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PubMed2006

Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases/reductases and aldo-keto reductases with retinoids.

Retinoic acid biosynthesis in vertebrates occurs in two consecutive steps: the oxidation of retinol to retinaldehyde followed by the oxidation of retinaldehyde to retinoic acid. Enzymes of the MDR (medium-chain dehydrogenase/reductase), SDR (short-chain dehydrogenase/reductase) and AKR (aldo-keto reductase) superfamilies have been reported to catalyse the conversion between retinol and retinaldehyde. Estimation of the relative contribution of enzymes of each type was difficult since kinetics were performed with different methodologies, but SDRs would supposedly play a major role because of their low K(m) values, and because they were found to be active with retinol bound to CRBPI (cellular retinol binding protein type I). In the present study we employed detergent-free assays and HPLC-based methodology to characterize side-by-side the retinoid-converting activities of human MDR [ADH (alcohol dehydrogenase) 1B2 and ADH4), SDR (RoDH (retinol dehydrogenase)-4 and RDH11] and AKR (AKR1B1 and AKR1B10) enzymes. Our results demonstrate that none of the enzymes, including the SDR members, are active with CRBPI-bound retinoids, which questions the previously suggested role of CRBPI as a retinol supplier in the retinoic acid synthesis pathway. The members of all three superfamilies exhibit similar and low K(m) values for retinoids (0.12-1.1 microM), whilst they strongly differ in their kcat values, which range from 0.35 min(-1) for AKR1B1 to 302 min(-1) for ADH4. ADHs appear to be more effective retinol dehydrogenases than SDRs because of their higher kcat values, whereas RDH11 and AKR1B10 are efficient retinaldehyde reductases. Cell culture studies support a role for RoDH-4 as a retinol dehydrogenase and for AKR1B1 as a retinaldehyde reductase in vivo.

Acyl-CoA Dehydrogenase↗
PubMed1997

Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate or retinoic acid.

The formation of all-trans retinoic acid is an oxidative process whereby retinol is converted to retinaldehyde and then to retinoic acid. Because retinol causes qualitative molecular changes similar to those produced by retinoic acid, we compared potency of retinol, retinaldehyde, and retinyl palmitate to retinoic acid and assessed the effects of occlusion. Retinoids were prepared in an experimental vehicle of 95% ethanol:propylene glycol (7:3) with anti-oxidant. Induction of retinoic acid 4-hydroxylase activity was the end point for comparison. Retinoic acid concentrations from 0.001% to 0.05% under occlusion produced a linear dose-response induction of 4-hydroxylase activity. The concentrations of the other retinoids under occlusion required to achieve significant induction of enzyme activity were 0.6% retinyl palmitate, 0.025% retinol, and 0.01% retinaldehyde. The linear dose-response was lost with retinoid concentrations in excess of 0.25% retinol or 0.5% retinaldehyde. Statistical analyses showed no difference in 4-hydroxylase activity between unoccluded and occluded retinol treated sites. By contrast, however, unoccluded sites treated with retinoic acid or retinyl palmitate had less induction of 4-hydroxylase activity than occluded sites. Retinol, retinaldehyde, and retinyl palmitate did not produce erythema but did increase epidermal thickness. Although retinol is a weaker retinoid than retinoic acid, the increased penetration of unoccluded retinol in comparison to unoccluded retinoic acid with this prototypic vehicle confers on retinol a more effective delivery of a retinoidal effect than unoccluded retinoic acid. Retinol at 0.25% may be a useful retinoid for application without occlusion because it does not irritate but does induce cellular and molecular changes similar to those observed with application of 0.025% retinoic acid.

Administration, Topical↗
PubMed1998

Differentiation of human epidermal keratinocytes is accompanied by increased expression of CRABP-II and increased cellular concentration of retinoic acids: retention of newly synthesized retinoic acids by CRABP-II.

