Fig. (2).

The role of Notch signaling and microglial activation in demyelination. The Notch signaling pathway has emerged as a central protagonist of neuroinflammation. γ Secretase inhibitors (GSIs) have been shown to mitigate demyelination in multiple sclerosis (MS). Microglia express Notch-1 in demyelinated regions. Coordinated modulation of Notch-1 signaling, which is driven by the RAS pathway and gastrodin, causes inflammation. In postnatal rats, elevated Notch-1, TNF-α, and IL-1β in activated microglia have been demonstrated. DAPT, a Notch cleavage inhibitor, reduces cytokine levels but paradoxically increases Notch-1 labeling. DAPT also suppresses microglial activation and cytokine production. Notably, inhibiting Notch-1 increases proinflammatory cytokines and enhances phagocytosis. These paradoxes suggest complex interactions within cellular signaling pathways. This finding demonstrates the intricate role of Notch signaling in neuroinflammation. (Created with BioRender.com).