RESUMO
Neurological disorders have for a long time been a global challenge dismissed by drug companies, especially due to the low efficiency of most therapeutic compounds to cross the brain capillary wall, that forms the blood-brain barrier (BBB) and reach the brain. This has boosted an incessant search for novel carriers and methodologies to drive these compounds throughout the BBB. However, it remains a challenge to artificially mimic the physiology and function of the human BBB, allowing a reliable, reproducible and throughput screening of these rapidly growing technologies and nanoformulations (NFs). To surpass these challenges, brain-on-a-chip (BoC) - advanced microphysiological platforms that emulate key features of the brain composition and functionality, with the potential to emulate pathophysiological signatures of neurological disorders, are emerging as a microfluidic tool to screen new brain-targeting drugs, investigate neuropathogenesis and reach personalized medicine. In this review, the advance of BoC as a bioengineered screening tool of new brain-targeting drugs and NFs, enabling to decipher the intricate nanotechnology-biology interface is discussed. Firstly, the main challenges to model the brain are outlined, then, examples of BoC platforms to recapitulate the neurodegenerative diseases and screen NFs are summarized, emphasizing the current most promising nanotechnological-based drug delivery strategies and lastly, the integration of high-throughput screening biosensing systems as possible cutting-edge technologies for an end-use perspective is discussed as future perspective.
Assuntos
Barreira Hematoencefálica , Encéfalo , Dispositivos Lab-On-A-Chip , Nanotecnologia , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Barreira Hematoencefálica/metabolismo , Nanotecnologia/métodos , Encéfalo/metabolismo , Animais , Sistemas de Liberação de Medicamentos/métodosRESUMO
Neurodegenerative diseases represent the most common cause of dementia. Protein aggregation is upstream in the pathological mechanisms and is a therapeutic target in the development of disease-modifying drugs in this patient population. Notably, α-synuclein or DNA-binding protein of 43kDa (TDP-43) is commonly involved in the pathomechanisms that contribute to non-Alzheimer neurodegenerative diseases. Several immunotherapy clinical trials on α-synuclein have progressed to phase 2, and small-molecule therapeutics are ongoing. With regard to TDP-43, immunotherapies that target protein aggregates are currently being developed, and research is underway to investigate several drugs that target the associated causative gene. Further research is warranted for deeper insight into both disease-modifying drugs; biomarker tests need to be developed to determine their efficacy. However, both proteins aggregate and accumulate in the brain in many neurodegenerative diseases and dementia; therefore, they are therapeutically significant, and future progress is expected in research and development.
Assuntos
Demência , Humanos , Demência/tratamento farmacológico , alfa-Sinucleína/metabolismo , Proteínas de Ligação a DNA/metabolismo , Imunoterapia , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
With the accelerated aging of the global population, the incidence of neurodegenerative diseases (NDDs) is increasing year by year. Because of the presence of the blood-brain barrier (BBB), the low concentration of the biomarkers in peripheral blood and the low penetration rate of the drugs through BBB into brain hinders the development of diagnosis and treatment of NDDs. As an effective mediator to penetrate through BBB in both directions, extracellular vesicles (EVs) have attracted much attention in the early diagnosis and treatment of NDDs because of their superior performance as drug carriers and detection biomarkers. Brain-derived EVs in body fluids contain disease-related biomolecules can be used as early diagnostic biomarkers for NDDs. In addition, as one of the subpopulations of EVs, exosomes, especially stem cell-derived exosomes, have great potential in the treatment of NDDs. The ability to cross the BBB, together with the feasibility of versatile functionalization of EV for NDDs pathogen targeting facilitate EVs a potential tool for targeted drug delivery systems for NDDs. In this review, the important role of EVs in the diagnosis and treatment of NDDs and the current research progress will be discussed. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.
