In demyelinating diseases, such as multiple sclerosis, demyelination of neuronal fibers impairs impulse conduction and causes axon degeneration. Although neuronal activity stimulates oligodendrocyte production and myelination in normal conditions, it remains unclear whether the activity of demyelinated axons restores their loss of function in a harmful environment. To investigate this question, we established a model to induce a moderate optogenetic stimulation of demyelinated axons in the corpus callosum at the level of the motor cortex in which cortical circuit activation and locomotor effects were reduced in adult freely moving mice. We demonstrate that a moderate activation of demyelinated axons enhances the differentiation of oligodendrocyte precursor cells onto mature oligodendrocytes but only under a repeated stimulation paradigm. This activity-dependent increase in the oligodendrocyte pool promotes an extensive remyelination and functional restoration of conduction, as revealed by ultrastructural analyses and compound action potential recordings. Our findings reveal the need for preserving an appropriate neuronal activity in the damaged tissue to promote oligodendrocyte differentiation and remyelination, likely by enhancing axon-oligodendroglia interactions. Our results provide new perspectives for translational research using neuromodulation in demyelinating diseases.

Multiple sclerosis (MS) encompasses a chronic, irreversible, and predominantly immune-mediated disease of the central nervous system that leads to axonal degeneration, neuronal death, and several neurological symptoms. Although various immune therapies have reduced relapse rates and the severity of symptoms in relapsing-remitting MS, there is still no cure for this devastating disease. In this brief review, we discuss the role of mitochondria dysfunction in the progression of MS, focused on the possible role of Nrf2 signaling in orchestrating the impairment of critical cellular and molecular aspects such as reactive oxygen species (ROS) management, under neuroinflammation and neurodegeneration in MS. In this scenario, we propose a new potential downstream signaling of Nrf2 pathway, namely the opening of hemichannels and pannexons. These large-pore channels are known to modulate glial/neuronal function and ROS production as they are permeable to extracellular Ca²⁺ and release potentially harmful transmitters to the synaptic cleft. In this way, the Nrf2 dysfunction impairs not only the bioenergetics and metabolic properties of glial cells but also the proper antioxidant defense and energy supply that they provide to neurons.

Oligodendrocytes are the myelin forming cells in the central nervous system (CNS). In addition to this main physiological function, these cells play key roles by providing energy substrates to neurons as well as information required to sustain proper synaptic transmission and plasticity at the CNS. The latter requires a fine coordinated intercellular communication with neurons and other glial cell types, including astrocytes. In mammals, tissue synchronization is mainly mediated by connexins and pannexins, two protein families that underpin the communication among neighboring cells through the formation of different plasma membrane channels. At one end, gap junction channels (GJCs; which are exclusively formed by connexins in vertebrates) connect the cytoplasm of contacting cells allowing electrical and metabolic coupling. At the other end, hemichannels and pannexons (which are formed by connexins and pannexins, respectively) communicate the intra- and extracellular compartments, serving as diffusion pathways of ions and small molecules. Here, we briefly review the current knowledge about the expression and function of hemichannels, pannexons and GJCs in oligodendrocytes, as well as the evidence regarding the possible role of these channels in metabolic and synaptic functions at the CNS. In particular, we focus on oligodendrocyte-astrocyte coupling during axon metabolic support and its implications in brain health and disease.

Recent studies indicate that connexin hemichannels do not act as freely permeable non-selective pores, but they select permeants in an isoform-specific manner with cooperative, competitive and saturable kinetics. The aim of this study was to investigate whether the treatment with a mixture of IL-1β plus TNF-α, a well-known pro-inflammatory condition that activates astroglial connexin 43 (Cx43) hemichannels, could alter their permeability to molecules. We found that IL-1β plus TNF-α left-shifted the dye uptake rate vs. dye concentration relationship for Etd and 2-NBDG, but the opposite took place for DAPI or YO-PRO-1, whereas no alterations were observed for Prd. The latter modifications were accompanied of changes in K_d (Etd, DAPI, YO-PRO-1 or 2-NBDG) and Hill coefficients (Etd and YO-PRO-1), but not in alterations of V_max. We speculate that IL-1β plus TNF-α may distinctively affect the binding sites to permeants in astroglial Cx43 hemichannels rather than their number in the cell surface. Alternatively, IL-1β plus TNF-α could induce the production of endogenous permeants that may favor or compete for in the pore-lining residues of Cx43 hemichannels. Future studies shall elucidate whether the differential ionic/molecule permeation of Cx43 hemichannels in astrocytes could impact their communication with neurons in the normal and inflamed nervous system.

: Myelin is a specialized membrane allowing for saltatory conduction of action potentials in neurons, an essential process to achieve the normal communication across the nervous system. Accordingly, in diseases characterized by the loss of myelin and myelin forming cells -oligodendrocytes in the CNS-, patients show severe neurological disabilities. After a demyelinated insult, microglia, astrocytes and oligodendrocyte precursor cells invade the lesioned area initiating a spontaneous process of myelin repair (i.e. remyelination). A preserved hallmark of this neuroinflammatory scenario is a local increase of oxidative stress, where several cytokines and chemokines are released by glial and other cells. This generates an environment that determines cell interaction resulting in oligodendrocyte maturity and the ability to synthesize new myelin. Herein we review the main features of the regulatory aspect of these molecules based on recent findings and propose new putative signal molecules involved in the remyelination process, focused in the etiology of Multiple Sclerosis, one of the main demyelinating diseases causing disabilities in the population.

The central nervous system (CNS) is particularly vulnerable to oxidative stress and inflammation, which affect neuronal function and survival. Nowadays, there is great interest in the development of antioxidant and anti-inflammatory compounds extracted from natural products, as potential strategies to reduce the oxidative/inflammatory environment within the CNS and then preserve neuronal integrity and brain function. However, an important limitation of natural antioxidant formulations (mainly polyphenols) is their reduced in vivo bioavailability. The biological compatible delivery system containing polyphenols may serve as a novel compound for these antioxidant formulations. Accordingly, in the present study, we used liposomes as carriers for grape tannins, and we tested their ability to prevent neuronal oxidative stress and inflammation. Cultured catecholaminergic neurons (CAD) were used to establish the potential of lipid-encapsulated grape tannins (TLS) to prevent neuronal oxidative stress and inflammation following an oxidative insult. TLS rescued cell survival after H₂O₂ treatment (59.4 ± 8.8% vs. 90.4 ± 5.6% H₂O₂ vs. TLS+ H₂O₂; p < 0.05) and reduced intracellular ROS levels by ~38% (p < 0.05), despite displaying negligible antioxidant activity in solution. Additionally, TLS treatment dramatically reduced proinflammatory cytokines’ mRNA expression after H₂O₂ treatment (TNF-α: 400.3 ± 1.7 vs. 7.9 ± 1.9-fold; IL-1β: 423.4 ± 1.3 vs. 12.7 ± 2.6-fold; p < 0.05; H₂O₂ vs. TLS+ H₂O₂, respectively), without affecting pro/antioxidant biomarker expression, suggesting that liposomes efficiently delivered tannins inside neurons and promoted cell survival. In conclusion, we propose that lipid-encapsulated grape tannins could be an efficient tool to promote antioxidant/inflammatory cell defense.