Melatonin: Parallels in pineal gland and retina

Wiechmann, Allan F.

doi:10.1016/0014-4835(86)90042-4

Cited by 162 publications

(72 citation statements)

References 133 publications

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“…There is good evidence that this rudimentary eye, though not able to detect light anymore (38), is still of vital importance for photoperiod perception (39), which is required for the physiological adaptations of the animal to seasonal changes. It is becoming increasingly clear that in mammals not only the pineal gland is responsible for the induction of such physiological responses (through the synthesis of melatonin directed by photic information received from the retina) but also the retina itself is capable of melatonin synthesis (40). A retinal layer, in which melatonin is synthesized (41), can still clearly be recognized in the mole rat eye (19).…”

Section: Discussionmentioning

confidence: 99%

“…The increased rate ih the mole rat lineage is a conservative estimate because it is the average over the last 40 Myr of evolution of aA. Although it obviously is uncertain when the effective loss of vision occurred, it seems reasonable to assume that the accelerated evolution of aA only began after the mole rats had fully adapted to a burrowing, subterranean way of life, probably 25 Myr ago according to fossil evidence (20).…”

Section: S G L D a G H S E R A I P V S Q E E K P S S A P L F Stop-codonmentioning

confidence: 99%

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The lens protein alpha A-crystallin of the blind mole rat, Spalax ehrenbergi: evolutionary change and functional constraints.

Hendriks¹,

Leunissen²,

Nevo³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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The complete structure of the single-copy aA-crystallin gene of the blind mole rat (Spalax ehrenbergi) has been determined in order to elucidate the evolutionary effects of the loss of vision on a lens-specific protein and its gene. The aA-crystallin gene appears to have all the necessary transcriptional and translational signal sequences to be expressed in the rudimentary lens of the mole rat and gives rise to probably two protein products by means of alternative splicing, as in rodents with normal vision. Comparisons of the blind mole rat aAcrystallin sequence with aA sequences from other rodents reveal a considerable acceleration of the substitution rate at nonsynonymous positions in the mole rat lineage, which reflects a relaxation of selective constraints, but the acceleration is not to the extent that might be expected if the gene were now without any function. The remaining evolutionary constraints still imposed upon the mole rat aA-crystallin gene may possibly reflect the need for a-crystallin expression as an indispensable component in the developmental program of the atrophied eye.Functional constraints working at the protein level are recognized as a major determinant of the rate of molecular evolution (1-3). Although several well-known examples clearly seem to illustrate this principle, such as the fastevolving fibrinopeptides versus the conserved histones (4), the structure-function relationships of most proteins are, in fact, not understood in sufficient detail to reliably correlate functional constraint with rate of evolution. This difficulty may also hamper the clear distinction of other types of constraints, such as amino acid composition (5), transcriptional and translational requirements (6), and developmental programs (7,8). The existence and importance of these additional selective forces might be revealed by studying genes whose protein products have lost their normal principal function in the course of evolution. The substitution rate of such a gene would be expected to increase and might eventually become as fast as in pseudogenes unless other constraints interfere. A unique opportunity for such a study is offered by the rudimentary eyes of blind vertebrate species. The eye-specific genes of these animals are no longer subject to the selective constraints associated with the maintenance of vision.The eye lens protein a-crystallin is very suitable for this purpose because much comparative and evolutionary data are available (9-11). a-Crystallin is a slowly evolving protein (10), and, thus, relaxation of constraints should be readily detectable. An important advantage, too, is the fact that the atA and aB subunits, of which at-crystallin is composed, are both encoded by single-copy genes located on different chromosomes (12). The aA and aB chains have =57% sequence homology, due to an ancient gene duplication (10), and conspicuous sequence similarity with the small heat shock proteins indicates that the ancestral ca-crystallin gene originated from this protein family (13,14). aA-Cry...

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Section: Discussionmentioning

confidence: 99%

Section: S G L D a G H S E R A I P V S Q E E K P S S A P L F Stop-codonmentioning

confidence: 99%

The lens protein alpha A-crystallin of the blind mole rat, Spalax ehrenbergi: evolutionary change and functional constraints.

