scholarly journals NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis

2020 ◽  
Author(s):  
Prakash Kharel ◽  
Naveen Kumar Singhal ◽  
Nicole West ◽  
Joram Rana ◽  
Lindsey Smith ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Neurodegenerative Diseases ◽  
Aspartic Acid ◽  
Neuronal Cells ◽  
Underlying Mechanism ◽  
Rna Oxidation ◽  
The Brain ◽  
Aspartate Transferase ◽  
Cognate Protein

AbstractRNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain hampers myelin integrity making neuronal axons more susceptible to damage, which contributes in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.

The brain 3β-HSD up-regulation in response to deteriorating effects of background emotional stress: an animal model of multiple sclerosis

2021 ◽  
Author(s):  
Sogol Meknatkhah ◽  
Monireh-Sadat Mousavi ◽  
Pouya Sharif Dashti ◽  
Leila Azizzadeh Pormehr ◽  
Gholam Hossein Riazi
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Emotional Stress ◽  
The Brain

scholarly journals Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yoonjung Kwon ◽  
Yeojin Bang ◽  
Soung-Hee Moon ◽  
Aeri Kim ◽  
Hyun Jin Choi
Keyword(s):  
Neurodegenerative Diseases ◽  
Depressive Disorders ◽  
Neuronal Cells ◽  
Protein Aggregates ◽  
Underlying Mechanism ◽  
Tricyclic Antidepressant ◽  
Autophagic Flux ◽  
Autophagosome Maturation

Abstract Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson’s disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.

scholarly journals Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

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.

scholarly journals Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar Maurya ◽  
Neetu Bhattacharya ◽  
Suman Mishra ◽  
Amit Bhattacharya ◽  
Pratibha Banerjee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Neuroprotective Effect ◽  
Inhibitory Effect ◽  
Dual Function ◽  
Redox Imbalance ◽  
The Brain

Microglia, a type of innate immune cell of the brain, regulates neurogenesis, immunological surveillance, redox imbalance, cognitive and behavioral changes under normal and pathological conditions like Alzheimer’s, Parkinson’s, Multiple sclerosis and traumatic brain injury. Microglia produces a wide variety of cytokines to maintain homeostasis. It also participates in synaptic pruning and regulation of neurons overproduction by phagocytosis of neural precursor cells. The phenotypes of microglia are regulated by the local microenvironment of neurons and astrocytes via interaction with both soluble and membrane-bound mediators. In case of neuron degeneration as observed in acute or chronic neurodegenerative diseases, microglia gets released from the inhibitory effect of neurons and astrocytes, showing activated phenotype either of its dual function. Microglia shows neuroprotective effect by secreting growths factors to heal neurons and clears cell debris through phagocytosis in case of a moderate stimulus. But the same microglia starts releasing pro-inflammatory cytokines like TNF-α, IFN-γ, reactive oxygen species (ROS), and nitric oxide (NO), increasing neuroinflammation and redox imbalance in the brain under chronic signals. Therefore, pharmacological targeting of microglia would be a promising strategy in the regulation of neuroinflammation, redox imbalance and oxidative stress in neurodegenerative diseases. Some studies present potentials of natural products like curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane to suppress activation of microglia. These natural products have also been proposed as effective therapeutics to regulate the progression of neurodegenerative diseases. The present review article intends to explain the molecular mechanisms and functions of microglia and molecular dynamics of microglia specific genes and proteins like Iba1 and Tmem119 in neurodegeneration. The possible interventions by curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane on microglia specific protein Iba1 suggest possibility of natural products mediated regulation of microglia phenotypes and its functions to control redox imbalance and neuroinflammation in management of Alzheimer’s, Parkinson’s and Multiple Sclerosis for microglia-mediated therapeutics.

scholarly journals Recent Advances and Future Perspectives in the Development of Therapeutic Approaches for Neurodegenerative Diseases

