Natalizumab, a monoclonal antibody effective against multiple sclerosis, paradoxically accelerates brain damage in neuromyelitis optica spectrum disorder (NMOSD) by disrupting critical protective interactions between blood vessel cells and astrocytes. The drug blocks VCAM1-integrin α4 binding, preventing astrocytes from receiving survival signals that normally help them resist AQP4-IgG autoantibody attacks. This mechanism explains why NMOSD patients treated with natalizumab experience rapid clinical deterioration rather than improvement. The finding represents a significant advance in understanding how the same therapeutic target can produce opposite outcomes in closely related neuroinflammatory diseases. While both MS and NMOSD involve immune system attacks on the central nervous system, their distinct cellular targets create dramatically different responses to integrin-blocking therapy. This research validates the critical importance of astrocyte-endothelial communication in maintaining brain barrier integrity and suggests that NMOSD requires fundamentally different therapeutic approaches than MS. The work also highlights how precision medicine must account for subtle but crucial differences in disease mechanisms, even within the same organ system and therapeutic class.