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Studies Published which Discuss Retinoids in the Central Nervous System and the link to other Neurological Diseases
2005 Prog Neurobiol. 2005 Mar;75(4):275-93. Lane MA, Bailey SJ. Role of retinoid signalling in the adult brain. Much of the research conducted on retinoid signalling in the nervous system has focussed on developmental effects in the embryonic or early postnatal brain. Here, we review the increasing body of evidence indicating that retinoid signalling plays an important role in the function of the mature brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids. Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases.
2004 The NeuroScientist 10(5):409-421 Mey J et al Mey J, McCaffery P. Neuroscientist. 2004 Oct;10(5):409-21 Isotretinoin is a very effective medication for the treatment of severe recalcitrant acne. Excellent review on Retinoic Acid Signalling. Section on 'Retinoic Acid in Learning and Neural Plasticity' (pg 410) and section on 'RA functions in the hippocampus - A potential role in Neurogenesis and Depression'.
2004 Ann N Y Acad Sci. Jun;1021:436-40 Sakai Y et al Sakai Y, Crandall JE, Brodsky J, McCaffery P.13-cis Retinoic acid (accutane) suppresses hippocampal cell survival in mice.Ann N Y Acad Sci. 2004 Jun;1021:436-40. Conclusion: We now show, in a mouse model, that endogenous RA generated by synthetic enzymes in the meninges acts on hippocampal granule neurons, and chronic (3-week) exposure to a clinical dose of 13-cis RA may result in hippocampal cell loss. In humans this may be conjectured to be the mechanism by which Accutane contributes to depression.
2004 Proc Natl Acad Sci U S A. Apr 6;101(14):5111-6 Crandall J et al Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery P (2004) 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proceedings of the National Academy of Sciences USA 101:5111-5116 Conclusion: This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.
2004 Program No. 437.15. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online. S.A. Ferguson, F.J. Cisneros, J.P. Hanig, B. Gough, K.J. Berry. CHRONIC ORAL ACCUTANE (ACC), BUT NOT ALL-TRANS-RETINOIC ACID (ATRA), TREATMENT CAUSES BEHAVIORAL ALTERATIONS IN THE FORCED SWIM TEST The anti-acne drug, ACC (isotretinoin, 13-cis-retinoic acid), is associated with depression, suicide ideation and suicide. The potential confounds inherent in human research necessitated the current animal study. Here, male and female Sprague-Dawley rats (n=6/sex/dose) were gavaged with 0 (soy oil), 7.5, or 22.5 mg/kg/day ACC beginning on postnatal day 82. Previous work indicates that 7.5 mg/kg produces blood ACC levels similar to those of humans taking recommended ACC doses (1 mg/kg/day). As a comparison for in vivo isomerization of ACC, separate groups of rats were gavaged with 10 or 15 mg/kg/day ATRA (n=6/sex/dose). After 7 weeks of chronic treatment, a forced swim test was conducted on two consecutive days. Each rat was placed in an inescapable cylindrical tank of 25oC water for 10 (day 1) or 5 (day 2) min. Tests began ~ 1 hour post-gavage. Dive frequency and durations of active swimming, immobility (including floating), and climbing/struggling were measured. Neither ACC nor ATRA altered diving or swim durations. ATRA treatment had no effect on any other measured behavior. However, rats treated with 7.5 mg/kg ACC engaged in longer durations of climbing/struggling and shorter durations of immobility than controls (p<.05). This ACC treatment effect did not interact with test session (day) or sex, although there were significant main effects of session and sex, and the effect was not caused by alterations in locomotor activity (see accompanying abstract for lack of open field activity changes). In general, short immobility and long climb/struggle durations are indications of decreased depression (i.e., antidepressant treatment shortens immobility time). Thus, ACC doses which produce blood levels similar to humans cause behavioral alterations in a rodent assessment designed to assess depression.
