Glaucoma, Uveitis and Melatonin
Ruth E. Rosenstein, PhD
Department of Human Biochemistry
School of Medicine, CEFyBO
University of Buenos Aires, CONICET
Paraguay 2155, 5th floor, (1121)
Buenos Aires, Argentina
54-11-45083672 ext 37 / 54-11-45083672 ext 31 (FAX)
ruthr@fmed.uba.ar
“Melatonin as a Therapeutic Tool in Ophthalmology: Implications for Glaucoma and Uveitis,”
J Pineal Res, 2010 Aug;49(1):1-13. 50244 (9/2013)

Kirk Hamilton: Can you please share with us your educational background and current position?

Ruth E. Rosenstein: I am chemist, with a PhD in biological chemistry at the School of Sciences, and pharmacist at the School of Pharmacy and Biochemistry, University of Buenos Aires. At present, I am full professor of Human Biochemistry at the School of Medicine, and principal researcher from the National Research Council (CONICET).

KH: What got you interested in studying the role of melatonin in the treatment/prevention of prevalent ocular disorders such as glaucoma and uveitis?

RER: Melatonin is a ubiquitous natural substance that is widely distributed in nature, both in plants as well as in animals. It is probably one of the first compounds that appeared in living organisms. I have many years of experience in the field of melatonin research. During my thesis work, I studied the relationship between the pineal gland in general, and melatonin in particular with the central GABAergic system. Since 1994, as an independent researcher, I have been studying the retinal physiopathology, and in that context, I have studied several aspects of the role of melatonin in the mammalian retina. In particular, with my group, we have demonstrated many attractive features of retinal melatonin, since this fascinating molecule has antioxidant, anti-nitridergic, anti-inflammatory properties, and it decreases excitotoxic damage.  Uveitis and glaucoma are highly prevalent ocular diseases, and constitute main causes of blindness. Uveitis is essentially an inflammatory disease, while glaucoma is an ocular dysfunction highly associated with ocular hypertension and characterized by a loss of retinal ganglion cells and optic nerve head atrophy. Uveitis and glaucoma differ in several aspects, including causes, risk factors, and retinal cell types involved, among many others. However, several lines of evidence support the inference that uveitis and glaucoma may share some of the etiopathogenic mechanisms, particularly oxidative damage and increased nitric oxide production. Indeed, there is experimental evidence supporting the value of antioxidant and anti-nitridergic compounds for treating both glaucoma and uveitis. Since melatonin by itself exhibits both antioxidant and anti-nitridergic properties, we decided to analyze the therapeutic effect of melatonin in experimental models of these ocular diseases.

KH: What is the biochemistry of melatonin that might alter the pathophysiology of uveitis?

RER: Uveitis, a disease with potentially blinding sequelae (synequiae, cataracts, macular and optic nerve edema, with loss of vision and loss of the eye), remains a challenging condition to ophthalmologists as the disease causes significant morbidity and the use of traditional forms of treatment is restricted by limited effectiveness and considerable side effects. Thus, it represents a significant public health concern. Several lines of evidence support the involvement of oxidative damage and increased nitric oxide and prostaglandinproduction as etiopathogenic mechanisms of uveitis. Melatonin could be a useful resource for uveitis treatment since by itself exhibits both antioxidant and anti-nitridergic properties and inhibits cyclooxygenase activity, among many other anti-inflammatory effects. Ocular inflammation is mainly treated with
topical and/or systemic application of corticosteroids. During long-term treatment with corticosteroids, however, care must be taken to guard against both ocular and systemic complications such as cataract, glaucoma, diabetes, hypertension, and osteoporosis. Therefore, the establishment of additive antiinflammatory approaches is desirable to decrease the rate and degree of these complications. We have obtained strong evidence in experimental models of uveitis in hamsters and cats supporting that melatonin, which lacks adverse collateral effects even at high doses, could be a promissory resource in the management of uveitis. Alone or combined with corticosteroid therapy, the anti-inflammatory effects of melatonin may benefit patients with chronic uveitis and decrease the rate and degree of corticosteroid-induced complications. Thus, melatonin appears as a potentially useful anti-inflammatory drug, particularly in ophthalmology, and as an alternative or eventually as a complement to glucocorticoids, since it was shown to be highly effective and it does not present the side effects of these steroids.

KH: What is the biochemistry of melatonin that might alter the pathophysiology of glaucoma?

