Neurotrophic Signaling, Sleep Physiology, and Retinal Neuroprotection: Integrative Mechanisms and Therapeutic Implications for Glaucoma

ABSTRACT

Glaucoma is conventionally characterized as an intraocular pressure‐dependent optic neuropathy; however, emerging evidence features glaucoma as a complex neurodegenerative disorder of the central nervous system, closely linked to systemic physiological dysregulation. This review aims to combine a rapidly expanding frontier in vision research: the integration of neurotrophic signaling, sleep architecture, and retinal neuroprotection. Neurotrophic factors, particularly the brain‐derived neurotrophic factor‐TrkB axis, are indispensable for the survival and synaptic integrity of retinal ganglion cells. In glaucoma, mechanical and metabolic stressors disrupt the retrograde axonal transport of these survival signals. Furthermore, recent paradigms reveal that neurotrophin expression and downstream signaling cascades are highly modulated by sleep‐wake cycles and circadian rhythms. Sleep fragmentation and chronic sleep disorders, such as obstructive sleep apnea, not only suppress central and ocular neurotrophin synthesis but also exacerbate neuroinflammation, trigger microglial activation, and induce nocturnal ocular perfusion pressure fluctuations. Moreover, the newly characterized ocular glymphatic system shows a highly sleep‐dependent waste clearance mechanism, where sleep deprivation compromises the elimination of neurotoxic aggregates from the optic nerve head. Rather than summarizing this previously separate literature in parallel, this review synthesizes them into a single causal context, explicitly graded by the level of evidentiary certainty, and extends this basis to the clinical dimension of retinal ganglion cell‐related mood disturbance. By integrating these distinct fields, this review proposes an interconnected pathophysiological loop where sleep disturbances diminish neurotrophic support and impair metabolic clearance, rendering retinal ganglion cells highly vulnerable to glaucomatous degeneration. Finally, this review will discuss the therapeutic implications of this network, highlighting chronotherapeutic optimization of intraocular pressure‐lowering agents, small‐molecule TrkB agonists, and targeted sleep interventions as novel, adjuvant neuroprotective strategies. Ultimately, bridging sleep science and sensory neuroscience offers a promising, holistic framework for preserving vision in glaucoma patients.