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Small-Molecule Approaches to Counteract Demyelination and Neurodegeneration

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Neuroscience".

Deadline for manuscript submissions: 20 August 2026 | Viewed by 184

Special Issue Editor


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Guest Editor
1. Department of Anatomy and Cell Biology, Medical University Varna, 9002 Varna, Bulgaria
2. Vascular Biology Research Group (RenEVA), Research Institute, Medical University – Varna, 9002 Varna, Bulgaria
Interests: neurodegeneration; neurorepair; neurogenesis; neuroplasticity; SEM/STEM/FIB-BSD imaging and ultrastructural analysis

Special Issue Information

Dear Colleagues,

Demyelination and axonal degeneration are hallmark features of many disorders of the central and peripheral nervous system, including multiple sclerosis, peripheral neuropathies, traumatic nerve injury, and neurodegenerative diseases. While biological therapies have advanced substantially, small molecules remain highly attractive therapeutic and diagnostic candidates due to their pharmacokinetic advantages, scalability, and ability to modulate intracellular pathways.

This Special Issue focuses on the identification, characterization, and therapeutic application of small molecules and other bioactive compounds that promote myelin repair, neuroprotection, and nerve regeneration. Particular emphasis is placed on the discovery of novel or unconventional molecules derived from evolutionarily diverse species, including primitive or non-mammalian organisms that display remarkable regenerative capacity, resistance to neurodegeneration, exceptional longevity, or functional “immortality.” Such bio-inspired approaches may uncover conserved or previously unexplored mechanisms relevant to nervous system repair as well as early diagnostics of neurodegeneration.

In addition, the Special Issue welcomes submissions describing innovative experimental protocols and novel tools for studying cellular, molecular, and ultrastructural changes in the nervous system during degeneration, regeneration, and repair. Topics of interest include modulators of oligodendrocyte and Schwann cell biology, remyelination-enhancing compounds, neurogenesis, neuroprotective and anti-inflammatory agents, pathway- and gene-targeted pharmacological strategies, and advanced imaging and ultrastructural analysis methods (including electron microscopy-based approaches).

Original research articles and reviews addressing therapeutic strategies, evolutionary and comparative biology-inspired discoveries, and cutting-edge tools for investigating nervous system pathology and repair in both the central and peripheral nervous systems are encouraged.

Dr. David Lutz
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • demyelination
  • neurorepair
  • small-molecule therapeutics
  • neurodegeneration

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Published Papers (1 paper)

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Research

22 pages, 2441 KB  
Article
Astrocyte Mitochondrial UCP4 Reprograms Neuronal Network Oscillations via GDNF-Dependent K+-Ca2+ Signaling in Alzheimer’s Disease Mice
by Aisylu Gaifullina, Chaima Belhi, Leonardo Restivo and Jean-Yves Chatton
Cells 2026, 15(7), 597; https://doi.org/10.3390/cells15070597 - 27 Mar 2026
Abstract
Neuron-targeted therapies for Alzheimer’s disease (AD) have shown limited efficacy, highlighting the need to explore glial-based mechanisms of neuroprotection. Here, we show that astrocyte mitochondrial uncoupling via viral overexpression of uncoupling protein 4 (UCP4) restores neuronal circuits and ion channel function in aged [...] Read more.
Neuron-targeted therapies for Alzheimer’s disease (AD) have shown limited efficacy, highlighting the need to explore glial-based mechanisms of neuroprotection. Here, we show that astrocyte mitochondrial uncoupling via viral overexpression of uncoupling protein 4 (UCP4) restores neuronal circuits and ion channel function in aged 3xTG AD mice with overt symptoms. Spontaneous local field potential recordings revealed a partial recovery of hippocampal and subicular sharp wave ripple oscillations, electrophysiological signatures of neuronal circuits known to be altered in AD. Combined whole-cell patch-clamp electrophysiology with two-photon Ca2+ imaging further demonstrated that UCP4 modulates activity-dependent Ca2+ influx, A-type potassium channel function, and enhances glial cell line-derived neurotrophic factor (GDNF) signaling. These findings identify astrocytic mitochondrial uncoupling as a potent mechanism enhancing neuronal resilience and restoring circuit function in symptomatic AD brains. Full article
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