RER: Glaucoma is a leading cause of blindness, characterized by specific visual field defects due to the loss of retinal ganglion cells and damage to the optic nerve head. Ocular hypertension is probably the most important risk factor in primary open angle glaucoma (POAG), the more frequent form of glaucoma. Besides ocular hypertension, several concomitant factors such as elevation of synaptic glutamate levels and a decrease in GABA levels, altered NO metabolism, and oxidative damage could significantly contribute to the neurodegeneration. Although the current management of glaucoma is mainly directed at the control of intraocular pressure (IOP), a therapy that prevents the death of retinal ganglion cells and optic nerve head fiber loss should be the main goal of treatment. Several lines of evidence strongly support that melatonin behaves as a neuroprotector in experimental animal models of various neurological and neurodegenerative disorders. We have developed a model of glaucoma in rats through intracameral injections of hyaluronic acid (HA). Weekly injections of HA in the rat anterior chamber significantly increase IOP as compared with vehicle-injected contra lateral eye. Moreover, chronic administration of HA significantly decreases the scotopic electroretinographic activity and provokes a significant loss of retinal ganglion cells (RGCs) and optic nerve fibers. Based on both functional and histological evidence, these results indicate that the intracameral injections of HA in the rat eye anterior chamber appear to mimic some key features of POAG. Using this experimental model, we have shown that an increase in glutamate and nitric oxide levels, a decrease in the GABAergic activity, and oxidative damage could be involved in glaucomatous neuropathy. Moreover, we have shown that melatonin is able to impair retinal glutamate neurotoxicity, decrease NO levels, increase GABA concentrations, and reduce oxidative stress. Thus, we hypothesized that melatonin could have a beneficial effect against glaucomatous damage. We have recently analyzed the effect of melatonin in the glaucoma model induced by HA injections. For this purpose, a pellet of melatonin was implanted 24 h before the first injection of HA, injections of HA were repeated once a week and the pellet of melatonin was replaced every 15 days. Melatonin did not affect IOP, but prevented the effect of ocular hypertension on retinal function (assessed by electroretinography), and diminished the vulnerability of RGCs to the deleterious effects of ocular hypertension. An effective neuroprotectant for glaucoma treatment must reach the optic nerve head and/or ganglion cells and will therefore probably have to be taken orally, and because it will reach other parts of the body, any side-effect of an appropriate neuroprotectant must be reduced to a minimum. Melatonin, a very safe compound for human use, is highly lipophilic and readily diffuses into tissues. Our recent results support that melatonin alone, or combined with an ocular hypotensive
therapy, should be considered as a new therapeutic resource, particularly for the treatment of glaucoma.

KH: Are there an intervention studies using melatonin in glaucoma? If so what daily dose of melatonin was used? How was it taken? With meals or away from meals? In a single dose or divided dose?

RER: Although we strongly believe in the translation relevance of our findings regarding the therapeutic benefit of melatonin for glaucoma and uveitis treatment, unfortunately, to our knowledge, there are no current studies to confirm the clinical use of melatonin in humans with these ocular diseases.

KH: Are there an intervention studies using melatonin in uveitis? If so what daily dose of melatonin was used? How was it taken? With meals or away from meals? In a single dose or divided dose?

RER: As already mentioned, there are no current studies to confirm the effectiveness of melatonin in human uveitis. However, a year ago, I received an e-mail from a Spanish woman who let me know that she was using 10 mg/day of melatonin with high success in reducing clinical symptoms of uveitis. In any case, these findings should be replicated in large-scale studies before definitive conclusions can be reached.

KH: Are there any side effects to melatonin therapy in the treatment of these inflammatory eye disorders?

RER: In our experimental studies, we did not find any side effect of melatonin treatment. Moreover, many lines of evidence strongly support that melatonin is a very safe compound for human use, even at high doses.

KH: Nitric oxide is a positive thing in some aspects of vascular disorders? Why would you want something that inhibits nitric oxide?

RER: Nitric oxide is a ubiquitous signaling molecule that participates in a variety of cellular functions. However, in concert with reactive oxygen species, nitric oxide can be transformed into a highly potent and effective cytotoxic entity of pathophysiological significance. In particular, NO can react with superoxide producing peroxynitrite, a powerful and deleterious oxidant. In agreement with these results, it was shown that uncontrolled NO elevation causes morphological and functional changes in the retina. Moreover, it has been demonstrated that inhibition of a particular isoform of nitric oxide synthase (NOS) (inducible NOS, iNOS), protects against retinal ganglion cell loss in an experimental model of glaucoma, supporting that activation of iNOS, may play a significant role in glaucomatous optic neuropathy. Furthermore, it has been demonstrated that multiple intraperitoneal injections of a NOS inhibitor, reduces clinical signs of uveitis, suggesting that NO could participate to the pathogenesis of experimental uveitis as a proinflammatory mediator.

KH: Who is a candidate for melatonin therapy? All subjects with these eye disorders? All aging individuals?

RER: As already mentioned, we have no experience with the use of melatonin in humans. However, based on experimental evidence, anyone, independently of age, could be potentially treated with melatonin for ocular disease therapy.

KH: How do you best assess melatonin status? Salivary, serum or urine melatonin or its metabolites?

RER: According to the literature, urine or salivary melatonin could be good markers of serum melatonin levels. I strongly believe that this information would be of interest for ophthalmologists treating glaucoma and uveitis, having the particular advantage of the safety of melatonin use in humans. From my point of view and based on our experimental results, melatonin should be included in the armamentarium of ophthalmic therapeutic resources, particularly for the treatment of these ocular diseases.

KH: Do you have any further comments on this very interesting subject?

RER: No further comments.