Melatonin, circadian rhythms and glaucoma: current perspective

Primary open-angle glaucoma as a causal factor for circadian disruption: Living by the clock, in alignment with external time cues is an important condition for human health and well-being. Periodic changes in the ambient light serve as a key factor to synchronize the endogenously generated circadian rhythms. The retina perceives the photic signals and transmits them to the central body clock, the suprachiasmatic nuclei (SCN), via the retinohypothalamic tract. Primary open angle glaucoma (POAG) is an optic neuropathy, in which disease progression can be monitored by assessing damage to the retinal ganglion cells (RGCs) (Pérez-Rico et al., 2010; Feigl et al., 2011; Kankipati et al., 2011). Damage of retinal ganglion cells, particularly of intrinsically photosensitive RGCs (ipRGCs), is also one of the causes of circadian disruption. Pathophysiological mechanisms of POAG are complex, including elevated intraocular pressure (IOP), which adds mechanical stress, causing damage, dysfunction, and death of the RGCs (Figure 1). Glaucoma progression affects both image-forming and non-image-forming visual functions of RGCs. A central role of ipRGCs is to convey non-image-forming photic information to the clock. Their damage reduces light signaling to the SCN. Already in early stages of glaucoma, ipRGCs are dysfunctional (Pérez-Rico et al., 2010; Feigl et al., 2011; Kankipati et al., 2011).Figure 1: Melatonin potential to counteract complex circadian alterations with aging, neurodegeneration, specifically in glaucoma.ipRGCs: Intrinsically photosensitive retinal ganglion cells; SNPs: single nucleotide polymorphisms.As RGCs are progressively altered, and non-image-forming function is affected, circadian rhythms are disrupted, sleep is impaired, and mood is altered (Graticelli et al., 2015; Gubin et al., 2019, 2021). Circadian rhythm alterations are found in POAG as compared to age-matched healthy peers (Gubin et al., 2019). Circadian disruption worsens in advanced POAG (Gubin et al., 2019, Neroev et al., 2020), correlating to the increasing loss of ipRGCs with disease progression (Obara et al., 2016). Circadian rhythms also change with increasing age. Age-dependent circadian alterations are not necessarily related to retinal damage, as photic transduction to the central clock is not always compromised. When they are related to retinal damage, they can be due to either neurodegenerative ipRGCs damage, or to ipRGC damage caused by increased mean or deregulated circadian IOP. The intriguing principal difference between the presence or absence of retinal damage in aging is that the reduced light transmitted to the SCN by damaged ipRGCs phase-delays circadian rhythms, but ipRGC-uncompromised aging is commonly associated with phase-advanced circadian rhythms (Gubin et al., 2019). Since individual differences in sensitivity to light, and/or in endogenous melatonin production may interfere with this theoretical modeling, the search for specific genetic factors that may determine such individual differences constitutes a promising approach. In conditions where photic entrainment is compromised, not only is the alignment with external time cues altered, so can be the variability of overt physiologic functions. We showed that large inter-individual variability obscured the circadian IOP rhythm in POAG (Neroev et al., 2020). Circadian IOP rhythms had specific alterations manifested in advanced, but not in mild POAG, which were associated with the progressive damage and dysfunction of RGCs. In patients with RGCs’ global loss volume above 15%, as assessed by high-definition optical coherence tomography, the 24-hour IOP rhythm peaked during the night, whereas in patients with stable POAG and a two-eye mean RGCs’ global loss volume less than 10%, the IOP peaked predominantly during the daytime. Misalignment between circadian rhythms in body temperature and IOP increased as a function of global loss volume loss. Higher nocturnal IOP in POAG may adversely affect the disease state, fostering damage to RGCs (Neroev et al., 2020). Depending on individual genetic factors, these changes may manifest themselves to a different degree. Individual clock properties depend on numerous genetic factors, comprising clock genes and melatonin receptor genes, melatonin nuclear receptor 1b (MTNR1b) in particular, which may account for large individual differences in light sensitivity. Our pilot study of gene polymorphisms in POAG showed that the D-allele of the Angiotensin-converting enzyme holding a deletion of the 16th intron Alu repeat was significantly associated with alterations of the circadian IOP rhythm. It may also account for the resistance to IOP-lowering therapy (Neroev et al., 2020). Endogenous melatonin production in primary open-angle glaucoma: Glaucoma patients experienced reduced post-illumination pupil response (Kankipati et al., 2011) and reduced nocturnal melatonin suppression by light (Pérez-Rico et al., 2010). Clinical evidence for changes in the timing and mean values of endogenous melatonin production in POAG was also evident (reviewed in Gubin et al., 2021): in POAG, salivary melatonin can be lower than in age-matched controls without POAG; even greater alterations were observed In advanced stages of the disease. The main alteration concerned the time of maximal secretion of melatonin. Such altered melatonin production in POAG and other neurodegenerative pathologies can stem from different factors, including diminished light signaling due to a reduced sensitivity to light. The presence of certain gene polymorphisms can increase the susceptibility of carriers to these factors. We investigated 24-hour profiles of salivary melatonin under controlled lighting conditions and analyzed several clock genes and polymorphisms of the melatonin receptor gene MTNR1b (Gubin et al., 2021). Patients diagnosed with stable POAG had unaltered circadian rhythms of salivary melatonin and body temperature, which peaked at the anticipa