Abstract
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.
Highlights
Neurodegenerative disorders occur with a high incidence in the elderly
The A1 receptor agonist CPA decreased the number of apoptotic nuclei and glial fibrillary acidic protein (GFAP) immunoreactivity in the retina exposed to excessive light to induce neurodegeneration
The ionotropic glutamate NMDA receptors, on which glycine acts as a mandatory coagonist, exhibit uneven distribution in the retina: A great number of NMDA receptors can be found in the ganglion cell layer [9,83]
Summary
Neurodegenerative disorders occur with a high incidence in the elderly. These pathologies affect the motor system in Parkinson’s or Huntington’s diseases, memory in Alzheimer’s disease, or other additional critically important neural functions after impairments in cerebral blood circulation. We mention retinal hypoxia/ischemia, glaucomatous and diabetic neuropathies, and age-related macular degeneration and those that appear less frequently, such as human recessive retinitis pigmentosa or inherited photoreceptor degeneration These disorders may occur as a sudden pathological event or show a progressively declining clinical course, but vision may be seriously hampered or lost in all disorders. In spite of the extended research effort, the currently used therapeutics only slow down the progression of retinal neurodegenerative disorders, whereas normalization of impaired visual functions can be rarely achieved It is, mandatory to develop novel therapeutic interventions. This interaction is, further complicated by the findings that microglia, the resident immune cells of the central nervous system and retina, are involved in neuronal cell destructions and in compensatory neural repair following insulting influences [4,5]
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