2020 ◽  
Vol 10 (9) ◽  
pp. 633
Author(s):  
Melissa Bowerman
Keyword(s):  
Quality Of Life ◽  
Alzheimer’S Disease ◽  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Neuronal Cells ◽  
Future Perspectives ◽  
Therapeutic Approaches ◽  
Recent Advances ◽  
The Brain

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), severely impact the function of neuronal cells in the brain and have devastating consequences on the quality of life of patients and their families [...]

scholarly journals Quantum Dots Application in Neurodegenerative Diseases

Thrita ◽  
2021 ◽  
Vol 9 (2) ◽  
Author(s):  
Behnam Hasannejadasl ◽  
Farkhondeh Pooresmaeil Janbaz ◽  
Edris Choupani ◽  
Mahmood Fadaie ◽  
Mohammad Ali Hamidinejad ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Quantum Dots ◽  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Bright Light ◽  
Therapeutic Agents ◽  
High Quantum Yield ◽  
High Emission ◽  
Image Production ◽  
The Brain

: Quantum dots (QDs) are nanoparticles (NPs) with electronic and optical properties such as emitting bright light and fluorescence. They also carry specific characters such as photostability, high quantum yield, high emission, and size-turnable. Nowadays, a great interest is given to the extensive use of theranostic-NPs for sensing and imaging, as well as drug delivery. Moreover, QDs may yield great potential for the diagnosis and treatment of various central nervous system (CNS) diseases (e.g., Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis). The blood-brain barrier (BBB) protects the brain tissue. Only certain small molecules like water and gases can cross BBB, whereas larger molecules enter via receptors, but many drugs are incapable of passing the barrier. A series of great advances have been achieved concerning using different NPs (e.g., QDs) to deliver drugs to the brain and CNS imaging. In this review, we discussed a wide variety of QDs along with their production, passive or active delivery of therapeutic agents for neurodegenerative diseases, and different image production.

Human neuronal cells: epigenetic aspects

2013 ◽  
Vol 4 (4) ◽  
pp. 319-333 ◽  
Author(s):  
Jessica Kukucka ◽  
Tessa Wyllie ◽  
Justin Read ◽  
Lauren Mahoney ◽  
Cenk Suphioglu
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Neuronal Cells ◽  
Hdac Inhibitors ◽  
Histone Acetyltransferases ◽  
Human Neuronal Cells ◽  
The Brain

AbstractHistone acetyltransferases (HATs) and histone deacetylases (HDACs) promote histone posttranslational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration. Alzheimer’s disease is the most common neurodegenerative disease of the brain, which has devastating effects on patients and loved ones. The use of pan-HDAC inhibitors has shown great therapeutic promise in ameliorating neurodegenerative ailments. Recent evidence has emerged suggesting that certain deacetylases mediate neurotoxicity, whereas others provide neuroprotection. Therefore, the inhibition of certain isoforms to alleviate neurodegenerative manifestations has now become the focus of studies. In this review, we aimed to discuss and summarize some of the most recent and promising findings of HAT and HDAC functions in neurodegenerative diseases.

scholarly journals Interactions between Neutrophils, Th17 Cells, and Chemokines during the Initiation of Experimental Model of Multiple Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Dagmara Weronika Wojkowska ◽  
Piotr Szpakowski ◽  
Dominika Ksiazek-Winiarek ◽  
Marcin Leszczynski ◽  
Andrzej Glabinski
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Th17 Cells ◽  
Inflammatory Cell ◽  
Autoimmune Encephalomyelitis ◽  
Preclinical Phase ◽  
Activated T Cell ◽  
Cell Subpopulations ◽  
The Brain ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) in which activated T cell and neutrophil interactions lead to neuroinflammation. In this study the expression of CCR6, CXCR2, and CXCR6 in Th17 cells and neutrophils migrating to the brain during EAE was measured, alongside an evaluation of the production of IL-17, IL-23, CCL-20, and CXCL16 in the brain. Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed. Th17 cells upregulate CXCR2 during the preclinical phase of EAE and a significant migration of these cells to the brain was observed. Neutrophils upregulated CCR6, CXCR2, and CXCR6 during EAE, accumulating in the brain both prior to and during acute EAE attacks. Production of IL-17, IL-23, CCL20, and CXCL16 in the CNS was increased during both preclinical and acute EAE. Intracerebral delivery of CXCL1 stimulated the early accumulation of neutrophils in normal and preclinical EAE brains but reduced the migration of Th17 cells to the brain during the preclinical stage of EAE. Modulation of EAE by anti-IL-23R antibodies ameliorated EAE by decreasing the intracerebral accumulation of Th17 cells.

