.313±0.008 and 3.72±0.20 µM and selectivity indices of 50.5 and 27.4, respectively. Pterostilbene was selective for MAO-B, with IC50 of 0.138±0.013 µM and selectivity index of 0.0103. The inhibition of resveratrol (MAO-A) and pterostilbene (MAO-B) was consistent with competitive time-independent mechanisms. Resveratrol 4'-glucoside was the only compound which inhibited MAO-A, but itself, resveratrol 3-glucoside, and pterostilbene 4'-glucoside failed to inhibit MAO-B. Additional studies are needed to establish the effects of these compounds on MAO-A and/or MAO-B in humans.


Assuntos
Doenças do Sistema Nervoso Central/dietoterapia , Monoaminoxidase/química , Estilbenos/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Envelhecimento/fisiologia , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Cromatografia Líquida de Alta Pressão , Curcumina/farmacologia , Eugenol/análogos & derivados , Eugenol/farmacologia , Guaiacol/administração & dosagem , Guaiacol/análogos & derivados , Guaiacol/farmacologia , Humanos , Hidroxiquinolinas/farmacologia , Concentração Inibidora 50 , Cinuramina/química , Cinuramina/farmacologia , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Resveratrol/química , Resveratrol/farmacologia
6.
Int J Mol Sci ; 20(2)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30658442

RESUMO

Central nervous system (CNS) injury, such as stroke or trauma, is known to increase susceptibility to various infections that adversely affect patient outcomes (CNS injury-induced immunodepression-CIDS). The endocannabinoid system (ECS) has been shown to have immunoregulatory properties. Therefore, the ECS might represent a druggable target to overcome CIDS. Evidence suggests that cannabinoid type 2 receptor (CB2R) activation can be protective during the early pro-inflammatory phase after CNS injury, as it limits neuro-inflammation and, therefore, attenuates CIDS severity. In the later phase post CNS injury, CB2R inhibition is suggested as a promising pharmacologic strategy to restore immune function in order to prevent infection.


Assuntos
Doenças do Sistema Nervoso Central/metabolismo , Endocanabinoides/metabolismo , Traumatismos do Sistema Nervoso/metabolismo , Imunidade Adaptativa , Animais , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/etiologia , Humanos , Imunidade Inata , Neuroimunomodulação , Transdução de Sinais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Fatores de Tempo , Traumatismos do Sistema Nervoso/diagnóstico , Traumatismos do Sistema Nervoso/etiologia
7.
Biomed Pharmacother ; 111: 666-675, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611991

RESUMO

In recent years, the researchers and drug designers have given growing attention to new nanotechnology strategies to improve drug delivery to the central nervous system (CNS). Nanotechnology has a great potential to affect the treatment of neurological disorders, mainly Alzheimer's disease, Parkinson's disease, brain tumors, and stroke. With regard to neurodegeneration, several studies showed that nanomaterials have been successfully used for the treatments of CNS disorders. In this regard, nanocarriers have facilitated the targeted delivery of chemotherapeutics resulting in the efficient inhibition of disease progression in malignant brain tumors. Therefore, the most efficacious application of nanomaterials is the use of these substances in the treatment of CNS disease that enhances the overall effect of drug and highlights the importance of nano-therapeutics. This study was conducted to review the evidence on the applications of nanotechnology in designing drug delivery systems with the ability to cross through the blood-brain barrier (BBB) in order to transfer the therapeutic agents to the CNS.


Assuntos
Fármacos do Sistema Nervoso Central/administração & dosagem , Sistema Nervoso Central/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Nanotecnologia/métodos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Fármacos do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Humanos , Nanotecnologia/tendências
8.
Biomed Pharmacother ; 111: 791-801, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30616078

RESUMO

Lycopene is an aliphatic hydrocarbon carotenoid extracted from plants like tomatoes, papayas, and watermelons. Previous studies have shown that lycopene can exert prophylactic and/or therapeutic effects in different disorders, such as heart failure and neoplasm via anti-oxidative, anti-inflammatory, and anti-proliferative activities. In the central nervous system (CNS), lycopene also has prophylactic and/or therapeutic effects in different type of disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), cerebral ischemia, epilepsy, and depression. Lycopene also improves cognition and memory ability of rodents in different pathological conditions, such as diabetes, colchicine exposure, high-fat diet (HFD), and aging. Further, lycopene can prevent neuro-toxicities induced by monosodium glutamate (MSG), trimethyltin (TMT), methylmercury (MeHg), tert-butyl hydroperoxide (t-BHP), and cadmium (Cd). In some special conditions such as ethanol addiction and haloperidol-induced orofacial dyskinesia, lycopene administration displays special therapeutic effects. Mechanisms including inhibition of oxidative stress and neuroinflammation, inhibition of neuronal apoptosis, and restoration of mitochondrial function have been shown to mediate the neuroprotective effects of lycopene. Other mechanisms, such as inhibition of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), activation of the nuclear factor erythroid 2-related factor (Nrf2) and brain-derived neurotrophic factor (BDNF) signaling, and restoration of intracellular Ca2+ homeostasis, may be also involved in the neuroprotective effect of lycopene. In hope of get a clear impression about the role of lycopene in the CNS, we summarize and discuss the pharmacological effects of lycopene as well as its possible mechanisms in CNS disorder prevention and/or therapy.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Licopeno/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Carotenoides/farmacologia , Carotenoides/uso terapêutico , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Humanos , Licopeno/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Resultado do Tratamento
9.
Glia ; 67(4): 668-687, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30585359