Keratinocytes differentiating in vitro exhibit greater cytosolic capacity for retinoic acid synthesis from retinol or retinaldehyde as compared to nondifferentiated cells (Siegenthaler et al. 1990. Biochem. J. 268: 371-378), and increased expression of CRABP-II (Siegenthaler et al. 1988. Exp. Cell Res. 178: 114-126). Based on these observations, the content and disposition of [3H]retinoic acids were determined in intact, nondifferentiated and differentiating keratinocytes incubated with [3H]retinaldehyde or [3H]retinol. Differentiating keratinocytes contained higher levels of [3H] retinoic acids compared to undifferentiated cells when either [3H]retinaldehyde or [3H]retinol was the substrate. The largest increases in [3H]retinoic acids were achieved with [3H]retinaldehyde. Differentiation-associated increases in [3H]retinoic acids correlated with cellular content of retinoid alcohol substrates in incubations with retinaldehyde but not in incubations with retinol. Consistent with previous observations, CRABP-II was significantly increased in differentiating cells. Moreover, newly synthesized [3H]retinoic acids were retained within cells bound to CRABP-II. The results suggest that increasing cellular concentration of retinoic acids in in vitro differentiating keratinocytes is achieved by a combination of increased activity of the retinoic acid synthesis pathway and increased cellular content of CRABP-II.

Biological Transport↗
PubMed2003

The photoreceptive capacity of the developing pineal gland and eye of the golden hamster (Mesocricetus auratus).

Anatomical and physiological studies have suggested that the pineal gland of neonatal mammals has a photoreceptive capacity. Using the golden hamster (Mesocricetus auratus) as our model, we applied biochemical approaches to look for a functional photopigment within the pineal during early development. Immunocytochemistry and enzyme-linked immunosorbent assay (ELISA) were used to localize and quantify opsin, and high-performance liquid chromatography (HPLC) to identify photopigment chromophore (11-cis and all-trans retinaldehyde) in the developing eye and pineal. For HPLC analysis, retinaldehydes were converted to their corresponding retinoid oximes. Eluted retinoids were identified by comparison with standard vitamin A1 retinoid oxime isomers on the basis of relative elution sequence and characteristic absorbance spectra. Both immunocytochemistry and ELISA suggested an increase in the opsin content of the pineal during the first week of life. In the eye, 11-cis retinaldehyde was first detected between days 3 and 5 after birth. In three separate extractions, and using a considerable excess of pineal tissue, we failed to identify chromophore within the pineal during the first week of postnatal development. The appearance of 11-cis retinaldehyde within the eye between postnatal days 3-5 is consistent with the hypothesis that retinol isomerase activity is coordinated with outer segment development. The failure to identify chromophore within the neonatal pineal suggests that this gland lacks a functional opsin-based photopigment. These data contradict physiological evidence suggesting that the neonatal pineal of mammals contains photoreceptors.

Animals↗
PubMed1988

Quantitation of the enterohepatic circulation of retinol in the rat.

Studies were done to determine whether vitamin A is reabsorbed in the enterohepatic circulation in forms that can be reutilized by the body for vision and reproduction. Micelles containing [11,12(n)-3H]retinol were administered orally to mesenteric lymph duct-cannulated rats. Lymph containing [3H]retinyl esters and small amounts of [3H]retinol and [3H]retinaldehyde was collected from these rats and an aliquot was injected into the jugular vein of a second group of mesenteric lymph duct-cannulated rats. The total radioactivity recovered in 24-h lymph collections from recipient rats was only 1.6% of that injected, and the [3H]retinyl esters, [3H]retinol and [3H]retinaldehyde recovered was only 0.9% of that injected. Thus, the amount of vitamin A recovered in the enterohepatic route in forms that can be reutilized by the body for vision and reproduction appears to be very small. Notable differences were observed in the composition of mesenteric lymph containing newly absorbed vitamin A and mesenteric lymph containing recycled vitamin A. In the former, 87% of the total lymph radioactivity was associated with retinyl esters, 5% with retinol, 3% with retinaldehyde and 5% with unidentified mostly nonpolar compounds. In the latter, only 41% of the total lymph radioactivity was associated with retinyl esters, 12% with retinol, 3% with retinaldehyde and 44% with unidentified mostly polar compounds.

