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Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 26748

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Dr. Anne Vejux

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Team “Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism”, Université de Bourgogne, 21000 Dijon, France
Interests: oxysterols; very-long-chain fatty acids; lipid metabolism; diet, peroxisomes; biotherapies; inflammation; cancer; cell cycle and apoptosis; autophagy; biological membranes; oxidative damage; biomarkers; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues, “Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules” and "Cell Death and Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules".

Neurodegenerative diseases represent a major societal challenge. These are not diseases with a short, life-threatening prognosis, but they are very debilitating, inflicting heavy demands on carers and requiring the establishment of appropriate centers for patient care. It is therefore important to know even more about the mechanisms involved in the physiopathogenesis of these diseases.

Neurodegenerative diseases include demyelinating neurodegenerative diseases: multiple sclerosis and peroxisomal and nondemyelinating leukodystrophies—Alzheimer’s disease, Parkinson’s disease, Niemann–Pick disease, Huntington’s disease, and amyotrophic lateral sclerosis or Charcot disease. Among the mechanisms involved in these pathologies, inflammation, oxidative stress, and cell death play very important roles in their pathophysiology. It is therefore important to better understand the involvement of cell death, inflammation, and oxidative stress, as well as the cellular and molecular mechanisms leading to it, and to identify the natural or unnatural molecules that can thwart these mechanisms. Apoptosis, autophagy, necroptosis, or other forms of cell death can be interesting therapeutic targets to combat the development of these neurodegenerative diseases. Cytokinic and non-cytokinic inflammation, as well as processes generating oxidative stress, could also be interesting targets to fight these pathologies.

Dr. Anne Vejux
Guest Editor

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Keywords

apoptosis
autophagy
necrosis
reticulum stress
natural molecules
oxidative stress
therapeutic
signalling pathways

Published Papers (9 papers)

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Research

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14 pages, 39658 KiB

Open AccessArticle

Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner

by Christopher Simon, Tomoko Soga and Ishwar Parhar

Int. J. Mol. Sci. 2023, 24(7), 6056; https://doi.org/10.3390/ijms24076056 - 23 Mar 2023

Cited by 1 | Viewed by 1515

Abstract

The hypothalamic neurohormone kisspeptin-10 (KP-10) was inherently implicated in cholinergic pathologies when aberrant fluctuations of expression patterns and receptor densities were discerned in neurodegenerative micromilieus. That said, despite variable degrees of functional redundancy, KP-10, which is biologically governed by its cognate G-protein-coupled receptor, GPR54, attenuated the progressive demise of α-synuclein (α-syn)-rich cholinergic-like neurons. Under explicitly modeled environments, in silico algorithms further rationalized the surface complementarities between KP-10 and α-syn when KP-10 was unambiguously accommodated in the C-terminal binding pockets of α-syn. Indeed, the neuroprotective relevance of KP-10’s binding mechanisms can be insinuated in the amelioration of α-syn-mediated neurotoxicity; yet it is obscure whether these extenuative circumstances are contingent upon prior GPR54 activation. Herein, choline acetyltransferase (ChAT)-positive SH-SY5Y neurons were engineered ad hoc to transiently overexpress human wild-type or E46K mutant α-syn while the mitigation of α-syn-induced neuronal death was ascertained via flow cytometric and immunocytochemical quantification. Recapitulating the specificity observed on cell viability, exogenously administered KP-10 (0.1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated apoptosis and mitochondrial depolarization in cholinergic differentiated neurons. In particular, co-administrations with a GPR54 antagonist, kisspeptin-234 (KP-234), failed to abrogate the robust neuroprotection elicited by KP-10, thereby signifying a GPR54 dispensable mechanism of action. Consistent with these observations, KP-10 treatment further diminished α-syn and ChAT immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn. Overall, these findings lend additional credence to the previous notion that KP-10’s binding zone may harness efficacious moieties of neuroprotective intent. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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22 pages, 11081 KiB

Open AccessArticle

LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

by Irais E. Valenzuela-Arzeta, Luis O. Soto-Rojas, Yazmin M. Flores-Martinez, Karen M. Delgado-Minjares, Bismark Gatica-Garcia, Juan U. Mascotte-Cruz, Porfirio Nava, Omar Emiliano Aparicio-Trejo, David Reyes-Corona, Irma A. Martínez-Dávila, M. E. Gutierrez-Castillo, Armando J. Espadas-Alvarez, Carlos E. Orozco-Barrios and Daniel Martinez-Fong

