Vitamin X About To Crack Rar 12

Chemical structures of the main retinoids metabolized in the body. Retinol (vitamin A) is directly provided by animal sources. Carotenoids, such as β-carotene, are precursors of retinol from vegetable sources that can be converted into retinol by the organism. Retinol is metabolized into retinal by enzymes of the RDHs family, which can also be converted back to retinol. Retinal can be metabolized into 11 cis retinal. A key bioactive metabolite produced from retinal is RA (all trans retinoic acid), which is irreversibly metabolized by a RALDH protein (ALDH1A1 belongs to RALDHs). RA can be metabolized in 11-Cis Retinal, which is an active metabolite in the retina, and in 9-cis RA, another key active metabolite for the brain. Alternatively, retinol can be transformed in 9CDHRA, an endogenous RXR ligand. RDHs, retinol dehydrogenases; RALDHs, retinaldehydes dehydrogenases.

Through its nuclear receptors (more often RAR-RXR heterodimers), RA controls the transcription of hundreds of genes, belonging to various gene pathways, including dopamine signaling and plasticity [3, 15]. Throughout life, RA is involved in cell growth, differentiation and cell death: during development, the action of RA is crucial since it is involved in the patterning of tissues, especially in the central nervous system [1, 5]; at adult age, RA continues to be involved in the maintenance and homeostasis of cells [16], and controls inflammatory responses, hormone actions, reproduction and vision [16]. The endocrine system is also tightly related to the retinoid system because RXR forms heterodimers (sometimes in an obligatory role) for some hormone nuclear receptors, such as thyroid or vitamin D receptors [17].

Model of RA metabolism and signaling in the nigro-striatal pathway. Retinol (vitamin A) is transported in the extracellular fluids by RBP, and internalized into the cells by STRA6. Retinol can also diffuse across the plasma membrane or through other transporters, not yet identified. Retinol is then bound to CRBP and metabolized into retinal by enzymes of the RDHs family. Retinal is further metabolized into RA by a RALDH protein (notably ALDH1A1 in a sub-population of SNc neurons). RA is then transported to the nucleus bound to CRABP protein. In the nucleus, RA binds to RA receptors (RARs), which activate the control of gene expression by RAR/RXR dimers on genes with a RARE sequence in their promoter. Furthermore, as a trans-synaptic factor, RA can travel trans-synaptically from SNc neurons to striatum neurons [24]. From the literature, it is possible that alpha-synuclein may serve as a cargo protein for the trans-synaptic transport of RA [26]. Finally, RA can be degraded by the Cyp26B1 enzyme. RBP, retinol binding proteins; STRA6, transporter stimulated by retinoic acid 6; CRBP, cellular retinol binding protein; CRABP, cellular retinoic acid binding protein; RDHs, retinol dehydrogenases; RALDHs, retinaldehyde dehydrogenases family (including ALDH1A1); RARE, retinoic acid receptor response element.

Beyond the use of retinoid derivatives, some studies have directly investigated the role of dietary vitamin A in the pathogenesis and pathophysiology of PD (Tables 2 and 3). Vitamin A deficient rats have motor impairments similar to those observed in rat models of PD or in mice lacking retinoid receptors [84]. Another study reported that vitamin A deficiency impaired dopaminergic transmission [85]. Furthermore, the only study that has investigated the impact of dietary vitamin A supplementation showed that vitamin A administration for 4 weeks before the 6-OHDA lesion in the SNc improved movement deficits in 6-OHDA rats [86]. While the behavioural improvement was small, the effect on neuronal survival was not clear. Therefore, more studies are needed with vitamin A supplementation in animal models.

In this context, it is logical to investigate the potential anti-inflammatory role of vitamin A in PD. Indeed, vitamin A is involved in the development, maturation and differentiation of immune organs and cells [103]. Moreover, vitamin A has the propensity to reduce pro-inflammatory factors and enhance anti-inflammatory factors, in the periphery as well as in the brain [104, 105]. Specific to neuroinflammation, in vitro studies demonstrate that application of RA to astrocytes or microglial cells reduces inflammatory responses induced by lipopolysaccharide (LPS), a bacterial endotoxin [106, 107]. Related to PD, a study clearly demonstrated that pharmacological stimulation of RAR in vitro and in vivo reduces neurodegeneration of midbrain dopaminergic neurons induced by an immune challenge. A more recent study observed a protective effect of dietary vitamin A in a rat model of PD by reducing pro-inflammatory factors (TNF-α, IL-1β, Iba-1), which was accompanied with an increase in GFAP staining, suggesting increased astrocytic reactivity [86].