Absorption↗
PubMedDate not supplied

UVA and UVB decrease the expression of CD44 and hyaluronate in mouse epidermis, which is counteracted by topical retinoids.

The transmembrane glycoprotein CD44 is currently thought to be the main cell surface receptor for the glycosaminoglycan hyaluronate. We previously showed that (1) CD44 regulate keratinocyte proliferation; (2) topical retinoids dramatically increase the expression of CD44, hyaluronate and hyaluronate synthase (HAS)s in mouse epidermis; (3) topical retinaldehyde restores the epidermal thickness and CD44 expression which are correlated with clinical improvement in lichen sclerosus et atrophicus lesions; and (4) retinaldehyde-induced proliferative response of keratinocytes is a CD44-dependent phenomenon and requires the presence of HB-EGF, erbB1 and matrix metalloproteinases. In this study, we analyzed the effect of UV irradiation on the levels of epidermal hyaluronate and CD44 in mice, as well as its potential prevention by topical retinoids. UVA (10 J/cm(2)) or UVB (1 J/cm(2)) irradiation significantly decreased the expression of CD44 and hyaluronate in the epidermis of hairless mice after 2 h. Expression of both epidermal CD44 and hyaluronate was reconstituted within 24 h. Topical application of retinaldehyde for 3 days prior to UVA or UVB irradiation prevented the decrease of CD44 and hyaluronate expression. Topical retinol and retinoic acid also increased the basal levels of epidermal CD44 and hyaluronate, although their preventive effect on UV-induced decrease of these molecules was less pronounced as compared to topical retinaldehyde. These data confirm the relationships between retinoid and CD44 pathways, although the primary target(s) of UV leading to CD44 and hyaluronate degradation remain to be elucidated.

Administration, Topical↗
PubMed1993

Retinoid effects in purified cultures of chick embryo retina neurons and photoreceptors.

PURPOSE: To investigate the effects of retinoic acid, retinol, and 11-cis retinaldehyde on proliferation, differentiation, and survival of cultured embryonic chick neural retina cells; to describe the metabolic transformations of these retinoids by the cultured cells. METHODS: Retinoids were added to glia-free, low-density cultures of neural retina cells, which underwent subsequent examination to determine the numbers of neurons and photoreceptors that differentiated and survived under differing conditions. Cells and conditioned medium were extracted to identify and quantify retinoid metabolic products by high pressure liquid chromatography. RESULTS: Retinoid treatment resulted in dose-dependent increases in the number of differentiated photoreceptors present in the cultures after 6 days; smaller increases in nonphotoreceptor neurons were also observed. Retinoids were more effective when added at culture onset than at later times, but they did not stimulate cell proliferation. The order of potency was retinol > 11-cis retinaldehyde > retinoic acid. Exogenous retinoic acid was recovered unmodified after a 24-hr incubation period; retinol was also stable and unmetabolized, except for the formation of a small quantity of retinyl acetate. 11-cis retinaldehyde was less stable, and was metabolized into both retinoic acid and retinol. CONCLUSIONS: Retinol, 11-cis retinaldehyde, and retinoic acid can promote the survival (and possibly differentiation) of cultured embryonic retina neurons and photoreceptors in the absence of glia and retinal pigment epithelium. Although retinoic acid is likely to function by interacting with one of the known nuclear receptors for this retinoid, the effectiveness of retinol in the absence of metabolic transformation into retinoic acid suggests the possible existence of a distinct, yet undiscovered receptor.

Animals↗
PubMed1996

In vivo biosynthesis of retinoic acid from beta-carotene involves and excentric cleavage pathway in ferret intestine.

