scholarly journals Cerebral sterile inflammation in neurodegenerative diseases

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Kento Otani ◽  
Takashi Shichita
Keyword(s):  
Immune Responses ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Therapeutic Agents ◽  
Sterile Inflammation ◽  
Cellular Damage ◽  
Cellular Mechanisms ◽  
Abnormal Accumulation ◽  
The Brain ◽  
Lateral Sclerosis

AbstractTherapeutic strategies for regulating neuroinflammation are expected in the development of novel therapeutic agents to prevent the progression of central nervous system (CNS) pathologies. An understanding of the detailed molecular and cellular mechanisms of neuroinflammation in each CNS disease is necessary for the development of therapeutics. Since the brain is a sterile organ, neuroinflammation in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) is triggered by cerebral cellular damage or the abnormal accumulation of inflammatogenic molecules in CNS tissue through the activation of innate and acquired immunity. Inflammation and CNS pathologies worsen each other through various cellular and molecular mechanisms, such as oxidative stress or the accumulation of inflammatogenic molecules induced in the damaged CNS tissue. In this review, we summarize the recent evidence regarding sterile immune responses in neurodegenerative diseases.

scholarly journals Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1158 ◽  
Author(s):  
Dongmei Chen ◽  
Tao Zhang ◽  
Tae Ho Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cellular Mechanisms ◽  
Wide Range ◽  
Public Health Challenge ◽  
Cumulative Evidence ◽  
The Brain ◽  
Lateral Sclerosis

Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.

scholarly journals Neurodegenerative disorders and sterile inflammation: lessons from a Drosophila model

2019 ◽  
Vol 166 (3) ◽  
pp. 213-221 ◽  
Author(s):  
Firzan Nainu ◽  
Emil Salim ◽  
Rangga Meidianto Asri ◽  
Aki Hori ◽  
Takayuki Kuraishi
Keyword(s):  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Biological Significance ◽  
Sterile Inflammation ◽  
Medical Interventions ◽  
Drosophila Model ◽  
Progressive Neurodegeneration ◽  
Molecular Patterns ◽  
The Brain ◽  
Lateral Sclerosis

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

scholarly journals Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Musbau Adewumi Akanji ◽  
Damilare Emmanuel Rotimi ◽  
Tobiloba Christiana Elebiyo ◽  
Oluwakemi Josephine Awakan ◽  
Oluyomi Stephen Adeyemi
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Redox Homeostasis ◽  
Reactive Species ◽  
Cellular Damage ◽  
Cellular Mechanisms ◽  
Cellular Redox ◽  
Redox Imbalance ◽  
Cellular Processes ◽  
The Brain

Reactive species, such as those of oxygen, nitrogen, and sulfur, are considered part of normal cellular metabolism and play significant roles that can impact several signaling processes in ways that lead to either cellular sustenance, protection, or damage. Cellular redox processes involve a balance in the production of reactive species (RS) and their removal because redox imbalance may facilitate oxidative damage. Physiologically, redox homeostasis is essential for the maintenance of many cellular processes. RS may serve as signaling molecules or cause oxidative cellular damage depending on the delicate equilibrium between RS production and their efficient removal through the use of enzymatic or nonenzymatic cellular mechanisms. Moreover, accumulating evidence suggests that redox imbalance plays a significant role in the progression of several neurodegenerative diseases. For example, studies have shown that redox imbalance in the brain mediates neurodegeneration and alters normal cytoprotective responses to stress. Therefore, this review describes redox homeostasis in neurodegenerative diseases with a focus on Alzheimer’s and Parkinson’s disease. A clearer understanding of the redox-regulated processes in neurodegenerative disorders may afford opportunities for newer therapeutic strategies.

scholarly journals P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

2020 ◽  
Vol 21 (17) ◽  
pp. 5996
Author(s):  
Peter Illes
Keyword(s):  
Neurodegenerative Diseases ◽  
Life Quality ◽  
Bioactive Molecules ◽  
Cellular Damage ◽  
P2x7 Receptors ◽  
The Brain ◽  
Intracellular Ions ◽  
Lateral Sclerosis ◽  
Pro Inflammatory Cytokines ◽  
Receptor Channel

ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na+, Ca2+, and K+, but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca2+ influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.

