ZINC

ZINC

Zinc (Zn) is the second most abundant trace element in the human body, recipe its total content is approximately 2 grams (female ~1.5g, men ~2.5g).[1],[2] Experimental evidence suggest that Zn has both positive and negative effects on the physiology of the cell in relation to localization (extracellular vs. intracellular), local concentration and/or state (bound vs. free).[3]

ZINC in the Ocular Tissue

The Zn concentration in ocular tissue is high and therefore suggesting a pivotal role in the tissue.  Zn is present, in descending concentration, in the retina and choroid, ciliary body, iris, optic nerve, sclera, cornea, and the lens.[4]  According to Grahn et al development and progression of several chronic eye diseases in North America may be caused/influenced by suboptimal Zn status.  Zn deficiency in humans has been associated with abnormal dark adaption.

THE RETINA

Zinc plays a critical role in the retinal pathology and its physiology.  Endogenous chelatable Zn in the retina is localized mainly to the retinal pigment epithelial cells and the photoreceptors suggesting a role for Zn in the regulation of the light-perception process.  Zn is also localized in other parts of the retina, believed to modulate synaptic transmission and serve as an antioxidant.  The role of Zn in the process of retinal ischaemia has been investigated, revealing a positive effect if administered in low concentrations, while high concentrations act as a toxin and exacerbate the influence of the insult.

AGE Related Macular Degeneration (AMD)

Age related macular degeneration (AMD) is an accumulation of sub-retinal pigment epithelial deposits (sRPEds), including drusen and basal laminar or linear deposits, in Bruch’s membrane (BM) and causes blindness in the elderly.[5],[6]  Zinc might be involved in deposit formation in AMD as it is known that Zn contributes to deposit formation in neurodegenerative diseases.  Reports on Zn status and vision loss in AMD are conflicting, though suggestions of beneficial effects on delaying, arresting or preventing the disease have been made.[7],[8],[9]  Lack of information on the biological role of Zn in the retina and surrounding tissues is one of the major problems.

Epidemiological studies and Zn-supplementation trials have yielded conflicting results on the role of Zn in AMD.  Two Cochrane reviews revealed no beneficial effects from Zn supplementation on AMD.[10],[11]  The first review was from randomized trials on subjects from the general population having at least 12 months of antioxidant vitamin and/or mineral supplementation.  No evidence of a preventative effect or delay of the onset of AMD was observed.10  In the second review, Chong et al supported this outcome further in a systematic review and a meta-analysis.  However, some indication of a modest benefit in subjects with moderate-to-severe signs of AMD from taking antioxidant vitamin and Zn supplementation was found, more so in those subjects who already lost vision in one eye due to wet AMD.[12]  According to Grahn et al Zn has important functions in the retina and the retinal pigment epithelium (REP), where Zn is believed to interact with vitamin A and taurine.

RETINAL Pigment Epithelium (RPE)

Zinc is abundant in the retinal pigment epithelium (RPE)-choroid complex, which is the actual interface where sRPEds form.  Accumulations of e.g. Ab 1-40/42, complement factor H (FH), serum albumin and crystallines in drusen, all bind Zn in pathological conditions.[13],[14],[15]  Both bio-available and strongly bound Zn has been found in macular and peripheral sRPEds and Bruch´s membrane, suggesting that pathological release of Zn from surrounding tissues might be involved in the formation of sRPEds5,[16]and in the development and/or progression of AMD.  Bio-available Zn is differentially concentrated within internal microstructures of drusen, suggesting a deposit formation similar to plaque deposition in Alzheimer´s Disease.

Accumulation of high Zn concentration and polymorphisms of FH in the outer retina (a major regulator of complement activation), are both factors associated with AMD.[17]  Zn inhibits the factor I-mediated cleavage of C3b leading to uncontrolled inflammation.[18]  Nan et al found that monomeric FH aggregates in the presence of Zn and unexpectedly, also other metals like copper (Cu), induce different degrees of uncontrolled FH oligomer formation.  Stress factors like smoking, oxidative stress or excessive light might lead to cellular damage in the RPE, triggering the release of pathological levels of Zn which can initiate FH oligomerization and its precipitation into sRPEds[19]   AMD is associated with Tyr402His polymorphism of CFH, and inhibition/oligomerization of CFH by Zn is a key factor in the development of AMD.[20],[21],[22],[23]

There seems to be contradiction between Zn involvement in the initiation of AMD and the clinical observation that Zn supplements are able to slow down the development of blindness in patients.[24],[25]  Lengyel et al[26] suggests that too much bioavailable Zn in the early stages of AMD can trigger the problem by facilitating the formation of sRPEds.  AMD is a progressive disease and decades elapse between the appearance of sRPEds and the degeneration leading to blindness, whilst Zn supplementation can be beneficial decades later when much of the Zn in the tissues is trapped in sRPEds and the surrounding tissues are relatively depleted.

It is not known when the potential negative interaction with genetic and/or other risk factors start or at what stage the protective effects of Zn may be important. The role of Zn in AMD pathogenesis needs to be clarified.  Pharmacological manipulation of free Zn in the eye could be beneficial against AMD development as free Zn is an ubiquitous and essential signal ion in biology.[27]  It is possible to selectively remove the free Zn from the plaques with Zn-buffers as they do not strip Zn from proteins, but stabilize the concentration of free Zn in the milieu.[28]  To slow down or even prevent the development of AMD, restoration of optimal zinc balance in the eye might be a reasonable goal.

CONCLUSION

Zinc concentration in ocular tissue is high and therefore suggests a pivotal role in the tissue.  Evidence reveals conflicting results regarding the influence of zinc supplementation on ocular tissue.  The role of zinc is likely to be complex in the pathogenesis of AMD and needs further research.

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