This study was done to determine whether retinoic acid can be produced by excentric cleavage of beta-carotene in vivo. By using an inhibitor of retinaldehyde oxidation, citral, either retinaldehyde or beta-carotene was incorporated in a micellar solution and perfused through the upper portion of small intestine of ferrets. After 2 h perfusion of 1 microM retinaldehyde, retinoic acid rose in portal blood (+3.5 +/- 1.3 nmol/L) and was detected in the intestinal mucosa (30 +/- 2 pmol/g). When citral was added at 2 mM along with retinaldehyde, retinoic acid decreased in the portal blood and retinoic acid was not detected in the intestinal mucosa. With or without the presence of citral (2 mM), the perfusion of beta-carotene (10 microM) during 2 h caused a significant rise of retinoic acid in portal blood (+2.6 +/- 0.6 nmol/L and + 4.1 +/- 0.6 nmol/L, respectively) and in liver; moreover, significant amounts of retinoic acid were detected in the intestinal mucosa (19 +/- 3 pmol/g and 36 +/- pmol/g, respectively. This study demonstrates that after intestinal perfusion of beta-carotene in the ferret in vivo, a substantial amount of retinoic acid is formed via an excentric cleavage pathway.

Acyclic Monoterpenes↗
PubMed2004

RPE65 gene mutation prevents development of autofluorescence in retinal pigment epithelial phagosomes.

During senescence, autofluorescent lysosomal storage bodies known as lipofusin or age pigment accumulate in many post-mitotic types of cells. Among these cell types is the retinal pigment epithelium (RPE) of the mammalian eye. The mechanisms of lipofuscin formation and accumulation have been studied more extensively in the RPE than in any other cell type. Substantial evidence indicates that Vitamin A derivatives (retinoids) are required for RPE lipofuscin formation. The RPE and adjacent retina contain retinoids in the forms of retinol, retinyl esters, and retinaldehyde. Previous research has demonstrated that retinaldehydes are directly involved in the formation of one RPE lipofuscin fluorophore. However, RPE lipofuscin contains many other fluorophores. It has not been determined which retinoids are involved in the formation of these fluorescent compounds. Mice with a mutation in the Rpe65 gene contain substantial levels of retinol and retinyl esters in the RPE, but little if any retinaldehydes in either the RPE or retina. Therefore, these mice could be used to determine whether retinaldehydes are required for formation of all of the RPE lipofuscin fluorophores. Normal mice were given intraocular injections of a protease inhibitor, which resulted in the rapid accumulation in the RPE of lipofuscin-like inclusions. These inclusions exhibited fluorescence properties typical of RPE lipofuscin. Rpe65-/- mice treated with the protease inhibitor also accumulated inclusions similar to those observed in the normal mice. However, these inclusions did not fluoresce under the conditions used to visualize lipofuscin fluorescence. These findings indicate that the aldehyde form of Vitamin A is required for the formation of not only one, but all of the RPE lipofuscin fluorophores.

Aging↗
PubMed1993

Mitogenesis and retinal pigment epithelial cell antigen expression in the rat after krypton laser photocoagulation.