Excitotoxicity as a Target Against Neurodegenerative Processes

2020 ◽  
Vol 26 (12) ◽  
pp. 1251-1262 ◽  
Author(s):  
Octavio Binvignat ◽  
Jordi Olloquequi
Keyword(s):  
Neurodegenerative Diseases ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Mitochondrial Dysfunctions ◽  
Beneficial Effects ◽  
Clinical Investigations ◽  
Turn Over ◽  
Excitotoxic Cell Death ◽  
Lateral Sclerosis

: The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. : Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. : In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

scholarly journals Molecular mechanisms of cell death in neurological diseases

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.

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

Biology ◽  
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.

scholarly journals Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases

2009 ◽  
Vol 45 (4) ◽  
pp. 607-618 ◽  
Author(s):  
Graciela Cristina dos Santos ◽  
Lusânia Maria Greggi Antunes ◽  
Antonio Cardozo dos Santos ◽  
Maria de Lourdes Pires Bianchi
Keyword(s):  
Neurodegenerative Diseases ◽  
Health Risks ◽  
Coenzyme Q10 ◽  
Cellular Respiration ◽  
Irreversible Loss ◽  
Beneficial Effects ◽  
Pathological Conditions ◽  
Electron Transportation ◽  
The Brain ◽  
Lateral Sclerosis

According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q10 (CoQ10) has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP). The property of CoQ10 to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ10 has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ10 before exposing patients to unnecessary health risks at significant costs.

ATP-binding cassette transporters and neurodegenerative diseases

2021 ◽  
Author(s):  
Jared S. Katzeff ◽  
Woojin Scott Kim
Keyword(s):  
Neurodegenerative Diseases ◽  
Abc Transporters ◽  
Brain Diseases ◽  
Atp Binding ◽  
Future Directions ◽  
Diverse Range ◽  
The Brain ◽  
Lateral Sclerosis ◽  
Atp Binding Cassette

Abstract ATP-binding cassette (ABC) transporters are one of the largest groups of transporter families in humans. ABC transporters mediate the translocation of a diverse range of substrates across cellular membranes, including amino acids, nucleosides, lipids, sugars and xenobiotics. Neurodegenerative diseases are a group of brain diseases that detrimentally affect neurons and other brain cells and are usually associated with deposits of pathogenic proteins in the brain. Major neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. ABC transporters are highly expressed in the brain and have been implicated in a number of pathological processes underlying neurodegenerative diseases. This review outlines the current understanding of the role of ABC transporters in neurodegenerative diseases, focusing on some of the most important pathways, and also suggests future directions for research in this field.

scholarly journals Radon Exposure and Neurodegenerative Disease

2020 ◽  
Vol 17 (20) ◽  
pp. 7439
Author(s):  
Silvia Gómez-Anca ◽  
Juan Miguel Barros-Dios
Keyword(s):  
Neurodegenerative Diseases ◽  
Scientific Evidence ◽  
Subsequent Development ◽  
Brain Anatomy ◽  
Inclusion Criteria ◽  
Motor Neuron Diseases ◽  
Radon Exposure ◽  
Bibliographic Search ◽  
The Brain ◽  
Lateral Sclerosis

Background: To carry out a systematic review of scientific literature about the association between radon exposure and neurodegenerative diseases. Methods: We performed a bibliographic search in the following databases: Pub med (Medline), Cochrane, BioMed Central and Web of Science. We collected the data by following a predetermined search strategy in which several terms werecombined. After an initial search, 77 articles were obtained.10 of which fulfilled the inclusion criteria. Five of these 10 studies were related to multiple sclerosis (MS), 2 were about motor neuron diseases (MND), in particular amyotrophic lateral sclerosis (ALS) and 3 were related to both Alzheimer’s disease (AD) and Parkinson’s disease (PD). Results: The majority of the included articles, suggested a possible association between radon exposure and a subsequent development of neurodegenerative diseases. Some of the studies that obtained statistically significant resultsrevealed a possible association between radon exposure and an increase in MS prevalence. Furthermore, it was also suggested that radon exposure increases MND and AD mortality. Regarding AD and PD, it was observed that certainde cay products of radon-222 (222Rn), specifically polonium-210 (210Po) and bismuth-210 (210Bi), present a characteristic distributionpattern within the brain anatomy. However, the study with the highest scientific evidence included in this review, which investigated a possible association between the concentration of residential radon gas and the MS incidence, revealed no significant results. Conclusions: It cannot be concluded, although it is observed, that there is a possible causal association between radon exposure and neurodegenerative diseases. Most of the available studies are ecological so, studies of higher statistical evidence are needed to establish a causal relationship. Further research is needed on this topic.

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