Optic nerve glymphatic system: Physiological characterization, ischemia-induced changes, and neuroprotection in ischemic optic neuropathy

The glymphatic system facilitates cerebrospinal fluid (CSF) circulation and metabolic waste clearance in the central nervous system. Its alterations and neuroprotective potentials in cerebral disorders also have been confirmed. However, its role in the optic nerve and involvement in optic neuropathy remain unclear. Here, we utilized the methodology combining fluorescent tracer injection with tissue clearing to visualize and quantify bidirectional glymphatic flow in the optic nerve in mice. Under physiological conditions, low-molecular-weight CSF tracers entered the optic nerve, while intraocular tracers were efficiently cleared via glymphatic pathway-both processes could be temporarily suppressed by using TGN-020. Acute ischemia induced by unilateral common carotid artery occlusion (UCCAO) enhanced CSF accumulation in the optic nerve and impaired intraocular solute clearance. Administration of TGN-020 30 min before ischemia induction reduced CSF accumulation during the ischemic phase and preserved retinal and optic nerve structure and function after ischemia. These findings further reveal a widespread, highly active glymphatic system in the optic nerve. Ischemia-induced dynamic changes of glymphatic function may contribute to optic nerve injury, while usage of TGN-020 during acute ischemia holds certain therapeutic potential in ischemic optic neuropathy.