Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

recovery, or with plus lens wear, develop reduced levels. Further, oral retinoic acid elongates the guinea pig eye, although emmetropia is retained (McFadden et al., 2004). Some eyes of visually deprived juvenile marmosets show accelerated growth, but others show reduced growth. In those eyes with accelerated eye growth, the rate of retinoic acid synthesis is elevated in both retina and choroid/retinal pigment epithelium, but the rates of retinoic acid synthesis are unaltered in these same tissues of eyes with reduced growth (Troilo et al., 2006).

It has been suggested that differences in retinoic acid between chicks and mammals might relate to species differences in the tissue constituents of sclera (McFadden et al., 2004; Troilo et al., 2006), even though retinoic acid decreases proteoglycan synthesis in vitro in both chick and marmoset sclera (Mertz and Wallman, 2000; Troilo et al., 2006). Despite uncertainties in interpreting these reports, retinoic acid may be involved in the visual pathway regulating eye growth.

E. Nitric Oxide

Nitric oxide synthase (NOS), the biosynthetic enzyme for nitric oxide, localizes to some retinal neurons, and to peripheral nerve fibers distributed to both posterior and anterior segment tissues. Initial evidence suggests that nitric oxide might participate in regulating refractive development in chick. While goggle wear does not alter the retinal content of nitric oxide products, the retina/RPE/choroid of form deprived chick eyes develops a modest reduction of the mRNA for the brain and inducible, but not the endothelial isoforms, of NOS (Fujii et al., 1998). Intravitreal injection of the NOS inhibitor L-NAME (NG-nitro-L-arginine methyl ester) blunts myopia and axial expansion induced by goggle or negative spectacle lens wear (Fujikado et al., 1997a, 2001). L-NAME inhibits choroidal thickening in eyes recovering from myopia or wearing a positive

spectacle lens (Nickla and Wildsoet, 2004), interferes with the protective anti-myopia effect of brief periods of clear vision in form deprived eyes, and both reduces chorioidal retinoic acid synthesis and alters scleral glycosaminoglycan synthesis in recovering eyes (Nickla et al., 2006). A Chinese traditional medicine, nacreous powder, applied topically, inhibits form deprivation myopia in the chick while also increasing in the RPE/choroid the activity of NOS and the content of NO products (Xu et al., 2001). Despite the need to clarify many issues in these studies, a potential role for nitric oxide in modulating eye growth and/or choroidal thickness is a useful hypothesis.

F. Prostaglandins

Intravitreal prostaglandin F2α inhibits the development of form deprivation myopia in chicks, but two other prostaglandins and indomethacin are without effect. Whether prostaglandin F2α exerts a direct or indirect effect on experimental myopia is unclear, but this report concludes that endogenous prostaglandins would seem unlikely to be direct mediators of form deprivation myopia (Jin and Stjernschantz, 2000).

G. Peptide Modulators

1. Glucagon

Immunohistochemical staining of the immediate-early gene product ZENK in chick retina is reduced by conditions stimulating eye growth (i.e. form deprivation, minus lens wear) and increased by conditions inhibiting eye growth (i.e. vision restoration after form deprivation, plus lens wear). Among identified cells, these changes are prominent in glucagoncontaining amacrine cells (Fischer et al., 1999a). Supporting a potential role for glucagon in vision-dependent eye growth in chick, exogenous glucagon, a glucagonrelated peptide and glucagon receptor agonists suppress form deprivation myopia; and a glucagon receptor antagonist inhibits

the refractive shift and growth compensation to plus lens wear (Feldkaemper and Schaeffel, 2002; Vessey et al., 2005a,b). Retinal or choroidal content of glucagon or its receptor mRNA levels also are altered in chicks under visual conditions modulating eye growth (Buck et al., 2004; Feldkaemper et al., 2004; Feldkaemper and Schaeffel, 2002).