Related to neuroinflammation and oxidative stress, studies exploring the role of vitamin A metabolism in the control of circadian rhythms and sleep deserve attention. A main prodromal symptom observed in PD is sleep disorder [110] and it is also observed in rat models of PD [111]. These sleep disorders are mainly a lack of REM sleep, but can also exhibit other forms of sleep deficits. Retinoid signaling is involved in sleep wave rhythms, as demonstrated in mice with RAR KO mice [112], vitamin A deficiency [85] or pharmacological inhibitors [113]. Importantly, these studies also highlight that reduced vitamin A function induced changes in sleep wave rhythms that were associated with alterations in striato-nigral dopaminergic transmission [85, 113].

In this context, vitamin A and RA are also promising molecules to enhance the generation and long-term survival of SVZ-derived neurons after PD lesions. Indeed, RA is a potent mitogen for SVZ neuroblasts, and is required for their migration to the olfactory bulb [123]. More recently, the manipulation of endogenous stem cell populations from the SVZ created an opportunity to induce neurogenesis and influence brain regenerative capacities in the adult brain. Herein, new approaches demonstrated the ability of RA loaded-nanoparticles to induce neurogenesis exclusively after being internalized by SVZ stem cells both in vivo and in vitro. Similarly, combined RA treatment with environmental enrichment enhanced the generation and long-term survival of SVZ-derived striatal neurons after stroke [127].

Model of the dual role played by ALDH1A1 in the nigro-striatal pathway. ALDH1A1 is involved in the metabolic pathway of RA because it synthesizes RA from retinal. In parallel, ALDH1A1 is involved in catabolic pathway of dopamine because it degrades DOPAL to DOPAC. Considering that RA controls the expression of ALDH1A1 through PITX3, the model proposes that ALDH1A1 expression is controlled by vitamin A bioavailability. SNc, substantia nigra pars compacta; SNR, substantia nigra pars reticulata.

Vitamin A deficiency may alter gut microbiota. In mice, vitamin A deficiency reduces bacteria from the Bacteroidetes phylum (to whom B. fragilis belongs to), which altered energy homeostasis of the animal overall, and resulted in glucose and insulin intolerance [181, 182]. Young rats from vitamin A deficient mothers also displayed a dysbiosis of colonic mucosal microbiota, in particular with reduced members of the Bacteriodetes phylum [183]. Another study revealed that retinol, but not other retinoids such as RA or beta-carotene, inhibits growth of B. vulgatus [184]. As a consequence, vitamin A deficiency in mice increases the growth of B. vulgatus, but the consequence of this imbalance was not evaluated. Conversely, RA is needed for Bifidobacterium growth [185].

From our overview, we propose that vitamin A metabolism may be involved in the pathogenesis and pathophysiology of PD in multiple ways (Fig. 4). Of note, other possible ways have not been discussed here, such as the potential role of retinoids in autophagy. At this stage, the most promising way by which vitamin A metabolism may influence PD pathogenesis and treatment is through the impact of vitamin A on ALDH1A1 expression and neuroinflammation. A first step is to understand the role of ALDH1A1 in controlling dopaminergic cell survival, within the schema of the catecholaldehyde hypothesis. However, other mechanisms of vitamin A metabolism are likely relevant including oxidative stress, neurogenesis in the SVZ, ENS function and microbiota, thyroid hormone and vitamin D function, but more data are needed to fully understand the role of individual or combined mechanisms.

Retinoids, compounds structurally related to vitamin A, are considered vitamin A derivatives that contribute to regular cellular morphogenesis, proliferation, and differentiation. Retinoids are involved in normal signaling cascades in modulating brain functions [180]. Retinoids modulate the availability of glucocorticosteroids in the brain, an important biological mechanism that can be explored in many stress-related pathologies to prevent alterations in the plasticity of the hippocampus [181]. Retinol metabolic pathways have shown that retinol can be stored intracellularly as retinyl esters and metabolized into all-trans-retinoic acid (ATRA) as a bioactive derivative. ATRA induces cellular differentiation and growth by reacting to retinoic acid receptors (RARs). Cellular retinol-binding proteins (CRBP-I and II) and cellular retinoic acid-binding proteins (CRABP-I, II) are distributed in the adult CNS. Furthermore, CRBP-I distribution parallels that of ATRA with expression in the meninges, hippocampus, amygdala, and olfactory bulb [182] (Figure 3). Under oxidative stress conditions such as metal exposure and production and accumulation of ROS, retinoids protect the cells against this imbalance through multiple mechanisms, including interference with ROS production, scavenging free radicals directly, upregulation of antioxidant enzymes, and signaling pathways involved in defense system such as Nrf2 signaling [183]. It has also been observed that retinoic acid has a protective effect on neuronal apoptosis and oxidative damage by reducing glutathione [184] and restoring SOD-1 and SOD-2 in the hippocampal cells [185]. The role of retinoid signal transduction in the control of dopaminergic neurotransmission was observed in the presence of high levels of retinoic acid-synthesizing enzymes [186] and RAR, which may play a critical role in controlling the survival, adaptation, and homeostatic regulation of the dopaminergic system [187]. Retinoid signaling play a physiological role in synaptic plasticity and learning and memory behaviors [188]. 2b1af7f3a8