Int. J. Mol. Sci. 2023, 24(5), 4628; https://doi.org/10.3390/ijms24054628 - 27 Feb 2023

Cited by 6 | Viewed by 2727

Abstract

Whether neuroinflammation leads to dopaminergic nigrostriatal system neurodegeneration is controversial. We addressed this issue by inducing acute neuroinflammation in the substantia nigra (SN) with a single local administration (5 µg/2 µL saline solution) of lipopolysaccharide (LPS). Neuroinflammatory variables were assessed from 48 h to 30 days after the injury by immunostaining for activated microglia (Iba-1 +), neurotoxic A1 astrocytes (C3 + and GFAP +), and active caspase-1. We also evaluated NLRP3 activation and Il-1β levels by western blot and mitochondrial complex I (CI) activity. Fever and sickness behavior was assessed for 24 h, and motor behavior deficits were followed up until day 30. On this day, we evaluated the cellular senescence marker β-galactosidase (β-Gal) in the SN and tyrosine hydroxylase (TH) in the SN and striatum. After LPS injection, Iba-1 (+), C3 (+), and S100A10 (+) cells were maximally present at 48 h and reached basal levels on day 30. NLRP3 activation occurred at 24 h and was followed by a rise of active caspase-1 (+), Il-1β, and decreased mitochondrial CI activity until 48 h. A significant loss of nigral TH (+) cells and striatal terminals was associated with motor deficits on day 30. The remaining TH (+) cells were β-Gal (+), suggesting senescent dopaminergic neurons. All the histopathological changes also appeared on the contralateral side. Our results show that unilaterally LPS-induced neuroinflammation can cause bilateral neurodegeneration of the nigrostriatal dopaminergic system and are relevant for understanding Parkinson’s disease (PD) neuropathology. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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21 pages, 3914 KiB

Open AccessArticle

Oxidative Stress and Mitochondrial Complex I Dysfunction Correlate with Neurodegeneration in an α-Synucleinopathy Animal Model

by Adriana Morales-Martínez, Paola A. Martínez-Gómez, Daniel Martinez-Fong, Marcos M. Villegas-Rojas, Francisca Pérez-Severiano, Miguel A. Del Toro-Colín, Karen M. Delgado-Minjares, Víctor Manuel Blanco-Alvarez, Bertha Alicia Leon-Chavez, Omar Emiliano Aparicio-Trejo, Mauricio T. Baéz-Cortés, Maria-del-Carmen Cardenas-Aguayo, José Luna-Muñoz, Mar Pacheco-Herrero, Quetzalli D. Angeles-López, Irma A. Martínez-Dávila, Citlaltepetl Salinas-Lara, José Pablo Romero-López, Carlos Sánchez-Garibay, Adolfo R. Méndez-Cruz and Luis O. Soto-Rojas Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(19), 11394; https://doi.org/10.3390/ijms231911394 - 27 Sep 2022

Cited by 16 | Viewed by 2514

Abstract

The α-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson’s disease (PD) is the most common worldwide, characterized by the accumulation of misfolded α-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how α-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic β-sitosterol β-D-glucoside (BSSG), which produces α-synucleinopathy. In this model, we aimed to evaluate the temporal pattern of levels in oxidative and nitrosative stress and mitochondrial complex I (CI) dysfunction and how these biochemical parameters are associated with neurodegeneration in different brain areas with α-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where α-syn aggregation spreads). Interestingly, an increase in oxidative stress and mitochondrial CI dysfunction accompanied neurodegeneration in those brain regions. Furthermore, in silico analysis suggests a high-affinity binding site for BSSG with peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-α) and gamma (PPAR-γ). These findings will contribute to elucidating the pathophysiological mechanisms associated with α-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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11 pages, 24304 KiB

Open AccessArticle

Brain Neurons during Physiological Aging: Morphological Features, Autophagic and Mitochondrial Contribution

by Vladimir Sukhorukov, Alina Magnaeva, Tatiana Baranich, Anna Gofman, Dmitry Voronkov, Tatiana Gulevskaya, Valeria Glinkina and Sergey Illarioshkin

Int. J. Mol. Sci. 2022, 23(18), 10695; https://doi.org/10.3390/ijms231810695 - 14 Sep 2022