RESUMO

The lack of endogenous repair following spinal cord injury (SCI) accounts for the frequent permanent deficits for which effective treatments are absent. Previously, we demonstrated that low sulfated modified heparin mimetics (LS-mHeps) attenuate astrocytosis, suggesting they may represent a novel therapeutic approach. mHeps are glycomolecules with structural similarities to resident heparan sulfates (HS), which modulate cell signaling by both sequestering ligands, and acting as cofactors in the formation of ligand-receptor complexes. To explore whether mHeps can affect the myelination and neurite outgrowth necessary for repair after SCI, we created lesioned or demyelinated neural cell co-cultures and exposed them with a panel of mHeps with varying degrees and positions of their sulfate moieties. LS-mHep7 enhanced neurite outgrowth and myelination, whereas highly sulfated mHeps (HS-mHeps) had attenuating effects. LS-mHeps had no effects on myelination or neurite extension in developing, uninjured myelinating cultures, suggesting they might exert their proregenerating effects by modulating or sequestering inhibitory factors secreted after injury. To investigate this, we examined conditioned media from cultures using chemokine arrays and conducted an unbiased proteomics approach by applying TMT-LC/MS to mHep7 affinity purified conditioned media from these cultures. Multiple protein factors reported to play a role in damage or repair mechanisms were identified, including amyloid betaA4. Amyloid beta peptide (1-42) was validated as an important candidate by treating myelination cultures and shown to inhibit myelination. Thus, we propose that LS-mHeps exert multiple beneficial effects on mechanisms supporting enhanced repair, and represent novel candidates as therapeutics for CNS damage.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/tratamento farmacológico , Heparitina Sulfato/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Recém-Nascidos , Antimetabólitos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Desoxiuridina/farmacologia , Embrião de Mamíferos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Neuritos/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia
10.
Neural Plast ; 2018: 4593530, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30150999

RESUMO

Adiponectin, the most abundant plasma adipokine, plays an important role in the regulation of glucose and lipid metabolism. Adiponectin also possesses insulin-sensitizing, anti-inflammatory, angiogenic, and vasodilatory properties which may influence central nervous system (CNS) disorders. Although initially not thought to cross the blood-brain barrier, adiponectin enters the brain through peripheral circulation. In the brain, adiponectin signaling through its receptors, AdipoR1 and AdipoR2, directly influences important brain functions such as energy homeostasis, hippocampal neurogenesis, and synaptic plasticity. Overall, based on its central and peripheral actions, recent evidence indicates that adiponectin has neuroprotective, antiatherogenic, and antidepressant effects. However, these findings are not without controversy as human observational studies report differing correlations between plasma adiponectin levels and incidence of CNS disorders. Despite these controversies, adiponectin is gaining attention as a potential therapeutic target for diverse CNS disorders, such as stroke, Alzheimer's disease, anxiety, and depression. Evidence regarding the emerging role for adiponectin in these disorders is discussed in the current review.


Assuntos
Adiponectina/metabolismo , Encéfalo/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Animais , Encéfalo/fisiopatologia , Humanos , Receptores de Adiponectina/metabolismo , Transdução de Sinais
11.
Physiol Res ; 67(Supplementum 1): S95-S113, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947531

RESUMO

Endothelin B (ET(B)) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ET(B) receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer's disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Abeta treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 microg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD.


