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  • ADOR immunoreactivity was high in parasympathetically

    2024-06-11

    ADOR immunoreactivity was high in parasympathetically-innervated smooth muscle, namely the iris sphincter muscle and the ciliary muscle. No ADOR immunoreactivity was noted in the sympathetically-innervated iris dilator muscle. Immunoreactivity against all four ADORs was noted in the ciliary epithelium, which produces aqueous humor. These findings suggest that ADOR antagonists could have effects on pupil size, amplitude of accommodation, and/or intraocular pressure (IOP). ADORA1 agonists decrease IOP by increasing the activity of collagen-degrading metalloproteinases, increasing outflow facility through the trabecular meshwork (Li et al., 2018). ADORA1 inhibition by A1-selective antagonists raises IOP. Conversely, ADORA2a/ADORA3 inhibition lowers IOP by modulating aqueous humor production (Avila et al., 2002; Crosson, 1995; Crosson and Gray, 1994, 1996; Wang et al., 2010). Since methylxanthines are non-selective ADOR inhibitors, the pro- and anti-hypertensive effects of ADOR inhibition appear to balance out. No differences in IOP or pupil size were noted between Rhesus monkeys given oral 7-MX versus age-matched controls given a normal diet (Hung et al., 2018). Also, in a small study, topical caffeine had no effect on IOP in patients with primary open angle glaucoma or ocular Ac-IEPD-AFC (Chandra et al., 2011). This indicates that though IOP can be affected by ADOR inhibition, methylxanthines appear to have a better safety profile than non-methylxanthines. Interestingly, the matrix metalloprotease/tissue inhibitor of metalloproteinase (MMP/TIMP) system, known to be modulated by ADORA1, is implicated in the scleral remodeling seen in form deprivation myopia (Liu et al., 2017), which may suggest a link between IOP control and myopia. The effect of methylxanthines on amplitude of accommodation has not been assessed. For a therapy to be beneficial, its therapeutic effects should outweigh its non-therapeutic effects; therefore it is important to be mindful of potential unwanted side effects. Because ADORs are found throughout the body, modulation of ADOR function as an anti-myopia therapy could have effects in systemic tissues. However, no adverse systemic effects of oral 7-MX administration in Rhesus monkeys (Hung et al., 2018) or children (Trier et al., 2008), have been reported. Caffeine is well known to cause systemic effects such as increased heart rate, blood pressure and wakefulness (Huang et al., 2005; Turnbull et al., 2017). The different effects of 7-MX and caffeine indicate that the adverse effects of each methylxanthine should be evaluated individually. Systemic side effects may be reduced by topical application. In the small intraocular pressure study mentioned above, instillation of 1% (52.5 mM) caffeine eye drops three times a day for 6 days had no effect on either blood pressure or subjective assessment of well-being (Chandra et al., 2011). One identified side effect of caffeine has the potential to become a therapy for cataract, the leading cause of blindness world-wide (Pascolini and Mariotti, 2012). The observation that caffeine added to culture medium prevents opacification of rat lenses in vitro after UVB irradiation (Varma et al., 2008) led to several in vivo studies demonstrating that pre-treatment with caffeine significantly reduced or eliminated opacification from multiple cataractogenic stimuli, primarily via caffeine's ability to scavenge reactive oxygen species (Kronschläger et al., 2013; Varma and Hegde, 2010; Varma et al., 2010a, 2010b). Because this is unrelated to ADOR inhibition, the crystalline lens was not evaluated in this study. Limitations of this study include lack of data on scleral gene expression. Grinding techniques strong enough Ac-IEPD-AFC to homogenize the tough tissue of the monkey sclera typically destroyed its delicate RNA content, therefore we were unable to analyze scleral ADORA mRNA expression. Another limitation is the small number of subjects (n = 6), since the expense of primate research renders large studies unfeasible. Another limitation was that our RT-qPCR analysis used only two reference genes instead of the recommended four (Bustin et al., 2009). Only two of the five reference genes tested satisfied our criteria of specificity, consistent amplification efficiency, and equal expression in the target tissues. Few studies have identified reference genes in Macaca mulatta, (Ahn et al., 2008; Noriega et al., 2010), and none have assessed their expression in the eye, indicating a need for further studies identifying ocular reference genes in the Rhesus monkey.