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Steering Functional Pathways, Genomic and Non-genomic, to Keep Neurodegeneration in Check

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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 (28 February 2022) | Viewed by 11847

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Special Issue Editor

Dr. Leo Veenman

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Guest Editor

The Ruth and Bruce Rappaport Faculty of Medicine, Department of Neuroscience, Haifa, Israel
Interests: TSPO; brain trauma; brain disease; neurodegeneration; mental disorder; astrocytes microglia, neurons; inflammation; treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegeneration is part and parcel of brain injury and also of brain disorders that are aptly called neurodegenerative diseases, for example, Alzheimer disease and Parkinson disease. Neurodegenerative diseases share a range of molecular and cellular pathologies, including protein aggregation, mitochondrial dysfunction, glutamate toxicity, inadequate glucose supply, energy crisis, calcium imbalance, proteolytic stress, oxidative stress, and neuroinflammation. Thus, efficacious treatment of neurodegeneration appears to require a multifaceted approach. In some detail, such treatment should include targeting programmed cell death of neurons, supportive functions of astrocytes, oligodendrocytes, and endothelial cells, as well as microglial activation as part of the neuroinflammatory/immune response. A handful of approaches appeared to be extraordinarily beneficial when applied to cell cultures, animal models, and some even in clinical studies (raloxifene and hyperbaric oxygen) (review by Veenman, 2020).

Briefly, their effects include modulation of programmed cell death, injury healing, inflammation and infection, cell and tissue regeneration, neurite growth, cell proliferation, cell migration, and differentiation of stem cells, as well as angiogenesis. At molecular biological levels, this includes modulation of metabolic pathways to sustain energy requirements, proteinogenesis, intracellular calcium balance, maintenance of transmitter systems at cell nuclear, cytosolic, and plasma membrane levels, and counteracting deleterious effects of oxidative stress and other radical formations. Molecules that have attracted attention include growth factors, sirtuins, cholesterol, Abeta, and many others. Beneficial effects of such efficacious agents and treatments include genomic as well as non-genomic targets and pathways. Genomic effects can relate to cell nuclear receptor signaling, as well as immediate early genes. Non-genomic effects can include interactions with molecules and receptors at various other intracellular locations.

Papers are sought that deepen our insights into the mechanisms of successful treatments for neurodegeneration.

Dr. Leo Veenman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Brain damage

Brain injury
Brain disease
Neurodegeneration
Mental disorder
Astrocytes
Microglia
Neurons
Inflammation
Treatment
Regeneration
Wound healing
Angiogenesis

Published Papers (2 papers)

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Research

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22 pages, 3068 KiB

Open AccessArticle

De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein

by Lorenzo Germelli, Eleonora Da Pozzo, Chiara Giacomelli, Chiara Tremolanti, Laura Marchetti, Christian H. Wetzel, Elisabetta Barresi, Sabrina Taliani, Federico Da Settimo, Claudia Martini and Barbara Costa

Int. J. Mol. Sci. 2021, 22(6), 3115; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063115 - 18 Mar 2021

Cited by 15 | Viewed by 4076

Abstract

Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery—in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes. Full article

(This article belongs to the Special Issue Steering Functional Pathways, Genomic and Non-genomic, to Keep Neurodegeneration in Check)

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Review

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31 pages, 1449 KiB

Open AccessReview

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

by Leo Veenman

Int. J. Mol. Sci. 2020, 21(20), 7586; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207586 - 14 Oct 2020

Cited by 21 | Viewed by 7190

Abstract

Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects—fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson’s disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health—on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer’s disease, raloxifene may not cure diagnosed Alzheimer’s disease. However, the onset of Alzheimer’s disease may be delayed or arrested by raloxifene’s capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer’s disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer’s disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved. Full article

(This article belongs to the Special Issue Steering Functional Pathways, Genomic and Non-genomic, to Keep Neurodegeneration in Check)

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