Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: Localization, expression and participation in neurodegenerative diseases

SummaryEmerging evidence demonstrates that thrombin exerts physiological and pathological functions in the central nervous system. Both prothrombin and its active form thrombin have been detected locally in the brain. The cellular functions of thrombin are mainly regulated by G protein-coupled protease-activated receptors (PARs). Thrombin can signal via PAR-1, PAR-3 and PAR-4. Some neurological diseases (e.g. Alzheimer’s disease or Parkinson’s disease) are characterized by increased levels of both active thrombin and PAR-1. This indicates that thrombin and its receptor may be closely involved in the development of neurodegenerative processes. The role of thrombin in brain injury can be either protective or deleterious, depending on the concentration of thrombin. Thrombin at high concentrations exacerbates brain damage. In contrast, low concentrations of thrombin rescue neural cells from death after brain insults. Also thrombin preconditioning has neuroprotective effects. Therefore, thrombin and thrombin receptors represent novel therapeutic targets for treating neurodegenerative diseases.

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Hypothalamic Neuropeptide Brain Protection: Focus on Oxytocin

Journal of Clinical Medicine ◽

10.3390/jcm9051534 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1534

Author(s):

Maria Antonietta Panaro ◽

Tarek Benameur ◽

Chiara Porro

Keyword(s):

Neurodegenerative Diseases ◽

Inflammatory Responses ◽

Active Form ◽

Neuroprotective Effects ◽

Positive Effects ◽

New Therapeutic Approaches ◽

Cytokines And Chemokines ◽

Anti Inflammatory ◽

Milk Ejection Reflex ◽

The Brain

Oxytocin (OXT) is hypothalamic neuropeptide synthetized in the brain by magnocellular and parvo cellular neurons of the paraventricular (PVN), supraoptic (SON) and accessory nuclei (AN) of the hypothalamus. OXT acts in the central and peripheral nervous systems via G-protein-coupled receptors. The classical physiological functions of OXT are uterine contractions, the milk ejection reflex during lactation, penile erection and sexual arousal, but recent studies have demonstrated that OXT may have anti-inflammatory and anti-oxidant properties and regulate immune and anti-inflammatory responses. In the pathogenesis of various neurodegenerative diseases, microglia are present in an active form and release high levels of pro-inflammatory cytokines and chemokines that are implicated in the process of neural injury. A promising treatment for neurodegenerative diseases involves new therapeutic approaches targeting activated microglia. Recent studies have reported that OXT exerts neuroprotective effects through the inhibition of production of pro-inflammatory mediators, and in the development of correct neural circuitry. The focus of this review is to attribute a new important role of OXT in neuroprotection through the microglia–OXT interaction of immature and adult brains. In addition, we analyzed the strategies that could enhance the delivery of OXT in the brain and amplify its positive effects.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

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A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms

Biology ◽

10.3390/biology10010034 ◽

2021 ◽

Vol 10 (1) ◽

pp. 34

Author(s):

Kohei Segawa ◽

Yukari Blumenthal ◽

Yuki Yamawaki ◽

Gen Ohtsuki

Keyword(s):

Neurodegenerative Diseases ◽

Lymphatic System ◽

Psychiatric Symptoms ◽

Neurological Diseases ◽

Immune Surveillance ◽

Brain Network ◽

Cellular Mechanisms ◽

Postmortem Brains ◽

New Interpretation ◽

The Brain

The lymphatic system is important for antigen presentation and immune surveillance. The lymphatic system in the brain was originally introduced by Giovanni Mascagni in 1787, while the rediscovery of it by Jonathan Kipnis and Kari Kustaa Alitalo now opens the door for a new interpretation of neurological diseases and therapeutic applications. The glymphatic system for the exchanges of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is associated with the blood-brain barrier (BBB), which is involved in the maintenance of immune privilege and homeostasis in the brain. Recent notions from studies of postmortem brains and clinical studies of neurodegenerative diseases, infection, and cerebral hemorrhage, implied that the breakdown of those barrier systems and infiltration of activated immune cells disrupt the function of both neurons and glia in the parenchyma (e.g., modulation of neurophysiological properties and maturation of myelination), which causes the abnormality in the functional connectivity of the entire brain network. Due to the vulnerability, such dysfunction may occur in developing brains as well as in senile or neurodegenerative diseases and may raise the risk of emergence of psychosis symptoms. Here, we introduce this hypothesis with a series of studies and cellular mechanisms.