PURPOSE: Polypeptide growth factors, such as the acidic and basic fibroblast growth factors (aFGF and bFGF), may be important in the pathogenesis of subretinal neovascularization. The authors studied the relationship of aFGF and bFGF expression to retinal pigment epithelial (RPE) cell and choriocapillary endothelial cell proliferation in krypton-laser-treated regions of the retina, RPE, and choroid of a model of subretinal neovascularization in the pigmented rat they developed. METHODS: Multiple krypton laser burns were applied to the posterior poles of the eyes of pigmented rats according to a protocol described for producing subretinal neovascularization in these animals. At intervals up to 80 days after treatment, the retinas, RPE, and choroid of these animals were examined by [3H]-thymidine autoradiography and electron microscopic immunocytochemistry, using antibodies to aFGF, bFGF, cytoplasmic retinaldehyde-binding protein, opsin, and various basement membrane macromolecules. RESULTS: Nuclear radiolabeling became evident in these layers when the label was injected as late as 75 days after photocoagulation, but the number of labeled nuclei was greatest when isotope was injected 2-5 days after laser treatment. Although there were labeled nuclei in the retina, RPE, and choroid, the frequency of labeling as a fraction of the total number of nuclei appeared to be greatest in the RPE and choriocapillaris. Non-laser-damaged RPE cells were immunocytochemically strongly positive for cytoplasmic retinaldehyde-binding protein, but were negative for aFGF and bFGF. After laser treatment, many RPE cells lost their cytoplasmic retinaldehyde-binding protein positivity but stained strongly for aFGF and bFGF within intracellular structures of variable shape and homogeneous appearance. Although these structures had an appearance suggestive of basement membrane, they did not stain with antibodies to collagens type IV or V, to laminin, or to heparan sulfate proteoglycan core protein. They also did not stain with an antibody to the N-terminal peptide of opsin. Choriocapillary endothelial cells were unreactive with antibodies to aFGF, bFGF, or cytoplasmic retinaldehyde-binding protein either before or after laser treatment. FGF-positive RPE cells persisted for the 80-day duration of the experiment. CONCLUSIONS: Because the presence of FGF-positive RPE cells coincides temporally with increased nuclear thymidine labeling in the RPE and choriocapillaris, aFGF and/or bFGF may be at least partly responsible for initiating the process of cell proliferation and subretinal neovascularization in these animals.

Animals↗
PubMed1994

Retinoid dynamics in chicken eye during pre- and postnatal development.

Changes in the steady state level of retinols, retinaldehydes and retinyl esters in the trans and 11-cis forms and trans retinoic acid were measured in whole chicken eye during development from day 6 in ovo to day 3 post-hatch. These retinoids, quantified by different HPLC systems, were detected in this time sequence: trans-retinol and trans-retinyl esters in the first week in ovo, 11-cis-retinol in the second week. The highest level of 11-cis-retinaldehyde and 11-cis-retinyl esters was reached at the end of development in ovo; however, their levels increased further after hatching. The retinoic acid level decreased at the end of the first week, rising again at the end of the second week. The enzyme activities involved in the metabolism of these retinoids-acyl-CoA: retinol acyltransferase, trans-retinol dehydrogenase, 11-cis-retinol dehydrogenase, trans-retinyl ester hydrolase and trans: 11-cis-retinol isomerase were also estimated and they were detectable already in the first week of development in ovo. At day 6 of the biosynthesis of retinoic acid by the retinaldehyde dehydrogenase activity from retina cytosol was also shown.

Alcohol Oxidoreductases↗
PubMed1989

Affinity labeling of bovine opsin by trans-retinoyl chloromethane.

All-trans-retinoyl chloromethane is a potent irreversible inactivator of bovine opsin in retinal rod outer segments. The inactivation appears to be due to specific modification of the apoprotein at the 11-cis-retinaldehyde binding site. The reaction follows pseudo first order kinetics at 37 degrees C. A moderate dissociation constant for the initial reversible complex of 6.1 mM could be derived with a first order rate constant of 1.8x10(-1) min-1 for the conversion to the irreversible inactivated form. Native rhodopsin or rhodopsin regenerated from opsin by addition of 11-cis-retinaldehyde is completely protected against inactivation by trans-retinoyl chloromethane. All-trans-retinaldehyde does not provide this protection for the irreversible inactivation.

Affinity Labels↗
PubMed1990

Uptake, processing and release of retinoids by cultured human retinal pigment epithelium.

Upon absorption of a photon, the 11-cis retinaldehyde chromophore of rhodopsin is isomerized and reduced to all-trans retinol (vitamin A) in the photoreceptor outer segments, whereupon it leaves the photoreceptors, and moves to the retinal pigment epithelium (RPE). To clarify the function of the RPE in the regeneration of 11-cis retinaldehyde, we delivered all-trans retinol to monolayer cultures of human RPE. During delivery the retinol was associated with its putative natural carrier, interphotoreceptor retinoid binding protein (IRBP). IRBP has been proposed as a carrier protein involved in the exchange of retinoids between the photoreceptors and the retinal pigment epithelium. The retinoid composition of RPE cells and culture medium was analyzed by HPLC following several incubation periods. The RPE monolayer was found to process all-trans retinol into two distinct end-products: all-trans retinyl palmitate, which remained within the RPE monolayer: and 11-cis retinaldehyde which was released into the culture medium. These results demonstrate retinoid isomerase, retinol oxidoreductase and retinyl ester synthetase activity in human RPE cells cultured under the appropriate conditions. They show that IRBP can serve as a carrier of retinol through an aqueous medium to the RPE, and they illustrate that the visual cycle can be studied in vitro.