Assuntos
Barreira Hematoencefálica , Vesículas Extracelulares , Doenças Neurodegenerativas , Nanomedicina Teranóstica , Humanos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/tratamento farmacológico , Vesículas Extracelulares/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Biomarcadores/metabolismo , Sistemas de Liberação de Medicamentos , CamundongosRESUMO
Neurodegenerative disorder refers to malfunctioning of neurons their degradation leading to death of neurons. Among various neurodegenerative disorders APHD (Alzheimer's, Parkinson's, and Huntington's Disease) are particularly concerning due to their progressive and debilitating nature. The therapeutic agent used for treatment and management of APHD often show unsatisfactory clinical outcome owing to poor solubility and limited permeability across blood brain barrier (BBB). The nose-to brain delivery can overcome this BBB challenge as it can transport drug directly to brain though olfactory pathways bypassing BBB. Additionally, the nanotechnology has emerged as a cutting-edge methodology to address this issue and specifically mucoadhesive micro/nanoemulsion can improve the overall performance of the drug when administered intranasally. Beyond the therapy neurotechnology has emerged as are revolutionary AI-driven BCI (Brain computer interface) aimed to restore independence in patients with function loss due to neuron degeneration/death. A promising BCI Neuralink has been recently explored for clinical trials and results revealed that a quadriplegia bearing person with implanted Neuralink chip was able to perform few normal functions of daily routine such as playing online games, text messaging, reading, and learning foreign languages online through accessing the particular websites. This review will discuss the fundamental concepts of neurodegeneration, application of micro/nanoemulsion through intranasal route and integration of neurotechnology for the management and treatment of APHD.
Assuntos
Administração Intranasal , Sistemas de Liberação de Medicamentos , Emulsões , Nanotecnologia , Doenças Neurodegenerativas , Administração Intranasal/métodos , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Nanotecnologia/métodos , Animais , Barreira Hematoencefálica/metabolismo , Nanopartículas/química , Nanopartículas/administração & dosagemRESUMO
Neurological disorders such as Alzheimer's disease (AD), and Parkinson's disease (PD) have no disease-modifying treatments, resulting in a global dementia crisis that affects more than 50 million people. Amyloid-beta (Aß), tau, and alpha-synuclein (α-Syn) are three crucial proteins that are involved in the pathogenesis of these age-related neurodegenerative diseases. Only a few approved AD medications have been used in the clinic up to this point, and their results are only partial symptomatic alleviation for AD patients and cannot stop the progression of AD. Immunotherapies have attracted considerable interest as they target certain protein strains and conformations as well as promote clearance. Immunotherapies also have the potential to be neuroprotective: as they limit synaptic damage and spread of neuroinflammation by neutralizing extracellular protein aggregates. Lately, disease-modifying therapies (DMTs) that can alter the pathophysiology that underlies AD with anti-Aß monoclonal antibodies (MAbs) (e.g., aducanumab, lecanemab, gantenerumab, donanemab, solanezumab, crenezumab, tilavonemab). Similarly, in Parkinson's disease (PD), DMTs utilizing anti-αSyn (MAbs) (e.g., prasinezumab, cinpanemab,) are progressively being developed and evaluated in clinical trials. These therapies are based on the hypothesis that both AD and PD may involve systemic impairments in cell-dependent clearance mechanisms of amyloid-beta (Aß) and alpha-synuclein (αSyn), respectively, meaning the body's overall inability to effectively remove Aß and αSyn due to malfunctioning cellular mechanisms. In this review we will provide possible evidence behind the use of immunotherapy with MAbs in AD and PD and highlight the recent clinical development landscape of anti-Aß (MAbs) and anti-αSyn (MAbs) from these clinical trials in order to better investigate the therapeutic possibilities and adverse effects of these anti-Aß and anti-αSyn MAbs on AD and PD.
Assuntos
Inibidores de Checkpoint Imunológico , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/imunologia , Doença de Parkinson/terapia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/imunologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/imunologia , alfa-Sinucleína/antagonistas & inibidores , Animais , Envelhecimento/imunologiaRESUMO
The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.
Assuntos
Fator de Iniciação 2B em Eucariotos , Animais , Camundongos , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Estresse Fisiológico/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Humanos , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Feminino , Acetamidas , CicloexilaminasRESUMO
Although decades of intensive drug discovery efforts to treat neurodegenerative disorders (NDs) have failed, around half a million patients in more than 2000 studies continue being tested, costing over USD 100 billion, despite the conclusion that even those drugs which have been approved have no better effect than a placebo. The US Food and Drug Administration (FDA) has established multiple programs to innovate the treatment of rare diseases, particularly NDs, providing millions of USD in funding primarily by encouraging novel clinical trials to account for issues related to study sizes and adopting multi-arm studies to account for patient dropouts. Instead, the FDA should focus on the primary reason for failure: the poor bioavailability of drugs reaching the brain (generally 0.1% at most) due to the blood-brain barrier (BBB). There are several solutions to enhance entry into the brain, and the FDA must require proof of significant entry into the brain as the prerequisite to approving Investigational New Drug (IND) applications. The FDA should also rely on factors other than biomarkers to confirm efficacy, as these are rarely relevant to clinical use. This study summarizes how the drugs used to treat NDs can be made effective and how the FDA should change its guidelines for IND approval of these drugs.
