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.

Mitochondrial dysfunction plays a key role in the development of neurodegenerative diseases in diabetes

2020 ◽  
Vol 318 (5) ◽  
pp. E750-E764 ◽  
Author(s):  
Han Cheng ◽  
Xiaokun Gang ◽  
Yujia Liu ◽  
Gang Wang ◽  
Xue Zhao ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Reactive Oxygen Species Generation ◽  
Hypoglycemic Agents ◽  
Neuroprotective Effects ◽  
Mitochondrial Dysfunctions ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Glucagon Like Peptide 1

Mitochondria have an essential function in cell survival due to their role in bioenergetics, reactive oxygen species generation, calcium buffering, and other metabolic activities. Mitochondrial dysfunctions are commonly found in neurodegenerative diseases (NDs), and diabetes is a risk factor for NDs. However, the role of mitochondria in diabetic neurodegeneration is still unclear. In the present study, we review the latest evidence on the role of mitochondrial dysfunctions in the development of diabetes-related NDs and the underlying molecular mechanisms. Hypoglycemic agents, especially metformin, have been proven to have neuroprotective effects in the treatment of diabetes, in which mitochondria could act as one of the underlying mechanisms. Other hypoglycemic agents, including thiazolidinediones (TZDs), dipeptidyl peptidase 4 (DPP-4) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, have gained more attention because of their beneficial effects on NDs, presumably by improving mitochondrial function. Our review highlights the notion that mitochondria could be a promising therapeutic target in the treatment of NDs in patients with diabetes.

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.

scholarly journals Anthocyanins and Their Metabolites as Therapeutic Agents for Neurodegenerative Disease

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 333 ◽  
Author(s):  
Aimee N. Winter ◽  
Paula C. Bickford
Keyword(s):  
Neurodegenerative Diseases ◽  
Nitrosative Stress ◽  
Therapeutic Potential ◽  
Stress Protein ◽  
Motor Impairments ◽  
Oxidative And Nitrosative Stress ◽  
Beneficial Effects ◽  
Neuronal Populations ◽  
Neurodegenerative Process ◽  
Lateral Sclerosis

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), are characterized by the death of neurons within specific regions of the brain or spinal cord. While the etiology of many neurodegenerative diseases remains elusive, several factors are thought to contribute to the neurodegenerative process, such as oxidative and nitrosative stress, excitotoxicity, endoplasmic reticulum stress, protein aggregation, and neuroinflammation. These processes culminate in the death of vulnerable neuronal populations, which manifests symptomatically as cognitive and/or motor impairments. Until recently, most treatments for these disorders have targeted single aspects of disease pathology; however, this strategy has proved largely ineffective, and focus has now turned towards therapeutics which target multiple aspects underlying neurodegeneration. Anthocyanins are unique flavonoid compounds that have been shown to modulate several of the factors contributing to neuronal death, and interest in their use as therapeutics for neurodegeneration has grown in recent years. Additionally, due to observations that the bioavailability of anthocyanins is low relative to that of their metabolites, it has been proposed that anthocyanin metabolites may play a significant part in mediating the beneficial effects of an anthocyanin-rich diet. Thus, in this review, we will explore the evidence evaluating the neuroprotective and therapeutic potential of anthocyanins and their common metabolites for treating neurodegenerative diseases.

scholarly journals Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

2020 ◽  
Vol 21 (10) ◽  
pp. 3719 ◽  
Author(s):  
Serena Stanga ◽  
Anna Caretto ◽  
Marina Boido ◽  
Alessandro Vercelli
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuronal Degeneration ◽  
Muscular Atrophy ◽  
Early Event ◽  
Mitochondrial Dysfunctions ◽  
The Core ◽  
Optimal Functioning ◽  
Mitochondrial Functions ◽  
Lateral Sclerosis ◽  
Common Target

Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the “mitochondrial switch” which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases.

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 Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 150 ◽  
Author(s):  
Qian Cai ◽  
Yu Young Jeong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cellular Energy ◽  
Age Related ◽  
Mitochondrial Turnover ◽  
Neuronal Functions ◽  
Lateral Sclerosis

Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer’s disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders.

scholarly journals Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of Amyotrophic Lateral Sclerosis

2018 ◽  
Author(s):  
Anthony Giampetruzzi ◽  
Eric W. Danielson ◽  
Maryangel Jeon ◽  
Valentia Gumina ◽  
Sivakumar Boopathy ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Nucleocytoplasmic Transport ◽  
Unknown Etiology ◽  
Nuclear Pore ◽  
Repeat Expansions ◽  
Lateral Sclerosis ◽  
Actin Homeostasis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansions, the most common mutations in ALS patients. Collectively, our data link NCT defects to ALS-associated pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.

scholarly journals Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Susanne Petri ◽  
Sonja Körner ◽  
Mahmoud Kiaei
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Leucine Zipper ◽  
Antioxidant Response ◽  
Related Factor ◽  
Mitochondrial Dysfunctions ◽  
Promising Target ◽  
Basic Region ◽  
Lateral Sclerosis

Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD).

scholarly journals Physical Exercise-Induced Myokines in Neurodegenerative Diseases

2021 ◽  
Vol 22 (11) ◽  
pp. 5795
Author(s):  
Banseok Lee ◽  
Myeongcheol Shin ◽  
Youngjae Park ◽  
So-Yoon Won ◽  
Kyoung Sang Cho
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Modification ◽  
Underlying Mechanism ◽  
Future Studies ◽  
Beneficial Effects ◽  
The Past ◽  
Progressive Degeneration ◽  
Novel Strategy ◽  
Exercise Induced ◽  
Lateral Sclerosis

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.

scholarly journals Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2197
Author(s):  
Zsolt Kovács ◽  
Brigitta Brunner ◽  
Csilla Ari
Keyword(s):  
Health Status ◽  
Life Expectancy ◽  
Neurodegenerative Diseases ◽  
Neuroprotective Effects ◽  
Psychological Burden ◽  
Beneficial Effects ◽  
Age Related ◽  
Healthy State ◽  
Therapeutic Tools ◽  
Lateral Sclerosis

Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.

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