Cells, Cultured↗
PubMed1994

beta-Carotene-15,15'-dioxygenase (EC 1.13.11.21) isolation reaction mechanism and an improved assay procedure.

beta-Carotene-15,15'-dioxygenase (EC 1.13.11.21; beta-carotene dioxygenase) activity in extracts from guinea-pig intestinal mucosa was assayed by supplying [15,15'-14C2]- or [15,15'-3H2] beta-carotene dissolved in Tween 80. Methods were developed to minimize the breakdown of labelled beta-carotene and beta-carotene cleavage products during the isolation procedure. Antioxidants and unlabelled carriers were added to extracting solvents and C18 Sep-Pak cartridges were used to isolate the remaining beta-carotene and retinaldehyde, which was the only cleavage product detected. The labelled material produced by the enzyme was analysed by either normal-phase TLC or reversed-phase HPLC and characterized chemically as retinaldehyde. The lack of other labelled apo-carotenals isolated in these experiments and the formation of between 1.5 and 2 mol retinaldehyde/mol beta-carotene consumed confirm the central cleavage mechanism for the enzyme's action. More beta-carotene dioxygenase activity was obtained from guinea-pig mucosa than from chicken or pig intestinal mucosa. The beta-carotene dioxygenase was obtained as a soluble enzyme which was partially purified by gel filtration and ion-exchange chromatography to a specific activity of 0.6 nmol retinaldehyde formed/mg protein per h. The formation of a lipid-protein aggregate containing the beta-carotene dioxygenase activity, which has been reported to be present in the exclusion volume of Sephadex columns, was avoided if the mucosal scrapings were homogenized in buffer at a proportion of 1:4 (w/v).

Animals↗
PubMed2005

Retinoid metabolism in the rat small intestine.

Vitamin A (retinol) is essential for epithelial cell growth, differentiation and proliferation. The absorption of retinol occurs in the small intestine, and the metabolism of this vitamin is not well studied in this organ. The intestinal epithelium has a high rate of cell proliferation and differentiation, and the present study looked at the level of retinoids and metabolizing enzymes involved in their interconversion along the villus-crypt axis under normal conditions. Intestine was removed from control rats, and enterocytes at various stages of maturation and differentiation were quantified by the metal chelation method. Using HPLC, various retinoid concentrations in the cell homogenate and the metabolizing enzymes in the cytosol were quantified. The proliferating crypt cells were found to have a higher level of retinoic acid as well as of the enzymes involved in its formation, such as retinaldehyde oxidase and retinol dehydrogenase, compared with the villus cells, suggesting a possible role for this compound in intestinal epithelial cell proliferation and differentiation. The high level of retinol and high retinaldehyde reductase activity in the villus cells suggest the important role played by this enzyme in the conversion of dietary beta-carotene to retinol via retinaldehyde. In summary, this study has given for the first time a detailed analysis of the retinoid levels and metabolizing enzymes in different cell populations in the rat small intestinal epithelium.

Animals↗
PubMed1991

The intracellular vitamin A-binding proteins: an overview of their functions.

