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

## TL;DR

This paper explores how glaucoma involves ischemia-driven neurodegeneration and suggests psychoplastogens as potential therapies to restore neural plasticity and reduce inflammation.

## Contribution

The paper introduces psychoplastogens as a novel therapeutic approach for glaucoma by targeting ischemia-induced neurodegeneration and neuroinflammation.

## Key findings

- Glaucoma involves ischemia, oxidative stress, and chronic neuroinflammation, which current therapies fail to address.
- Psychoplastogens promote neuroplasticity and have immunomodulatory effects, making them promising for neurorestoration in glaucoma.
- Preclinical evidence supports the potential of psychoplastogens in treating ocular ischemic neurodegeneration.

## 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.