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Distribution in the brain and possible neuroprotective effects of intranasally delivered multi-walled carbon nanotubes

Nanoscale Advances ◽

10.1039/d0na00869a ◽

2021 ◽

Author(s):

Marzia Soligo ◽

Fausto Maria Felsani ◽

Tatiana Da Ros ◽

Susanna Bosi ◽

Elena Pellizzoni ◽

...

Keyword(s):

Carbon Nanotubes ◽

Nervous System ◽

Electrochemical Properties ◽

Biomedical Applications ◽

Neurological Diseases ◽

Neuroprotective Effects ◽

Multi Walled Carbon Nanotubes ◽

Walled Carbon Nanotubes ◽

The Brain ◽

Active Investigation

Carbon nanotubes (CNTs) are currently under active investigation for their use in several biomedical applications, especially in neurological diseases and nervous system injury due to their electrochemical properties.

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The Use of Proteomics in Biomarker Discovery in Neurodegenerative Diseases

Disease Markers ◽

10.1155/2005/848676 ◽

2005 ◽

Vol 21 (2) ◽

pp. 81-92 ◽

Cited By ~ 60

Author(s):

Pia Davidsson ◽

Magnus Sjögren

Keyword(s):

Neurodegenerative Diseases ◽

Biomarker Discovery ◽

Neurological Diseases ◽

Synaptic Proteins ◽

Clinical Proteomics ◽

Protein Patterns ◽

Differential Protein ◽

Csf Proteins ◽

New Biomarkers ◽

The Brain

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein,β-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of bothβ-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-β-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.

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Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

10.1101/2020.06.16.153981 ◽

2020 ◽

Author(s):

Laura Casares ◽

Juan Diego Unciti ◽

Maria Eugenia Prados ◽

Diego Caprioglio ◽

Maureen Higgins ◽

...

Keyword(s):

Oxidative Stress ◽

Multiple Sclerosis ◽

Neurodegenerative Diseases ◽

Cell Models ◽

Therapeutic Approaches ◽

Neuroprotective Effects ◽

Anti Oxidant ◽

Anti Inflammatory ◽

The Brain

ABSTRACTOxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington’s disease, setting the basis for further developments in vivo.

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Neuroprotective Effects of Creatine Supplementation in Neurodegenerative Diseases

10.5327/1516-3180.234 ◽

2021 ◽

Author(s):

Maria Clara Lopes Rezende ◽

Maria Luiza Franco de Oliveira ◽

Júlia Campos Fabri ◽

Maria Júlia Filgueiras Granato ◽

Mariana Vanon Moreira ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Neuroprotective Effect ◽

Creatine Supplementation ◽

Complementary Therapy ◽

Neuroprotective Effects ◽

Mitochondrial Functions ◽

Parkinson’S Diseases ◽

The Subject ◽

Intracellular Energy ◽

The Brain

Introduction: Creatine is important in providing energy for the resynthesis of adenosine triphosphate (ATP) and in the deposition of intracellular energy, being present mainly in muscle fibers and in the brain. Supplementation with exogenous creatine can be used in neurodegenerative disorders that are related to bioenergetic deficits in the etiology and progression of the disease. Objective: Highlight the neuroprotective mechanisms of creatine supplementation in neurodegenerative diseases. Methods: In April 2021, a search was carried out on MEDLINE, with the descriptors: “Creatine” and “Neuroprotection”; and its variations, obtained in MeSH. Studies published in the last five years were included. Results: Of the 122 articles found, four were used in this work. They concluded that creatine supplementation contributes to brain bioenergetics by increasing phosphocreatine deposits, restoring mitochondrial functions and decreasing susceptibility to apoptosis. In addition, creatine intake shortly after the diagnosis of Huntington’s and Parkinson’s Diseases can be used as a complementary therapy, because improve performance in tasks of memory and intelligence. Finally, it buffers cellular concentrations of ATP, being a possible therapeutic strategy to delay or stop neurodegeneration diseases. Conclusion: Creatine promote important neuroprotective effect, but further studies on the subject are needed.