scholarly journals A State of the Art of Antioxidant Properties of Curcuminoids in Neurodegenerative Diseases

2021 ◽  
Vol 22 (6) ◽  
pp. 3168
Author(s):  
Serena Silvestro ◽  
Cinzia Sindona ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Oxidative Phosphorylation ◽  
Neurodegenerative Diseases ◽  
Neuronal Cells ◽  
Antioxidant Properties ◽  
Neuroprotective Effects ◽  
Energy Needs ◽  
Anti Oxidant ◽  
Therapeutic Properties ◽  
The Brain ◽  
Lateral Sclerosis

Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.

scholarly journals Neuronal Cell Death Induces Depressive Disorder in Rats Depression-Like Behaviors Caused by Chronic Stress

2020 ◽  
Vol 1 (2) ◽  
pp. 16-24
Author(s):  
Rachmat Hidayat ◽  
Mgs Irsan Saleh ◽  
Nita Parisa
Keyword(s):  
Animal Model ◽  
Prefrontal Cortex ◽  
Depressive Disorder ◽  
Cell Apoptosis ◽  
Neuronal Cells ◽  
Neuronal Cell ◽  
Normal Group ◽  
Experimental Animals ◽  
The Brain

Abstract Introduction Depression is believed to be a disorder in which an increase in serotonin activity in the brain. This has implications for the development of various antidepressant drugs that work to increase serotonin levels, by inhibiting serotonin reuptake. However, management with antidepressants is still believed to be not optimal, there are still various problems that have not been able to be solved only by increasing serotonin levels in the brain. Therefore, it is necessary to do further exploration to find out other possible pathophysiology of depressive disorders. This study intended to explore the role of apoptosis of neuronal cells in the prefrontal cortex to answer the hypothesis that depression was not only caused by increased serotonin levels but also  there was a role of dead neuronal cells in the prefrontal cortex which will trigger the body's homeostatic efforts to compensate by increasing serotonin levels.   Methods A total of 30 male Wistar rats (200 ± 20 g) were obtained from Eureka Research Laboratory (Palembang, Indonesia). Experimental animals were placed in cages under controlled conditions (12 hours of light / dark cycles with temperatures of 22 ± 1˚C and humidity of 40-60%), fed and drank ad libitum. Experimental animals with depression model were induced using Chronic Mild Stress (CMS). CMS procedures were performed with mild stressors such as repeated cold stress (4 ° C), space reduction in the homecage, changed cages and social interaction with other animals of the CMS group. To assess wether animal were being depression or not, the animal were tested using Forced Swimming Test (FST). After induction, rats were randomly divided into two groups which each contained 15 animals: the normal control group (not induced CMS) and the CMS group (negative control). Furthermore, the animal model was performed perfusion to maintain organ when evacuation was done, cell damage did not occur. To evaluate cell organ, immunohistochemistry examination and ELISA examination was performed. All data are presented as mean ± standard deviation and all statistical analyzes are performed with the SPSS 25 (IBM) program. Result This research showed that CMS animal model has a greater duration of immobility than the normal group and serotonin level in CMS animal models decreased almost threefold compared to the normal group. In addition, there were increased expression of caspase-3 indicates that more neuronal cells suffered from apoptosis. So, in this research, it was clearly stated that in depressive disorder, there were elevation of neuronal cell apoptosis in the prefrontal cortex. Conclusion Neuronal cell apoptosis in the prefrontal cortex plays a role in the pathophysiology of depression through activation of negative feedback on serotonin production.

Sign in / Sign up

Export Citation Format

Share Document