Assuntos
Esclerose Lateral Amiotrófica , Disponibilidade Biológica , Aprovação de Drogas , United States Food and Drug Administration , Humanos , Estados Unidos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Ensaios Clínicos como AssuntoRESUMO
INTRODUCTION: c-Jun N-terminal kinase (JNK) regulates various biological processes through the phosphorylation cascade and is closely associated with numerous diseases, including inflammation, cardiovascular diseases, and neurological disorders. Therefore, JNKs have emerged as potential targets for disease treatment. AREAS COVERED: This review compiles the patents and literatures concerning JNK inhibitors through retrieving relevant information from the SciFinder, Google Patents databases, and PubMed from 2015 to the present. It summarizes the structure-activity relationship (SAR) and biological activity profiles of JNK inhibitors, offering valuable perspectives on their potential therapeutic applications. EXPERT OPINION: The JNK kinase serves as a novel target for the treatment of neurodegenerative disorders, pulmonary fibrosis, and other illnesses. A variety of small-molecule inhibitors targeting JNKs have demonstrated promising therapeutic potential in preclinical studies, which act upon JNK kinases via distinct mechanisms, encompassing traditional ATP competitive inhibition, covalent inhibition, and bidentate inhibition. Among them, several JNK inhibitors from PregLem SA, Celegene SA, and Xigen SA have accomplished the early stage of clinical trials, and their results will guide the development and indications of future JNK inhibitors.
Assuntos
Desenvolvimento de Medicamentos , Proteínas Quinases JNK Ativadas por Mitógeno , Patentes como Assunto , Inibidores de Proteínas Quinases , Humanos , Animais , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Terapia de Alvo Molecular , Desenho de FármacosRESUMO
Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.
Assuntos
Ácido Fólico , Neoplasias , Doenças Neurodegenerativas , Humanos , Ácido Fólico/metabolismo , Ácido Fólico/uso terapêutico , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Carbono/metabolismo , Antagonistas do Ácido Fólico/uso terapêutico , Antagonistas do Ácido Fólico/farmacologiaRESUMO
Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.
Assuntos
Simulação de Acoplamento Molecular , Doenças Neurodegenerativas , Ligação Proteica , Receptor trkB , Receptor trkB/metabolismo , Receptor trkB/agonistas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Animais , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/agonistasRESUMO
Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423].
Assuntos
Envelhecimento , Ferroptose , Polipeptídeo Inibidor Gástrico , Transdução de Sinais , Animais , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Transdução de Sinais/efeitos dos fármacos , Camundongos , Envelhecimento/metabolismo , Envelhecimento/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Humanos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Receptores dos Hormônios Gastrointestinais/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Camundongos Endogâmicos C57BLRESUMO
Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC50 = 0.012 µM and 0.035 µM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.
Assuntos
Caenorhabditis elegans , Inibidores de Histona Desacetilases , Indóis , Animais , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Humanos , Caenorhabditis elegans/efeitos dos fármacos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/síntese química , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Relação Estrutura-Atividade , Doenças Neurodegenerativas/tratamento farmacológico , Animais Geneticamente Modificados , Drosophila , Doença de Parkinson/tratamento farmacológico , Modelos Animais de Doenças , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Doença de Alzheimer/tratamento farmacológicoRESUMO
BACKGROUND: Oxidative stress, a condition characterized by excessive production of reactive oxygen species (ROS), can cause significant damage to cellular macromolecules, leading to neurodegeneration. This underscores the need for effective antioxidant therapies that can mitigate oxidative stress and its associated neurodegenerative effects. KC14 peptide derived from liver-expressed antimicrobial peptide-2 A (LEAP 2 A) from Cyprinus carpio L. has been identified as a potential therapeutic agent. This study focuses on the antioxidant and neuroprotective properties of the KC14 peptide is to evaluate its effectiveness against oxidative stress and neurodegeneration. METHODS: The antioxidant capabilities of KC14 were initially assessed through in silico docking studies, which predicted its potential to interact with oxidative stress-related targets. Subsequently, the peptide was tested at concentrations ranging from 5 to 45 µM in both in vitro and in vivo experiments. In vivo studies involved treating H2O2-induced zebrafish larvae with KC14 peptide to analyze its effects on oxidative stress and neuroprotection. RESULTS: KC14 peptide showed a protective effect against the developmental malformations caused by H2O2 stress, restored antioxidant enzyme activity, reduced neuronal damage, and lowered lipid peroxidation and nitric oxide levels in H2O2-induced larvae. It enhanced acetylcholinesterase activity and significantly reduced intracellular ROS levels (p < 0.05) dose-dependently. Gene expression studies showed up-regulation of antioxidant genes with KC14 treatment under H2O2 stress. CONCLUSIONS: This study highlights the potent antioxidant activity of KC14 and its ability to confer neuroprotection against oxidative stress can provide a novel therapeutic agent for combating neurodegenerative diseases induced by oxidative stress.