Cited by 1 | Viewed by 2019

Abstract

Accumulating data suggest that the brain undergoes various changes during aging. Among them are loss of both white and gray matter, neurons and synapses degeneration, as well as oxidative, inflammatory, and biochemical changes. The above-mentioned age-related features are closely related to autophagy and mitochondria. Therefore, we aimed to reveal the most peculiar morphological features of brain nervous tissue and to characterize the expression of autophagy and mitochondrial immunohistochemical biomarkers in neurons of different human brain zones during aging. Counting the number of neurons as well as Microtubule-associated proteins 1A/1B light chain 3B (LC3B), Heat shock protein 70 (HSP70), Lysosome-associated membrane protein type 2A (LAMP2A), Alpha subunit of ATP synthase (ATP5A), and Parkinson disease protein 7 (DJ1) immunohistochemical staining were performed on FFPE samples of human prefrontal cortex, corpus striatum, and hippocampus obtained from autopsy. Statistical analysis revealed a loss of neurons in the studied elderly group in comparison to the young group. When the expression of macroautophagy (LC3B), chaperon-mediated autophagy (HSP70, LAMP2A), and mitochondrial respiratory chain complex V (ATP5A) markers for the young and elderly groups were compared, the latter was found to have a significantly higher rate of optical density, whilst there was no significance in DJ1 expression. These findings, while preliminary, suggest that both autophagy and mitochondria are involved in neuronal maintenance during aging and could indicate their potential role in adaptive mechanisms that occur in aging. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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18 pages, 2153 KiB

Open AccessArticle

Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels

by Nikolina Prtenjaca, Matea Rob, Muhammad S. Alam, Andrea Markovinovic, Cristiana Stuani, Emanuele Buratti and Ivana Munitic

Int. J. Mol. Sci. 2022, 23(12), 6829; https://doi.org/10.3390/ijms23126829 - 19 Jun 2022

Cited by 5 | Viewed by 2374

Abstract

Mutations in optineurin, a ubiquitin-binding adaptor protein, cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of motor neurons linked to chronic inflammation and protein aggregation. The majority of ALS patients, including those carrying the optineurin mutations, exhibit cytoplasmic mislocalization, ubiquitination, and aggregation of nuclear TAR DNA-binding protein 43 kDa (TDP-43). To address the crosstalk between optineurin and TDP-43, we generated optineurin knockout (KO) neuronal and microglial cell lines using the CRISPR/Cas9 approach. Interestingly, we observed that loss of optineurin resulted in elevated TDP-43 protein expression in microglial BV2 but not neuronal Neuro 2a and NSC-34 cell lines. No changes were observed at the mRNA level, suggesting that this increase was post-translationally regulated. To confirm this observation in primary cells, we then used microglia and macrophages from an optineurin loss-of-function mouse model that lacks the C-terminal ubiquitin-binding region (Optn^470T), mimicking optineurin truncations in ALS patients. As observed in the BV2 cells, we also found elevated basal levels of TDP-43 protein in Optn^470T microglia and bone marrow-derived macrophages. To test if inflammation could further enhance TDP-43 accumulation in cells lacking functional optineurin, we stimulated them with lipopolysaccharide (LPS), and we observed a significant increase in TDP-43 expression following LPS treatment of WT cells. However, this was absent in both BV2 Optn KO and primary Optn^470T microglia, which exhibited the same elevated TDP-43 levels as in basal conditions. Furthermore, we did not observe nuclear TDP-43 depletion or cytoplasmic aggregate formation in either Optn^470T microglia or LPS-treated WT or Optn^470T microglia. Taken together, our results show that optineurin deficiency and insufficiency post-translationally upregulate microglial TDP-43 protein levels and that elevated TDP-43 levels in cells lacking functional optineurin could not be further increased by an inflammatory stimulus, suggesting the presence of a plateau. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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20 pages, 2938 KiB

Open AccessArticle

Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response

by Katarina Milosevic, Ivana Stevanovic, Iva D. Bozic, Ana Milosevic, Marija M. Janjic, Danijela Laketa, Ivana Bjelobaba, Irena Lavrnja and Danijela Savic

Int. J. Mol. Sci. 2022, 23(7), 3561; https://doi.org/10.3390/ijms23073561 - 24 Mar 2022

Cited by 9 | Viewed by 3383

Abstract

Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O₂⁻ levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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8 pages, 1216 KiB

Open AccessCommunication

CCL2 Inhibition of Pro-Resolving Mediators Potentiates Neuroinflammation in Astrocytes

by Irene L. Gutiérrez, Fabiana Novellino, Javier R. Caso, Borja García-Bueno, Juan C. Leza and José L. M. Madrigal

Int. J. Mol. Sci. 2022, 23(6), 3307; https://doi.org/10.3390/ijms23063307 - 18 Mar 2022