2003 Behav Brain Res. 2003 Oct 17;145(1-2):37-49. Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret P, Jaffard R. Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Vitamin A and its derivatives, the retinoids, have recently been reported to be implicated in the synaptic plasticity of the hippocampus and in cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. We recently showed that a moderate (about 30%) hypoexpression of brain (and hippocampal) retinoid signalling, like that naturally occurring in the aged brain of mice, might be related to a selective relational memory deficit. To further assess this hypothesis, the present study investigated the effects of Vitamin A deprivation of varying duration both on the brain expression of retinoid receptors (RARbeta and RXRbeta/gamma) and two associated target genes [tissue-type transglutaminase (tTG) and neurogranin, (RC3)], and on radial maze discrimination learning using young adult mice as subjects. We observed that irrespective of its duration (i.e. 31 or 39 weeks), Vitamin A deprivation resulted in a significant reduction (25-30%) in the expression of brain RARbeta, RXRbeta/gamma and tTG mRNAs. Conversely, only the 39-week condition was found to induce a significant decrease in brain RC3 mRNAs contents and a selective relational memory impairment. Finally, daily administration of retinoic acid (RA) failed to reverse the 39-week Vitamin A deficiency (VAD)-related cognitive deficit and to fully normalise the associated brain retinoid hyposignalling. In particular, there was no evidence for an up-regulating effect of RA on whole brain (and hippocampal) RC3 mRNAs of the 39-week-depleted mice. The results show that post-natal VAD may induce a selective memory impairment and give further support to the hypothesis that the fine regulation of retinoid-mediated gene expression is important for optimal brain functioning and higher cognition.
2003 Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2901-5 Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer's disease The hypothesis of this article is that late onset Alzheimer's disease (AD) is influenced by the availability in brain of retinoic acid (RA), the final product of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and environmental/dietary evidence is cited supporting this hypothesis. Significant genetic linkages to AD are demonstrated for markers close to four of the six RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. Synthesis of the evidence supports retinoid hypofunction and impaired transport as contributing factors. These findings suggest testable experiments to determine whether increasing the availability of retinoid in brain, possibly through pharmacologic targeting of the RA receptors and the cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid plaque formation.
2002 NIMH meeting in 2002 entitled "Functional Effects of Retinoids in the Adolescent and Adult Central Nervous System" Click here for link...Baselines studies examining the effects of a range of retinoid doses and routes of admisinstration on neurochemical measures in models assessing mood, anxiety, aggression, implusivity and cognitive function.....
2000 Neuron, 27, 359-370 Mello, CV et al (New York) Site-Specific Retinoic Acid Production in the Brain of Adult Songbirds They found conclusive evidence for localized retinoic acid synthesis in an adult vertebrate brain and indicate that the retinoic acid-generating system plays a significant role in the maturation of a learned behaviour. The main implication is that processes under retinoid control appear to extend beyond the embryonic period into adulthood and affect the organisation of brain circuitry and behaviour.
1998 Proc. Natl. Acad. Sci, 95, 7240-7244. Goodman, AB Three independent lines of evidence suggest retinoids as causal to schizophrenia Three lines of evidence are suggested, which include (i)anomalies similar to those caused by retinoid dysfunction are found in schizophrenia and their relatives (ii) loci suggested to be linked to schizophrenia candidate genes regulated by retinoic acid and (iii) transcriptional activation of the dopamine receptor and numerous schizophrenia genes is regulated by retinoic acid.
1998 Proc. Natl. Acad. Sci, 95, 7240-7244. Goodman, AB Three independent lines of evidence suggest retinoids as causal to schizophrenia Three lines of evidence are suggested, which include (i)anomalies similar to those caused by retinoid dysfunction are found in schizophrenia and their relatives (ii) loci suggested to be linked to schizophrenia candidate genes regulated by retinoic acid and (iii) transcriptional activation of the dopamine receptor and numerous schizophrenia genes is regulated by retinoic acid.
1998 Science.279, 836-867 Chambon et al: Impaired Locomotion and Dopamine Signaling in Retinoid Receptor Mutant Mice. The authors demonstrated that retinoic acid are involved in the regulation of brain functions in adult murine brain. They also suggest that retinoic acid signalling defects may contribute to pathologies such as Parkinsons disease and schizophrenia. It clearly supports the involvement of retinoic acid in dopaminergic signalling.
1995 Am. J Med Gen, 60:335-348. Goodman AB: Chromosomal locations and modes of action of genes of the retinoid (Vitamin A) system support their involvement in the etiology of schizophrenia. This is a very important published study which sets out evidence of an association of retinoids in schizophrenia, comes from the recent discovery that genes of the retinoid system lie in very close proximity to candidate schizophrenia genes and it has been postulated that there is an increase likelihood that these schizophrenia genes are regulated by retinoids, due to this close chromosomal proximity.
1994 Nueroscience, 62, 899-918 Olson et al (Sweden) Localization of Cellular Retinoid-Binding Proteins Suggests Specific Roles for Retinoids in the Adult Central Nervous System. The authors find a widespread presence of two retinoic binding proteins in the brain and spinal cord of the adult rat, which suggest that retinoids have important roles of gene expression in normal brain function. Based on evidence from this study as well as other studies relating to the presence of these CRBP proteins in newborn, the authors suggest that the proteins are involved in processes of nerve growth and development as well as in adult neuronal plasticity.

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