How these findings with glucagon might apply to mammalian eyes requires further research. While glucagon receptors have been identified in mammalian retina, glucagon itself has so for not been detected (Feldkaemper et al., 2004; Vessey et al., 2005b). On the other hand, image defocus influences the expression of the same immediate-early gene in chicks and monkeys (Fischer et al., 1999a; Zhong et al., 2004), suggesting at the least that the experimental approach of identifying activated and/or deactivated retinal neurons may ultimately be useful in identifying potential retinal signals that modulate eye growth in primate eyes.

2. Vasoactive intestinal peptide

The expression of vasoactive intestinal peptide (VIP) in amacrine cells of the retina of rhesus monkeys with form deprivation myopia is markedly increased, as assayed by immunohistochemistry (Stone et al., 1988). While there are no evident changes in retinal immunohistochemistry for VIP in form deprived chick eyes, form deprivation myopia in chick is partially inhibited by VIP and fully inhibited by two VIP antagonists (Pickett Seltner and Stell, 1995). This evidence is consistent with a potential role of VIP in experimental myopia, but further definition is required.

3. Enkephalin

Locally administered naloxone, a nonselective antagonist to opiate receptors, inhibits form deprivation myopia in chick. Further pharmacologic studies have been inconclusive in identifying specific opioid receptor subtypes, and it was suggested that

cross-reactivity to N-methyl-D-aspartate receptors may account for these effects (Fischer et al., 1998d; Pickett Seltner et al., 1997). In the chick retina, a subpopulation of amacrine cells containing enkephalin, neurotensin and somatostatin reciprocally interacts with dopamine-containing amacrine cells. Presumably in response to the altered cycling of retinal dopamine, form deprivation suppresses the normal diurnal cycling of enkephalin; the diurnal cycling of enkephalin in form deprived eyes is corrected by restoring non-restricted vision and by strobe lighting conditions, both of which ameliorate myopia in chick (McKenzie et al., 1997; Megaw et al., 1996).

4. Growth factors

Based on known effects on fibroblast proliferation and extracellular matrix composition, ocular administration of basic fibroblast growth factor (bFGF) was found to inhibit form deprivation myopia in chick, a response suppressed by co-administration of transforming growth factor-beta (TGF-β) (Rohrer and Stell, 1994). Decreased content of bFGF in the sclera and increased content of TGF-β2 in both sclera and retina/RPE/ choroid (Seko et al., 1995), inhibitory effects of TGF-β on scleral cells in vitro (Honda et al., 1996) and the distribution of bFGF and its receptors in ocular tissues (Rohrer et al., 1997) each are consistent with potential involvement of these two growth factors in regulating eye growth. In eyes of tree shrews with lens-induced myopia or recovering from myopia, however, no change in endogenous FGF-2 levels was measured; but the mRNA expression for its high affinity receptor was elevated in myopic eyes, returning to normal levels during recovery (Gentle and McBrien, 2002). Whether growth factors act in parallel or downstream from retinal neurotransmitters seemingly involved in regulating eye growth is unknown (Rohrer et al., 1995), but could be a productive area for future investigation.

VII. EYES WITH NON-

RESTRICTED VISION

BOX 9.1

Many drugs that interact with neural receptors have influenced experimental myopia in visually deprived eyes, but do not alter the growth of eyes with nonrestricted vision. As examples, dopamine agonists, opioids, basic fibroblast growth factor, and glucagon-related peptides each inhibit experimental myopia, but do not seem to affect the refraction or growth of eyes with unimpaired visual input (Fischer et al., 1998d; Rohrer and Stell, 1994; Stone et al., 1989; Vessey et al., 2005b).

On the other hand, a few of the drugs already discussed as inhibitors of form deprivation myopia do modify the growth of eyes with non-restricted vision. The muscarinic antagonist pirenzepine reduces eye growth and shifts refraction towards hyperopia in non-deprived eyes (Truong et al., 2002). Several drugs interacting with GABA receptors, chiefly GABAA or GABAA0r subtypes, stimulate the growth of eyes with non-restricted vision (Stone et al., 2003). The local application of GABA selective agents induce complex effects on overall eye form. The GABAA agonist muscimol induces myopia in eyes with non-restricted vision, for instance, and stimulates vitreous cavity expansion in both the axial and equatorial dimensions. The GABAA0r antagonist TPMPA, while having a minimal net myopic effect, has a different effect on vitreous cavity form, stimulating growth in the axial dimension but actually causing the equatorial diameter to narrow (Stone et al., 2003). Why some drugs alter refractive development only under circumstances precluding visual feedback, and others influence eye growth under conditions with either restricted or non-restricted vision is speculative, but these differences could provide opportunities to study under-

lying mechanisms governing refractive development.

