To protect the brain from the damaging effects of immune cells, entry of these cells into the brain is severely restricted. However, entrance is not forbidden but is controlled by cellular networks such as the blood-brain barrier and the choroid plexus. Because entry through either route requires basement membrane degradation, inhibitors of degradation can prevent brain inflammation. Using a novel chemical synthesis, we created a chemical mimic that inhibits the enzyme, heparanase, and demonstrated that this mimetic prevents neuroinflammation. This proposal will investigate how neuroinflammation is prevented, identify which route into the brain is blocked, and determine if steady-state immune surveillance is blocked. Blocking the cellular migration into the brain is a proven mechanism to prevent immune-driven damage in neuroinflammatory diseases such multiple sclerosis. Our research dissects the molecular processes controlling immune-cell trafficking in health and disease and aids in the future development of novel therapeutics targeting this system.