Cited by 7 | Viewed by 2222

Abstract

The chemokine CCL2 participates in multiple neuroinflammatory processes, mainly through the recruitment of glial cells. However, CCL2 has also been proven to exert different types of actions on these cells, including the modification of their response to inflammatory stimuli. In the present study we analyzed the effect of CCL2 on the resolution of inflammation in astrocytes. We observed that genetic removal of CCL2 increases the expression of the enzymes responsible for the synthesis of specialized pro-resolving mediators arachidonate 15-lipoxygenase and arachidonate 5-lipoxygenase in the brain cortex of 5xFAD mice. The expression of FPR2 receptor, known to mediate the activity of pro-resolving mediators was also increased in mice lacking CCL2.The downregulation of these proteins by CCL2 was also observed in cultured astrocytes. This suggests that CCL2 inhibition of the resolution of inflammation could facilitate the progression of neuroinflammatory processes. The production of the pro-inflammatory cytokine IL-1beta by astrocytes was analyzed, and allowed us to confirm that CCL2 potentiates the activation of astrocytes trough the inhibition of pro-resolving pathways mediated by Resolvin D1. In addition, the analysis of the expression of TNFalpha, MIP1alpha and NOS2 further confirmed CCL2 inhibition of inflammation resolution in astrocytes. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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18 pages, 4037 KiB

Open AccessArticle

Synthesis, In Silico, and Biological Evaluation of a Borinic Tryptophan-Derivative That Induces Melatonin-like Amelioration of Cognitive Deficit in Male Rat

by Mónica Barrón-González, Martha C. Rosales-Hernández, Antonio Abad-García, Ana L. Ocampo-Néstor, José M. Santiago-Quintana, Teresa Pérez-Capistran, José G. Trujillo-Ferrara, Itzia I. Padilla-Martínez, Eunice D. Farfán-García and Marvin A. Soriano-Ursúa

Int. J. Mol. Sci. 2022, 23(6), 3229; https://doi.org/10.3390/ijms23063229 - 17 Mar 2022

Cited by 7 | Viewed by 2340

Abstract

Preclinical and clinical evidence supports melatonin and its analogues as potential treatment for diseases involving cognitive deficit such as Alzheimer’s disease. In this work, we evaluated by in silico studies a set of boron-containing melatonin analogues on MT1 and MT2 receptors. Then, we synthesized a compound (borolatonin) identified as potent agonist. After chemical characterization, its evaluation in a rat model with cognitive deficit showed that it induced ameliorative effects such as those induced by equimolar administration of melatonin in behavioral tests and in neuronal immunohistochemistry assays. Our results suggest the observed effects are by means of action on the melatonin system. Further studies are required to clarify the mechanism(s) of action, as the beneficial effects on disturbed memory by gonadectomy in male rats are attractive. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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25 pages, 1966 KiB

Open AccessReview

Noradrenaline in Alzheimer’s Disease: A New Potential Therapeutic Target

by Irene L. Gutiérrez, Cinzia Dello Russo, Fabiana Novellino, Javier R. Caso, Borja García-Bueno, Juan C. Leza and José L. M. Madrigal

Int. J. Mol. Sci. 2022, 23(11), 6143; https://doi.org/10.3390/ijms23116143 - 30 May 2022

Cited by 12 | Viewed by 6468

Abstract

A growing body of evidence demonstrates the important role of the noradrenergic system in the pathogenesis of many neurodegenerative processes, especially Alzheimer’s disease, due to its ability to control glial activation and chemokine production resulting in anti-inflammatory and neuroprotective effects. Noradrenaline involvement in this disease was first proposed after finding deficits of noradrenergic neurons in the locus coeruleus from Alzheimer’s disease patients. Based on this, it has been hypothesized that the early loss of noradrenergic projections and the subsequent reduction of noradrenaline brain levels contribute to cognitive dysfunctions and the progression of neurodegeneration. Several studies have focused on analyzing the role of noradrenaline in the development and progression of Alzheimer’s disease. In this review we summarize some of the most relevant data describing the alterations of the noradrenergic system normally occurring in Alzheimer’s disease as well as experimental studies in which noradrenaline concentration was modified in order to further analyze how these alterations affect the behavior and viability of different nervous cells. The combination of the different studies here presented suggests that the maintenance of adequate noradrenaline levels in the central nervous system constitutes a key factor of the endogenous defense systems that help prevent or delay the development of Alzheimer’s disease. For this reason, the use of noradrenaline modulating drugs is proposed as an interesting alternative therapeutic option for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0)

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