Chlorogenic acid (CGA), a polyphenol found mainly in coffee and tea, exerts antioxidant, anti-inflammatory and anti-apoptotic effects at the gastrointestinal level. However, although CGA is known to cross the blood–brain barrier (BBB), its effects on the CNS are still unknown. Oligodendrocytes (OLs), the myelin-forming cells in the CNS, are the main target in demyelinating neuroinflammatory diseases such as multiple sclerosis (MS). We evaluated the antioxidant, anti-inflammatory and anti-apoptotic roles of CGA in M03-13, an immortalized human OL cell line. We found that CGA reduces intracellular superoxide ions, mitochondrial reactive oxygen species (ROS) and NADPH oxidases (NOXs) /dual oxidase 2 (DUOX2) protein levels. The stimulation of M03-13 cells with TNFα activates the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway, leading to an increase in superoxide ion, NOXs/DUOX2 and phosphorylated extracellular regulated protein kinase (pERK) levels. In addition, tumor necrosis factor alpha (TNF-α) stimulation induces caspase 8 activation and the cleavage of poly-ADP-ribose polymerase (PARP). All these TNFα-induced effects are reversed by CGA. Furthermore, CGA induces a blockade of proliferation, driving cells to differentiation, resulting in increased mRNA levels of myelin basic protein (MBP) and proteolipid protein (PLP), which are major markers of mature OLs. Overall, these data suggest that dietary supplementation with this polyphenol could play an important beneficial role in autoimmune neuroinflammatory diseases such as MS.

Palmitic acid (PA), the most abundant saturated fatty acid (SFA) in humans, plays a key role in energy metabolism, membrane synthesis, and signaling. Oligodendrocyte precursor cells (OPCs), which generate mature oligodendrocytes (OLs) forming the myelin sheath, are responsive to metabolic and redox signals. Despite increasing interest in lipid metabolism and mitochondrial dynamics as regulators of OPC fate, the effects of PA remain unclear. This study investigates the biphasic, dose‐dependent effects of PA on OPCs using the oligodendrocyte precursor MO3.13 cell line and employs rat organotypic slice cultures to evaluate the effects of non‐toxic PA doses under pathological conditions and on axonal (re)‐myelination. In MO3.13 cells, high‐dose PA (100 µM) induces mitochondrial fragmentation and caspase‐7 activation, accompanied by reduced mitofusin‐2 (MFN2) and phosphorylated dynamin‐related protein 1 at Ser616 (p‐DRP1), indicating altered fusion‐fission balance and impaired reactive oxygen species (ROS) generation. In contrast, low‐dose PA (25 µM) triggers a protective response involving nuclear factor erythroid 2–related factor 2 (Nrf2) activation and upregulation of antioxidant and lipid‐regulatory genes (glutamate–cysteine ligase modifier subunit [GCLM], NAD(P)H dehydrogenase [quinone] 1 [NQO1], peroxisome proliferator‐activated receptor gamma [PPARγ], and cluster of differentiation 36 [CD36]) resulting in reduced intracellular ROS and enhanced lipid mobilization. PA 25 µM promotes OPC differentiation by inhibiting migration and cell cycle progression and increasing myelin basic protein (MBP) and proteolipid protein (PLP) expression. Notably, early exposure (1 day) favors mitochondrial fusion, whereas prolonged exposure (4 days) shows a physiological shift to fission. PA 25 µM prevents neurodegeneration in hippocampal organotypic slice cultures exposed to a neuroinflammatory insult. In cerebellar organotypic slice cultures, PA 25 µM enhances axonal myelination and accelerates remyelination following lysolecithin‐induced demyelination. These findings highlight the physiological relevance of low‐dose PA in modulating OLs.

The pivotal role of reactive oxygen species (ROS), especially peroxides, in multiple cell signalling pathways has been well-established. Superoxide dismutase 1 (SOD-1) represents a major intracellular source of hydrogen peroxide. Antigen-dependent activation of human T lymphocytes has been previously described by us to induce both SOD-1 production and secretion by T cells. SOD-1 mediated pathways have also been described to deliver proinflammatory signals and to affect the differentiation of immune-suppressor subsets (Treg). The mechanisms underlying extracellular SOD-1 export by activated T cells remain largely undefined. Indeed, SOD-1, like the leaderless proteins, is unable to exploit the conventional trans-Golgi vesicular secretion pathway. Here, we propose that ABCA1 transporters play a role in the mechanisms underlying SOD-1 secretion by activated T cells. Indeed, ABC transporter inhibition by using glyburide significantly decreases SOD-1 secretion by antigen-triggered human T cells in vitro. The effect has been confirmed by using four different detection techniques, as represented by Western blotting, ELISA, flow cytometry and confocal microscopy. Collectively, our findings indicate that ABCA1 transporter-dependent secretion supports the vesicular secretory machinery and might contribute to the extracellular release of SOD-1 by activated T cells. This mechanism highlights ABCA1 as a promising molecular target for therapeutic modulation of deranged immune activation.