Glaucoma is being increasingly
recognized as a multifactorial neurodegenerative optic neuropathy in which
intraocular pressure (IOP) is one of several stress amplifiers rather than a sole etiological factor.
IOP exposure interacts with, but
does not fully account for vascular dysregulation, impaired ocular perfusion,
mitochondrial susceptibility, metabolic failure, oxidative stress,
excitotoxicity, and neuroimmune dysregulation, seen as part of glaucomatous
neural degeneration.
However, IOP-related mechanical
and ischemic stress can disrupt axonal transport and amplify these processes,
increasing reactive oxygen species (ROS) and the release of damage-associated
molecular patterns (DAMPs) that activate innate immune pathways.
Resident glia respond to these
stress signals by releasing cytokines, including tumor necrosis factor-α
(TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which affect retinal ganglion cell (RGC) somas, axons, and synapses.
Within this inflammatory milieu,
synaptic structures are particularly vulnerable. Proinflammatory cytokines,
together with complement cascade activation, drive synapse elimination,
dendritic remodelling, and early functional disconnection of RGCs from their
central targets. This synaptic dysfunction represents a critical initiating
step in anterograde trans-synaptic degeneration, through which pathological
signals propagate from the retina to second- and third-order neurons in the
lateral geniculate nucleus (LGN) and visual cortex.
At the same time, retrograde signaling
mechanisms further contribute to neuronal loss, highlighting the bidirectional
nature of degeneration along the visual pathway.
Importantly, neuroinflammation is
not confined to the site of initial injury but spreads across synaptically
connected regions, where activated microglia and infiltrating immune cells
perpetuate cytokine production and sustain chronic inflammation.
Additional mechanisms, including
activation of intrinsic axonal degeneration pathways such as SARM1 and impaired
neurotrophic support, further facilitate the propagation of damage across
neuronal networks.
Collectively, these findings
support a multifactorial stress-amplification model that links local retinal
injury to central visual-pathway degeneration.
This concept is particularly
relevant to normal-tension glaucoma (NTG), which represents a large proportion
of primary open-angle glaucoma in Asian populations, and to patients who
continue to progress despite IOP being maintained within the target range.