The intracellular retinoid-binding proteins bind retinol, retinaldehyde, and retinoic acid for purposes of protection against decomposition, solubilize them in aqueous medium, render them nontoxic, and transport them within cells to their site of action. These binding proteins also function by presenting the retinoids to the appropriate enzymes for metabolism. The cytosolic retinol and retinoic acid-binding proteins--CRBP, CRABP, CRBP (II)--function in transport and metabolism of retinoids within parenchymal, intestinal, reproductive, and fetal cells and across blood-organ barriers. A different group of retinoid-binding proteins, more related to serum retinol-binding protein, functions in epididymis and uterus. Retinaldehyde-binding protein aids in the oxidation-reduction reaction of 11-cis-retinol-11-cis-retinaldehyde in the retina, where the interphotoreceptor retinol-binding protein transports retinol between pigment epithelium and photoreceptors. Finally, a group of retinoic acid-binding proteins termed "receptors" functions in the nucleus by attaching to promoter regions of a number of specific genes to stimulate their transcription and thus affect growth, development, and differentiation.

Animals↗
PubMed2004

Characterization of retinoic acid neuromodulation in the carp retina.

Visual sensation in vertebrates starts with the isomerization of 11-cis retinaldehyde into all-trans retinaldehyde. Aldehyde dehydrogenases, present in the pigment epithelium and some retinal cells, convert all-trans retinaldehyde into all-trans retinoic acid (at-RA). Evidence in the retina and the hippocampus has accumulated, showing that at-RA, besides being a morphogenetic factor, also acts as a neuromodulator. In mature retina, at-RA affects visual processing by acting on gap junctional conductances and the synaptic transfer between photoreceptors and horizontal cells. We present evidence supporting a neuromodulatory role of at-RA in the carp retina. High performance liquid chromatography (HPLC) measurements and an RA bioassay indicate a light dependency of at-RA formation, which can explain the observed effects of at-RA on spinule formation at horizontal cell dendrites in this retina. Furthermore, inhibiting endogenous metabolism and catabolism of at-RA affects formation and persistence of spinules in a way, supporting a direct involvement of at-RA in this light-dependent mechanism of synaptic plasticity. The action of at-RA, however, seems independent of the dopaminergic system, known for its light-signaling role in the retina, because at-RA effects on spinule formation persisted in retina depleted of dopaminergic neurons or in the presence of haloperidol. Together, these data indicate that at-RA acts effectively as a direct neuromodulator in carp retina, transmitting information about ambient light conditions to the neuronal retina.

Animals↗
PubMed1997

Retinoic acid synthesis in normal and Alzheimer diseased brain and human neural cells.

Retinoids play fundamental roles in CNS development, but their distribution, metabolism, and function within the mature human CNS are unknown. In these studies, extracts of autopsy tissues recovered from histopathologically confirmed control and Alzheimer diseased brains were tested for their ability to synthesize retinoic acid. Retinaldehyde dehydrogenase (RLDH), the enzyme that forms retinoic acid from retinaldehyde, was present in hippocampus, frontal cortex, and parietal cortex. The RLDH activity of hippocampus and parietal cortex from Alzheimer diseased brains was 1.5- to 2-fold higher (p < 0.05) compared to the controls. In contrast, the RLDH activity of frontal cortex was the same for both Alzheimer diseased and control groups. A cultured human glioblastoma (U251) and neuroblastoma (LA-N-5) cell line synthesized retinoic acid from retinaldehyde or retinol, suggesting that a variety of neural cell types possess this activity. LA-N-5 cells grown in vitamin A-depleted medium had higher (p < 0.05) RLDH activity (0.35 +/- 0.04 nmol/mg/h) than LA-N-5 cells grown in vitamin A-replete media (0.15 +/- 0.02 nmol/mg/h). This difference was lost when retinol was added back to the medium, confirming that a reduction in vitamin A supply can induce RLDH activity in neural cells. However, this feedback mechanism does not appear to explain the higher RLDH activity of Alzheimer diseased hippocampus and parietal cortex, because the overall vitamin A status as indicated by serum retinol and carotenoid levels and by hippocampal retinoid content was similar for the Alzheimer diseased and control groups. These studies establish the presence of retinoids and RLDH activity in human brain tissues, and indicate that retinoic acid synthesis is modulated in some regions of Alzheimer diseased brain.

Alzheimer Disease↗