Hendriks¹,

Leunissen²,

Nevo³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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“…In numerous non-mammalian and mammalian species, melatonin is rhythmically synthesized in this specialized CNS structure, in both a subpopulation of photoreceptor cells and the retinal pigment epithelium. In some nonmammalian organisms, it is also released to the blood in certain quantities [19,30,35,77,145,153,155]. However, primates and ungulates so-far investigated exhibited high nocturnal expression levels of AA-NAT, but are reported to not form melatonin at substantial rates, because the NASconverting enzyme, hydroxyindole O-methyltransferase (HIOMT) is poorly expressed [13,65,66].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

112

110

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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“…Melatonin, an indoleamine, is produced mainly by the pineal gland with some synthesis occurring in the retina also [140]. It is well established that melatonin has antioxidant properties [141] and has the ability to scavenge free radicals, induce expression of antioxidant enzymes and reduce lipid peroxidation to mitigate oxidative stress in neural tissues…”

Section: Protective Effect Of Melatonin In Hypoxiamentioning

confidence: 99%

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Kaur¹,

Rathnasamy²,

Foulds³

et al. 2015

J Neurol Exp Neurosci

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Loss of retinal ganglion cells (RGCs) occurs in retinal degenerative diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion and ischemic central retinal vein thrombosis in adults and in retinopathy of prematurity in infants. A critical role of hypoxia, which underlies most of the above disorders, has been reported in causing RGC death. Disruption of blood-retinal barrier (BRB) occurs due to increased production of vascular endothelial growth factor and nitric oxide in response to hypoxia resulting in extravasation of serum derived substances and retinal edema and this may be one of important factors mediating RGC death. Activation of microglial cells in response to hypoxia and subsequent increased release of proinflammatory cytokines by them such as tumor-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) target the TNF-receptor 1 and IL-receptor 1 on RGCs. Excess release of glutamate in retinal tissue under hypoxia activates the ionotropic glutamate receptors causing excitotoxicity through increased influx of calcium into the RGCs. Increased production of TNF-α, IL-1β and enhanced intracellular calcium results in RGC death through activating several pathways such as caspase signaling, mitochondrial dysfunction and oxidative stress. In our investigations, melatonin, an antioxidant, was shown to reduce RGC death in the adult and neonatal hypoxic retina, through suppression of TNF-α, IL-1β and glutamate levels as well as oxidative stress. Moreover, the function and structure of BRB was well preserved in these animals along with reduction in retinal edema. In view of our observations, we suggest that melatonin could be considered as a therapeutic agent to reduce RGC death in various retinal pathologies, in addition to other potential drugs/molecules of therapeutic interest that could render protection to RGCs. However, future in-depth research on the effects of melatonin on the retina under hypoxic conditions needs to be undertaken to explore its full potential in preventing/ameliorating RGC death. Factors Mediating RGC DeathSeveral factors induced or upregulated by hypoxia may be involved in causing RGC death. These factors include, among others, disruption of the blood-retinal barrier, activation of microglial cells and the accompanying enhanced release of inflammatory cytokines and excess release and accumulation of glutamate in the retinal tissues. Hypoxia and the blood-retinal barrierThe BRB regulates the passage of molecules from blood into the retina [11,12]. It consists of an inner BRB formed by the tight junctions (TJ) between capillary endothelial cells and an outer barrier formed by TJ between retinal pigment epithelial cells [12][13][14][15][16]. The TJ are made up of transmembrane proteins such as occludin, claudin-5 and cytoplasmic proteins such as zona occludens (ZO)-1 that are structurally and functionally important for maintaining the integrity of the BRB. The proper functioning of the inner BRB also requires the collective co...

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Melatonin: Parallels in pineal gland and retina

Cited by 162 publications

References 133 publications

The lens protein alpha A-crystallin of the blind mole rat, Spalax ehrenbergi: evolutionary change and functional constraints.

The lens protein alpha A-crystallin of the blind mole rat, Spalax ehrenbergi: evolutionary change and functional constraints.

Melatonin Metabolism in the Central Nervous System

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

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