Ischemia-Induced Neurodegeneration in Glaucoma: Mechanistic Insights and Translational Opportunities for Psychoplastogen-Based Therapies

Glaucoma is an ischemic neurodegenerative disease driven not only by high eye pressure but also by vascular, metabolic, and inflammatory damage that progressively disconnects retinal neurons from the brain. Current treatments lower eye pressure but do not address this neurodegeneration or restore lost connections. Ischemia triggers excitotoxicity, oxidative stress, and chronic inflammation involving microglia and astrocytes, which suppress the brain's natural ability to repair itself. Psychoplastogens—compounds like ketamine, psilocybin, and DMT—rapidly enhance structural and functional neuroplasticity through BDNF-TrkB-mTOR signaling and also exert anti-inflammatory effects. This review integrates insights from cerebral ischemia to propose psychoplastogens as potential neurorestorative and anti-inflammatory agents for glaucoma, while outlining translational challenges.

Study at a glance

Abstract

Glaucoma is increasingly recognized as an ischemic neurodegenerative disorder that extends beyond elevated intraocular pressure (IOP) to involve complex vascular, metabolic, and inflammatory mechanisms. Retinal ganglion cells are particularly vulnerable to ischemia-reperfusion injury, oxidative stress, and chronic neuroinflammation, leading to progressive disconnection from central visual pathways. Current therapies primarily target IOP reduction but fail to address ischemia-driven neurodegeneration or to restore lost neuronal connectivity. Ischemia triggers excitotoxicity, oxidative stress, and a maladaptive inflammatory response involving activated microglia and astrocytes, perpetuating neuronal injury and suppressing intrinsic regenerative capacity. Thus, restoring neural plasticity and mitigating neuroinflammation represent key unmet therapeutic needs. Psychoplastogens are a class of compounds capable of rapidly enhancing structural and functional neuroplasticity and have recently emerged as promising multitarget agents. Compounds such as ketamine, psilocybin, N,N-dimethyltryptamine (DMT), and some newly synthesized non-hallucinogenic analogs act through convergent signaling pathways involving BDNF-TrkB-mTOR, promoting dendritic growth, synaptogenesis, and glial modulation. Beyond their neurotrophic effects, psychoplastogens seem to exert potent immunomodulatory actions. In this review we will explore the interplay between ischemia, neurodegeneration, neuroinflammation, and impaired plasticity in glaucoma, integrating mechanistic insights from cerebral ischemia. We discuss emerging preclinical evidence supporting psychoplastogens as neurorestorative and anti-inflammatory agents, propose their potential application in ocular ischemic neurodegeneration, and outline translational challenges for future studies.