Chemicals with distinct neurotoxic effects also alter the growth and refraction of eyes with non-restricted vision. These drugs include N-methyl-D-aspartate (at toxic but not pharmacologic doses), kainic acid, tetrodotoxin and colchicine (Ehrlich et al., 1990; Fischer et al., 1999b; Fischer et al., 1998d; McBrien et al., 1995; Wildsoet and Pettigrew, 1988b). Many but not all of these agents induce myopia, and these drugs can exert different anterior and posterior segment effects. Their refractive outcomes are generally assumed to result from an effect on the retina. While the use of neurotoxins has so far had limited utility in identifying specific cellular or receptor mechanisms modulating refraction (Fischer et al., 1998c), these results generally conform to a role for the retina in regulating eye growth. Cautions in interpreting this work include potential action on non-retinal eye tissues (Watsky et al., 1991) and potential unexpected ocular toxicity from drugs well characterized and seemingly specific in non-ocular tissues (Stone et al., 2001).

VIII. CONCLUDING THOUGHTS

Understanding the pathogenesis of myopia and introducing clinically validated and effective anti-myopia therapies has been and remains a frustrating endeavor. Contemporary laboratory models of refractive development, form deprivation, spectacle lens wear, and photoperiod disruption, predictably alter eye growth in animals. Each shows properties that mimic certain anatomical features of human ammetropias. These models have demonstrated that the retinal image in large part regulates normal eye growth, but so far have not revealed a clear mechanism for common human myopia. Stimulated by form deprivation and lens induced myopia, it has been suggested blur, perhaps

from degraded images, defocus or other optical aberrations might be a mechanism for myopia (He et al., 2002; Thorn et al., 2000); but validated and unambiguous clinical data to support blur or defocus as directly causing human myopia have so far not been forthcoming.

Regardless of the qualifications about each of these laboratory models of refractive development, applying neuropharmacology methods, principally to the chick, is proving productive. Many of the neurotransmitters discussed above localize to one or more subtypes of retinal amacrine cells and suggest involvement of signaling at the inner retina. Based on refractive responses to specific drugs and immunohistochemistry using one or more of these models, the onand off-retinal signaling systems may contribute independently to the emmetropization process in chick (Crewther, 2000; Crewther and Crewther, 2003) and rhesus monkeys (Zhong et al., 2004). It is not now possible to describe the detailed molecular pathways linking visual input and refractive development, but several general concepts have emerged. Most importantly, retinal signaling modulates refractive development, including in all likelihood both normal growth and the growth perturbations leading to ametropia. Given the diversity of implicated neurotransmitters and neuromodulators, interacting and/or redundant pathways seem probable. Novel applications of gene expression or proteomic platforms might be useful in supplying clues to overall molecular signaling pathways that are now difficult to formulate from the existing diverse observations.

Recently reviewed elsewhere (Stone and Flitcroft, 2004), one of the implications of both available pharmacology results and related optical considerations is that the shape of the eye, as distinct from its size, may be a physiologically regulated variable, and that eye shape might provide a useful parameter to subclassify and study human myopia mechanisms. Traditionally,