Assuntos
Endotelinas/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Receptor de Endotelina B/agonistas , Animais , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Ensaios Clínicos como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Endotelinas/farmacologia , Humanos , Regeneração Nervosa/fisiologia , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos/farmacologia , Receptor de Endotelina B/metabolismo
12.
Nutrients ; 10(6)2018 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-29882776

RESUMO

Magnesium is well known for its diverse actions within the human body. From a neurological standpoint, magnesium plays an essential role in nerve transmission and neuromuscular conduction. It also functions in a protective role against excessive excitation that can lead to neuronal cell death (excitotoxicity), and has been implicated in multiple neurological disorders. Due to these important functions within the nervous system, magnesium is a mineral of intense interest for the potential prevention and treatment of neurological disorders. Current literature is reviewed for migraine, chronic pain, epilepsy, Alzheimer’s, Parkinson’s, and stroke, as well as the commonly comorbid conditions of anxiety and depression. Previous reviews and meta-analyses are used to set the scene for magnesium research across neurological conditions, while current research is reviewed in greater detail to update the literature and demonstrate the progress (or lack thereof) in the field. There is strong data to suggest a role for magnesium in migraine and depression, and emerging data to suggest a protective effect of magnesium for chronic pain, anxiety, and stroke. More research is needed on magnesium as an adjunct treatment in epilepsy, and to further clarify its role in Alzheimer’s and Parkinson’s. Overall, the mechanistic attributes of magnesium in neurological diseases connote the macromineral as a potential target for neurological disease prevention and treatment.


Assuntos
Encéfalo/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Magnésio/metabolismo , Medula Espinal/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/fisiopatologia , Humanos , Magnésio/uso terapêutico , Prognóstico , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia
13.
Acta Neurobiol Exp (Wars) ; 78(1): 14-20, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29694337

RESUMO

Cerebral hemispherectomy is a neurosurgical procedure that involves surgically removing one hemisphere of the brain, used as a therapeutic option in severe cases of intractable epilepsy. Several animal models have contributed to our understanding of the underlying neuromechanisms. The review was based on a PubMed search using the terms "hemispherectomy" and "mouse" or "rat" or "rodent", with no limitation of year of study or language. We identified a series of elements that were collected and analyzed that add up to our contemporary knowledge of this procedure. Our search returned 29 articles out of which only 15 are relevant to our purposes. Most of the current literature is concerned with the different molecular and electrophysiological issues of neuroplasticity, exhibiting the neurochemical background on which brain plasticity is founded. Experimental neurosurgery is quintessential in understanding the process in which various pathologies respond to in vivo animal models and recreating conditions otherwise difficult or impossible to obtain in humans. The aim of our study was to evaluate the current literature on the modern comprehension that animal models offer for histopathological, neurochemical and microsurgical research. In addition, the review is focused on the neuroplastic/compensatory mechanisms developed after hemispherectomy. Further research is of vital importance in exploring neurotherapeutical aspects of neuroplasticity in central nervous system (CNS) diseases.


Assuntos
Doenças do Sistema Nervoso Central/fisiopatologia , Doenças do Sistema Nervoso Central/cirurgia , Modelos Animais de Doenças , Hemisferectomia/métodos , Animais , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Plasticidade Neuronal/fisiologia , PubMed , Roedores
14.
Future Med Chem ; 10(4): 433-459, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29451400

RESUMO

Nicotinic receptors are membrane proteins involved in several physiological processes. They are considered suitable drug targets for various CNS disorders or conditions, as shown by the large number of compounds which have entered clinical trials. In recent years, nonconventional agonists have been discovered: positive allosteric modulators, allosteric agonists, site-specific agonists and silent desensitizers are compounds able to modulate the receptor interacting at sites different from the orthodox one, or to desensitize the receptor without prior opening. While these new findings can further complicate the pharmacology of these proteins and the design and optimization of ligands, they undoubtedly offer new opportunities to find drugs for the many therapeutic indications involving nicotinic receptors.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Desenho de Drogas , Agonistas Nicotínicos/farmacologia , Agonistas Nicotínicos/uso terapêutico , Antagonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Ligantes , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/síntese química , Antagonistas Nicotínicos/química
15.
Curr Neuropharmacol ; 16(9): 1375-1384, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29473514

RESUMO

The blood-brain barrier (BBB) is a layer between the blood circulation and neural tissue. It plays a pivotal role in maintaining the vulnerable extracellular microenvironment in the neuronal parenchyma. Neuroinflammatory events can result in BBB dysregulation by disturbing adherens junctions (AJs) and tight junctions (TJs). VE-cadherin, as one of the most important components of the vascular system, is specifically responsible for the assembly of AJs and BBB architecture. Here, we present a review, which highlights recently available insights into the relationship between the neuroinflammation and BBB dysregulation. We then explore the specific interaction between VE-cadherin and BBB. Finally, we discuss the changes of VE-cadherin with different neurological diseases from both experimental and clinical studies. An understanding of VE-cadherin in BBB regulation may indicate that VE-cadherin can partially be a biomarker of neuroinflammation disease and lead to novel approaches for abating BBB dysregulation under pathological conditions and the opening of the BBB following central nervous system (CNS) drug delivery.


