Neurodegenerative–neuroinflammatory disorders of the retina seriously hamper human
vision. In searching for key factors that contribute to the development of these pathologies,
we considered potential interactions among purinergic neuromodulation, glycinergic
neurotransmission, and microglia activity in the retina. Energy deprivation at cellular
levels is mainly due to impaired blood circulation leading to increased release of
ATP and adenosine as well as glutamate and glycine. Interactions between these modulators
and neurotransmitters are manifold. First, P2Y purinoceptor agonists facilitate reuptake
of glycine by glycine transporter 1, while its inhibitors reduce reverse-mode operation;
these events may lower extracellular glycine levels. The consequential changes in
extracellular glycine concentration can lead to parallel changes in the activity of
NR1/NR2B type NMDA receptors of which glycine is a mandatory agonist, and thereby
may reduce neurodegenerative events in the retina. Second, P2Y purinoceptor agonists
and glycine transporter 1 inhibitors may indirectly inhibit microglia activity by
decreasing neuronal or glial glycine release in energy-compromised retina. These inhibitions
may have a role in microglia activation, which is present during development and progression
of neurodegenerative disorders such as glaucomatous and diabetic retinopathies and
age-related macular degeneration or loss of retinal neurons caused by thromboembolic
events. We have hypothesized that glycine transporter 1 inhibitors and P2Y purinoceptor
agonists may have therapeutic importance in neurodegenerative–neuroinflammatory disorders
of the retina by decreasing NR1/NR2B NMDA receptor activity and production and release
of a series of proinflammatory cytokines from microglial cells.