refractive research has addressed ocular parameters oriented along the visual axis, an understandable emphasis given the favorable clinical outcomes of prescribing glasses based on the axial refraction. For over 80 years, though, it has been known that human eyes are not necessarily spherical in shape, but instead can be elongated (prolate), widened (oblate) or even asymmetrical, with a bulge in the vitreous chamber. Sporadic clinical reports have suggested that these eye shapes may be informative, perhaps even predictive, for refractive development. Specific visual and/or pharmacologic manipulations in chick reproducibly mimic these ocular forms found in humans. In just a few examples involving drugs, treatment of form deprivation myopia with muscarinic antagonists or dopamine agonists inhibits axial, but not equatorial, expansion of the chick eye (Stone et al., 1991, 1989), shifting overall eye form towards an oblate shape. Treating visually non-restricted chick eyes with a drug that blocks the GABAA0r receptor subtype elongates the eye while reducing the equatorial diameter, thus shifting overall eye form towards a prolate shape (Stone et al., 2003). The mechanisms of regulating the anterior segment are easily dissociated from those regulating the vitreous cavity (Stone and Flitcroft, 2004) and are not as well understood (Stone et al., 2006b). Clinical researchers are now studying eye shape more intensively (e.g. Singh et al., 2006). It is not possible at present to predict how or if conceptualizing the eye in three-dimensional terms instead of twodimensional terms will prove informative either for revealing clinical myopia mechanisms or for predicting responsiveness to therapeutic interventions, but the combined visual, optical and pharmacological results in chick suggest that it might (Stone and Flitcroft, 2004).

The extension of pharmacologic findings from form deprivation myopia of chicks to humans has been remarkable, especially in the context of the skepticism

previously directed towards avian refractive research in the past (e.g. Zaknik and Mutti, 1995). Originally identified using form deprived chick eyes, the efficacy of pirenzepine against juvenile myopia in children is certainly the most advanced example. Besides pointing towards a non-accom- modative mechanism for the anti-myopia activity of muscarinic antagonists, pirenzepine is the only anti-myopia therapeutic since the introduction of atropine that has shown potentially meaningful clinical efficacy in multi-center clinical trials, including optical therapies as well as biofeedback and visual training approaches (Gilmartin et al., 1991; Goss, 1982; Helve-ston, 2005). At the least, the results of the pirenzepine trials demonstrate that innovative drugs can modify refractive development in children, and that findings from laboratory pharmacology can be informative for refractive development in children. While the FDA’s position cut short the development of pirenzepine as a clinical therapy before many questions could be answered, such as long-term efficacy, persistence of myopia inhibition after terminating therapy, etc., the tools of pharmacology remain a viable means to study refractive mechanisms in laboratory animals and may provide clinical treatments in the future.

Other extensions of laboratory pharmacology also offer promise for mechanistic insights, if not alternative approaches to therapy. Initially motivated by dopamine pharmacology, the discovery of diurnal rhythms in ocular dimensions such as axial length and choroidal thickness likely can be extended by direct study in human patients with continuing refinements in clinical measurement methods. Research in this area ultimately may more closely relate refractive development to circadian physiology. Only further research can establish how the initial clinical extensions of nicotinic pharmacology might apply to human refractive development, but a number of new clinical initiatives can be developed from the available findings.

Finally, the progress in laboratory pharmacology and the available clinical extensions underscore a central question in seeking a cause for myopia: what should be the conceptual framework for studying myopia pathogenesis? Based on the ocular responses to defocus from spectacle lens wear, the small effects in some of the bifocal intervention studies and much largely hypothetical clinical literature, many suggest that myopia develops from adaptive physiologic responses to visual or related demands of modern societies. However, form deprivation myopia has yielded many informative laboratory findings with initial clinical extensions, and the visual impact of form deprivation certainly is a highly nonphysiologic insult under most clinical circumstances. Both form deprivation myopia, and the disordered eye development under constant light rearing, suggest alternatively that myopia may develop from physiologically inappropriate processes that may override, rather than exploit, normal regulatory mechanisms. Available data, either in the laboratory or in the clinic, are inadequate to distinguish these two general concepts.

IX. ACKNOWLEDGMENTS

Supported by grants from NIH (R21EY015760 and P30-EY01583), the Paul and Evanina Bell Mackall Foundation Trust and Research to Prevent Blindness. The author is a co-inventor on patents on anti-myopia therapeutics, all of which are assigned to the University of Pennsylvania in accordance with its guidelines.

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