Assuntos
Antígenos CD/metabolismo , Barreira Hematoencefálica/metabolismo , Caderinas/metabolismo , Permeabilidade Capilar/fisiologia , Doenças do Sistema Nervoso Central/metabolismo , Animais , Humanos
16.
Nihon Yakurigaku Zasshi ; 151(1): 27-33, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29321393

RESUMO

The functions of n-3 fatty acids are known to be diverse, and they play roles in cardiovascular and neuronal systems and in lipid metabolism. Docosahexaenoic acid (DHA), which is the most abundant n-3 fatty acid in the brain, is essential for the maintenance of brain functions throughout the human lifespan. Epidemiological studies have demonstrated that reduced n-3 fatty acid intake is closely associated with the onset of mental and neurological diseases such as brain developmental disorders, depression, and Alzheimer's disease. DHA is primarily involved in neurogenesis, synapse formation, neuronal differentiation, neurite outgrowth, maintenance of membrane fluidity, anti-inflammatory action, and antioxidant action. Its mechanism of action include: 1) the effects on ion channels and membrane bound receptors/enzymes achieved by changing membrane fluidity, as a cell membrane constituent, and 2) free DHA molecules, derived from the cell membrane that directly or metabolically, by conversion to protectin D1 and other molecules, indirectly regulates the gene expression and the activity of intracellular proteins. Although future studies are required, the supplementation of n-3 fatty acids such as DHA may suppress the deterioration of brain functions, delay the onset and progression of various mental/neurological diseases, and further improve the outcome of the neuronal diseases.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Neurônios/metabolismo , Animais , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Transtornos Cognitivos/metabolismo , Humanos , Metabolismo dos Lipídeos , Neurogênese
17.
Chem Pharm Bull (Tokyo) ; 66(1): 37-44, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29311510

RESUMO

Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M4 receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M4-deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M1/M4 mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M4 mAChR have been reported as promising ligands that not only have antipsychotic effects, but can also improve cognitive impairment and motor dysfunction. However, challenges remain due to the high homology of the orthosteric binding site among all muscarinic receptors. In this review, we summarize our approach to the identification of M4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M4 mAChR structural information and structure-activity relationship studies. These findings indicate that selective M4 mAChR activators are promising potential therapeutic agents for several central nervous system conditions.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas , Piridinas/farmacologia , Receptor Muscarínico M4/agonistas , Tiadiazóis/farmacologia , Animais , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Estrutura Molecular , Piridinas/química , Receptor Muscarínico M4/deficiência , Receptor Muscarínico M4/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/química
18.
Eur J Med Chem ; 144: 318-329, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29275231

RESUMO

A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC50 = 0,1 µM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity. Docking and molecular dynamics experiments have been used to analyze the binding mode and to explain the observed selectivity against PTP1B. An In vivo experiment has demonstrated that 10a can cross the BBB, thus promoting the possibility of moving forward these candidates for the development of drugs for the treatment of CNS disorders, such as drug addiction and neurodegenerative diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Proteínas de Transporte/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Citocinas/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Proteínas de Transporte/síntese química , Proteínas de Transporte/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doenças do Sistema Nervoso Central/metabolismo , Citocinas/síntese química , Citocinas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Ratos , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Relação Estrutura-Atividade
19.
Biomed Pharmacother ; 98: 222-232, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29268243

RESUMO

There are various types of receptors in the central nervous system (CNS). G protein-coupled receptors (GPCRs) have the highest expression with a wide range of physiological functions. A newer sub group of these receptors namely orphan GPCRs have been discovered. GPR3, GPR6, GPR17, GPR26, GPR37, GPR39, GPR40, GPR50, GPR52, GPR54, GPR55, GPR85, GPR88, GPR103, and GPR139 are the selected orphan GPCRs for this article. Their roles in the central nervous system have not been understood well so far. However, recent studies show that they may have very important functions in the CNS. Hence, in the present study, we reviewed most recent findings regarding the physiological roles of the selected orphan GPCRs in the CNS. After a brief presentation of each receptor, considering the results from genetic and pharmacological manipulation of the receptors, their roles in the pathophysiology of different diseases and disorders including anxiety, depression, schizophrenia, epilepsy, Alzheimer's disease, Parkinson's disease, and substance abuse will be discussed. At present, our knowledge regarding the role of GPCRs in the brain is very limited. However, previous limited studies show that orphan GPCRs have an important place in psychopharmacology and these receptors are potential new targets for the treatment of major CNS diseases.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Fármacos do Sistema Nervoso Central/farmacologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Humanos , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
20.
Bioorg Med Chem Lett ; 28(2): 61-70, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29223589

RESUMO

Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds. In this review, we highlight recent progress in the clinical development of NAS drug candidates, in addition to preclinical breakthroughs in the identification of novel NASs, mainly for GABAA and NMDA receptor modulation.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas , Neurotransmissores/farmacologia , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Doenças do Sistema Nervoso Central/metabolismo , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Neurotransmissores/química , Relação Estrutura-Atividade
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