Assuntos
Antioxidantes , Carpas , Peróxido de Hidrogênio , Fármacos Neuroprotetores , Estresse Oxidativo , Espécies Reativas de Oxigênio , Peixe-Zebra , Animais , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Carpas/metabolismo , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Proteínas de Peixes/farmacologia , Proteínas de Peixes/metabolismo , Proteínas de Peixes/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos/farmacologia , Óxido Nítrico/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismoRESUMO
Aims: Early detection and treatment of neurodegenerative Langerhans cell histiocytosis (ND-LCH) have been suggested to prevent neurodegenerative progression. The aim of the study is to validate a standardized multidisciplinary diagnostic work-up to monitor the intravenous immunoglobulins (IVIG) treatment response and the natural course of the disease in untreated patients. Methods: Patients with abnormal somatosensory evoked potentials (SEPs) received monthly 0.5 g/kg IVIG. The diagnostic protocol included structural 3T MRI, neurological examination, brainstem auditory evoked potentials (BAEPs) and SEPs. Results: Twenty-two patients were followed for 5.2 years (median) from the first MRI evidence of ND-LCH. Eleven patients received IVIG for 1.7 years (median). At treatment start neurological examination was abnormal in 10 patients, of whom two had severe clinical impairment and four had abnormal BAEPs. At last follow-up, 1/11 remained stable and 7/11 improved, while worsening of neurological or neurophysiological findings, or both, occurred in 3/11. Risk factors for worsening were a severe clinical or MRI ND-LCH at treatment initiation and prolonged exposure to LCH. Of the 11 untreated patients, none improved and three worsened. Conclusions: Using a standardized diagnostic protocol, we demonstrated that IVIG treatment can lead to clinical stabilization or improvement in all pauci-symptomatic patients with an MRI grading of less than 4.
Assuntos
Histiocitose de Células de Langerhans , Imunoglobulinas Intravenosas , Imageamento por Ressonância Magnética , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/diagnóstico , Masculino , Feminino , Potenciais Somatossensoriais Evocados , Resultado do Tratamento , Pré-Escolar , Criança , Adolescente , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/diagnóstico , Lactente , Adulto , Potenciais Evocados Auditivos do Tronco EncefálicoRESUMO
The review considers the use of exogenous neurotrophic factors in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and others. This group of diseases is associated with the death of neurons and dysfunction of the nervous tissue. Currently, there is no effective therapy for neurodegenerative diseases, and their treatment remains a serious problem of modern medicine. A promising strategy is the use of exogenous neurotrophic factors. Targeted delivery of these factors to the nervous tissue can improve survival of neurons during the development of neurodegenerative processes and ensure neuroplasticity. There are methods of direct injection of neurotrophic factors into the nervous tissue, delivery using viral vectors, as well as the use of gene cell products. The effectiveness of these approaches has been studied in numerous experimental works and in a number of clinical trials. Further research in this area could provide the basis for the creation of an alternative treatment for neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Terapia Genética , Fatores de Crescimento Neural , Doenças Neurodegenerativas , Humanos , Fatores de Crescimento Neural/uso terapêutico , Fatores de Crescimento Neural/administração & dosagem , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Terapia Genética/métodos , Animais , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Esclerose Múltipla/tratamento farmacológico , Vetores Genéticos , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/química , Animais , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
INTRODUCTION: Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge. AREAS COVERED: This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target. EXPERT OPINION: VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.