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Young plasma ameliorates aging-related acute brain injury after intracerebral hemorrhage

Bioscience Reports ◽

10.1042/bsr20190537 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 4

Author(s):

Jun-Jie Yuan ◽

Qin Zhang ◽

Chang-Xiong Gong ◽

Fa-Xiang Wang ◽

Jia-Cheng Huang ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Brain Damage ◽

Mrna Level ◽

Acute Brain Injury ◽

Aging Brain ◽

Neural Cells ◽

Neuroprotective Effects ◽

The Brain ◽

Brain Tissues

Abstract Aging has been shown to contribute to both the declined biofunctions of aging brain and aggravation of acute brain damage, and the former could be reversed by young plasma. These results suggest that young plasma treatment may also reduce the acute brain damage induced by intracerebral hemorrhage (ICH). In the present study, we first found that the administration of young plasma significantly reduced the mortality and neurological deficit score in aging ICH rodents, which might be due to the decreased brain water content, damaged neural cells, and increased survival neurons around the perihematomal brain tissues. Then, proteomics analysis was used to screen out the potential neuroprotective circulating factors and the results showed that many factors were changed in health human plasma among young, adult, and old population. Among these significantly changed factors, the plasma insulin-like growth factor 1 (IGF-1) level was significantly decreased with age, which was further confirmed both in human and rats detected by ELISA. Additionally, the brain IGF-1 protein level in aging ICH rats was markedly decreased when compared with young rats. Interestingly, the relative decreased brain IGF-1 level was reversed by the treatment of young plasma in aging ICH rats, while the mRNA level was non-significantly changed. Furthermore, the IGF-1 administration significantly ameliorated the acute brain injury in aging ICH rats. These results indicated that young circulating factors, like IGF-1, may enter brain tissues to exert neuroprotective effects, and young plasma may be considered as a novel therapeutic approach for the clinical treatment of aging-related acute brain injury.

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Literature Evidence and ARRIVE Assessment on Neuroprotective Effects of Flavonols in Neurodegenerative Diseases' Models

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666171221110139 ◽

2018 ◽

Vol 17 (1) ◽

pp. 34-42 ◽

Cited By ~ 4

Author(s):

Ana Carolina Bombardi Duarte ◽

Maycon Giovani Santana ◽

Guilherme di Camilo Orfali ◽

Carlos Tadeu Parisi de Oliveira ◽

Denise Goncalves Priolli

Keyword(s):

Neurodegenerative Diseases ◽

Neuroprotective Effects ◽

Major Health Problem ◽

Multifactorial Diseases ◽

Research Fields ◽

Literature Evidence ◽

Evidence Analysis ◽

High Concentrations

Background and Objective: This paper was based on a literature search of PubMed and Scielo databases using the keywords “Flavonoids, Neuroprotection, Quercetin, Rutin, Isoquercitrin, Alzheimer, Parkinson, Huntington” and combinations of all the words. Method: We collected relevant publications, during the period of 2000 to 2016, emphasizing in vivo and in vitro studies with neurological assessment of flavonol's potentials, as well as classifying studies according to evidence levels, in order to elucidate evidence-based literature and its application on clinical research. In addition, we highlight the importance of flavonols in modern research fields, indicating their neuroprotective potential and use thereof as preventive and therapeutic treatment of numerous neurodegenerative disease. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, represent worldwide a major health problem with great financial impact. They are multifactorial diseases, hallmarked by similar pathogenesis that covers conditions such as oxidative stress, formation of free radicals, abnormal protein dynamics (degradation and aggregation), mitochondrial dysfunction, lipid peroxidation and cellular death or senescence. Flavonols are polyphenolic compounds, widely distributed in the plant kingdom and found in high concentrations in vegetables, fruits and teas. Their neuroprotective effects are mainly related to their antioxidant, anti-proliferative and anti-inflammatory properties. Conclusion: It was this paper's intention to contribute with an evidence analysis of recent studies approaching neuroprotective effects of flavonols and the potential to conduct human clinical studies.

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Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22147710 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7710

Author(s):

Ying-Chieh Wu ◽

Tuuli-Maria Sonninen ◽

Sanni Peltonen ◽

Jari Koistinaho ◽

Šárka Lehtonen

Keyword(s):

Stem Cell ◽

Neurodegenerative Diseases ◽

Blood Brain Barrier ◽

Current Knowledge ◽

Neurological Diseases ◽

Induced Pluripotent Stem Cell ◽

Brain Barrier ◽

Blood Brain ◽

Induced Pluripotent ◽

The Brain

The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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