Assuntos
Terapia de Alvo Molecular , Doenças Neurodegenerativas , Proteínas de Transporte Vesicular , Humanos , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/tratamento farmacológico , Proteínas de Transporte Vesicular/metabolismo , Animais , Transporte Proteico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Mutação de Sentido Incorreto , Desenvolvimento de MedicamentosRESUMO
Central neurodegenerative disorders (e.g. Alzheimer's disease (AD) and Parkinson's disease (PD)) are tightly associated with extensive neuron loss. Current therapeutic interventions merely mitigate the symptoms of these diseases, falling short of addressing the fundamental issue of neuron loss. Cell reprogramming, involving the transition of a cell from one gene expression profile to another, has made significant strides in the conversion between diverse somatic cell types. This advancement has been facilitated by gene editing techniques or the synergistic application of small molecules, enabling the conversion of glial cells into functional neurons. Despite this progress, the potential for in situ reprogramming of astrocytes in treating neurodegenerative disorders faces challenges such as immune rejection and genotoxicity. A novel avenue emerges through chemical reprogramming of astrocytes utilizing small molecules, circumventing genotoxic effects and unlocking substantial clinical utility. Recent studies have successfully demonstrated the in situ conversion of astrocytes into neurons using small molecules. Nonetheless, these findings have sparked debates, encompassing queries regarding the origin of newborn neurons, pivotal molecular targets, and alterations in metabolic pathways. This review succinctly delineates the background of astrocytes reprogramming, meticulously surveys the principal classes of small molecule combinations employed thus far, and examines the complex signaling pathways they activate. Finally, this article delves into the potential vistas awaiting exploration in the realm of astrocytes chemical reprogramming, heralding a promising future for advancing our understanding and treatment of neurodegenerative diseases.
Assuntos
Astrócitos , Reprogramação Celular , Doenças Neurodegenerativas , Neurônios , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Humanos , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doenças Neurodegenerativas/terapia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Reprogramação Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Neurodegenerative diseases (NDDs) are an increasing group of chronic and progressive neurological disorders that ultimately lead to neuronal cell failure and death. Despite all efforts throughout decades, their burden on individuals and society still casts one of the most massive socioeconomic problems worldwide. The neuronal failure observed in NDDs results from an intricacy of events, mirroring disease complexity, ranging from protein aggregation, oxidative stress, (neuro)inflammation, and even blood-brain barrier (BBB) dysfunction, ultimately leading to cognitive and motor symptoms in patients. As a result of such complex pathobiology, to date, there are still no effective treatments to treat/halt NDDs progression. Fortunately, interest in the bioavailable low molecular weight (LMW) phenolic metabolites derived from the metabolism of dietary (poly)phenols has been rising due to their multitargeted potential in attenuating multiple NDDs hallmarks. Even if not highly BBB permeant, their relatively high concentrations in the bloodstream arising from the intake of (poly)phenol-rich diets make them ideal candidates to act within the vasculature and particularly at the level of BBB. In this review, we highlight the most recent - though still scarce - studies demonstrating LMW phenolic metabolites' ability to modulate BBB homeostasis, including the improvement of tight and adherens junctional proteins, as well as their power to decrease pro-inflammatory cytokine secretion and oxidative stress levels in vitro and in vivo. Specific BBB-permeant LMW phenolic metabolites, such as simple phenolic sulfates, have been emerging as strong BBB properties boosters, pleiotropic compounds capable of improving cell fitness under oxidative and pro-inflammatory conditions. Nevertheless, further studies should be pursued to obtain a holistic overview of the promising role of LMW phenolic metabolites in NDDs prevention and management to fully harness their true therapeutic potential.
Assuntos
Barreira Hematoencefálica , Polifenóis , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Humanos , Animais , Polifenóis/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Peso Molecular , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/metabolismo , Fenóis/metabolismo , Fenóis/farmacologia , Estresse Oxidativo/fisiologia , Estresse Oxidativo/efeitos dos fármacosRESUMO
Neurodegenerative diseases are characterized by progressive memory impairment and cognitive decline. This review aims to unravel the molecular mechanisms involved in the enhancement of memory function and mitigation of memory impairment through the activation of PPARγ agonists in neurodegenerative diseases. The findings suggest that PPARγ agonists modulate various molecular pathways involved in memory formation and maintenance. Activation of PPARγ enhances synaptic plasticity, promotes neuroprotection, suppresses neuroinflammation, attenuates oxidative stress, and regulates amyloid-beta metabolism. The comprehensive understanding of these molecular mechanisms would facilitate the development of novel therapeutic approaches targeting PPARγ to improve memory function and ultimately to alleviate the burden of neurodegenerative diseases. Further research, including clinical trials, is warranted to explore the efficacy, safety, and optimal use of specific PPARγ agonists as potential therapeutic agents in the treatment of memory impairments associated with neurodegenerative diseases.