tretinoin and Multiple-Sclerosis

Vitamin A is an essential nutrient with important roles in immunological responses and in brain development. Its main metabolite is retinoic acid (RA), which is responsible for the neuroimmunological functions related to vitamin A. In the brain, RA is known to have interactions with other nuclear receptor-mediated signalling pathways. RA is involved in plasticity, regeneration, cognition and behaviour. In the peripheral blood, RA plays a major role both in increasing tolerance and in decreasing inflammation, through balancing T-lymphocyte populations. It is likely that RA synthesis may be manipulated by complex cross-talk among cells during infection and inflammation. The role of vitamin A in multiple sclerosis (MS) could be dual: at the same time as it decreases inflammation and increases tolerance of autoimmunity, it may also help in brain protection. The present review discusses the beneficial effects that vitamin A might have for controlling MS, although it must be clearly stated that, at the present time, there is no clear indication for using vitamin A as a treatment for MS. However, the results from the present review should encourage clinical trials with vitamin supplementation as a potential treatment or as an add-on option. Vitamin A acts in synergy with vitamin D, and the immunological homeostasis ensured by these vitamins should not be unbalanced in favour of only one of them.

Topics: Animals; Dietary Supplements; Humans; Multiple Sclerosis; Tretinoin; Vitamin A

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS.

Topics: Animals; Disease Models, Animal; Humans; Microglia; Models, Biological; Multiple Sclerosis; Neurons; PPAR gamma; Prostaglandin D2; Tretinoin

To determine the effects of combination all-trans retinoic acid (RA) and interferon beta-1b therapy on immune system functions potentially relevant to multiple sclerosis (MS).. Interferon gamma-secreting cells, T suppressor cell function, and lymphocyte proliferative responses were assayed using peripheral blood mononuclear cells from patients with MS and control subjects under control conditions and in the presence of interferon beta-1b, RA, and the 2 combined.. A university hospital MS clinic.. Seventeen patients with secondarily progressive MS and 25 control subjects.. Interferon beta-1b use increased interferon gamma-secreting cell counts, augmented T suppressor cell function, and inhibited T-cell proliferation. Therapy with RA decreased interferon gamma-secreting cell counts, had a minimal positive effect on T suppressor cell function, and had no effect on T-cell proliferation. When RA and interferon beta-1b were combined, the inhibitory effect of RA on interferon gamma-secreting cells predominated, T suppressor cell function increased synergistically over the increment observed with interferon beta-1b use alone, and the inhibitory effect of interferon beta-1b alone on T-cell proliferation remained unchanged.. Treatment with interferon beta-1b partially restores defective T suppressor cell function in patients with MS. This potentially beneficial action is synergistically potentiated by RA. Interferon beta-1b increases the number of interferon gamma-secreting cells in the circulation when treatment is initiated. A similar increment in interferon gamma-secreting cells is observed when interferon beta-1b is added to cultural peripheral blood mononuclear cells in vitro. This potentially deleterious action of interferon beta-1b is reversed by RA. Interferon beta-1b inhibits lymphocyte proliferation modestly but reproducibly. This action of interferon beta-1b is unaltered by RA. These data provide a rationale for a trial of combination treatment with interferon beta-1b and RA in patients with MS.

Topics: Antineoplastic Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Humans; Immunosuppression Therapy; Interferon-beta; Interferon-gamma; Interleukin-10; Killer Cells, Natural; Lymphotoxin-alpha; Multiple Sclerosis; Tretinoin

Multiple sclerosis (MS) is a potentially disabling autoimmune disease of the central nervous system. Neither the pathogenesis nor the effectiveness of treatment of MS has been fully understood. This in vitro trial evaluated the beneficial immunomodulatory effects of single and combined treatments of all-trans retinoic acid (ATRA) and docosahexaenoic acid (DHA) on the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting MS (RRMS) patients who were receiving interferon beta (IFN-β).. The PBMCs of 15 RRMS patients were isolated, cultured, and treated with single and combined treatments of ATRA and DHA. The expressions of IL-2, IL-4, T-bet, and GATA3 genes were evaluated using real-time PCR.. The results showed that a single treatment of ATRA could significantly suppress the gene expression of the pro-inflammatory cytokine, IL-2 (P < 0.05), and related transcription factor, T-bet (P < 0.001). The gene expression level of the anti-inflammatory cytokine, IL-4, and its transcription factor, GATA3, were not significantly changed. The expression of IL-2 and T-bet genes was significantly decreased in combination treatments of ATRA and DHA (P < 0.001). Significant suppression of IL-2 and T-bet (P < 0.001) was observed in ATRA and DHA combination therapy with half doses of their single treatment, which suggested a synergistic effect of these components.. Co-administration of vitamin A and DHA, an omega-3 fatty acid derivative, may exert a synergistic effect in modulating the immune system in MS patients; however, more studies are needed to evaluate the exact effects and mechanism of their actions on the immune cells.

Topics: Cytokines; Docosahexaenoic Acids; GATA3 Transcription Factor; Humans; Interleukin-2; Interleukin-4; Leukocytes, Mononuclear; Multiple Sclerosis; Tretinoin

Demyelinating disorders, with a particular focus on multiple sclerosis (MS), have a multitude of detrimental cognitive and physical effects on the patients. Current treatment options that involve substances promoting remyelination fail in the clinics due to difficulties in reaching the central nervous system (CNS). Here, the dual encapsulation of retinoic acid (RA) into lipid nanocapsules with a nominal size of 70 nm, and a low PdI of 0.1, coupled with super paramagnetic iron oxide nanoparticles (SPIONs) was accomplished, and joined by an external functionalization process with a transferrin-receptor binding peptide. This nanosystem showed a 3-fold improved internalization by endothelial cells compared to the free drug, ability to interact with oligodendrocyte progenitor cells and microglia, and improvements in the permeability through the blood-brain barrier by 5-fold. The lipid nanocapsules also induced the differentiation of oligodendrocyte progenitor cells into more mature, myelin producing oligodendrocytes, as evaluated by high-throughput image screening, by 3-5-fold. Furthermore, the ability to tame the inflammatory response was verified in lipopolysaccharide-stimulated microglia, suppressing the production of pro-inflammatory cytokines by 50-70%. Overall, the results show that this nanosystem can act in both the inflammatory microenvironment present at the CNS of affected patients, but also stimulate the differentiation of new oligodendrocytes, paving the way for a promising platform in the therapy of MS.

Topics: Animals; Cell Differentiation; Demyelinating Diseases; Endothelial Cells; Inflammation; Lipids; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Nanocapsules; Neurodegenerative Diseases; Oligodendroglia; Tretinoin

The balance of effector versus regulatory T cells (Tregs) controls inflammation in numerous settings, including multiple sclerosis (MS). Here we show that memory phenotype CD4

Topics: Animals; Central Nervous System; Diacylglycerol O-Acyltransferase; Encephalomyelitis; Gene Knockout Techniques; Humans; Inflammation; Mice; Multiple Sclerosis; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Tretinoin

Transplantation of bone marrow mesenchymal stem cells (MSCs) promotes functional recovery in multiple sclerosis (MS) patients and in a murine model of MS. However, there is only a modicum of information on differentiation of grafted MSCs into oligodendrocyte-like cells in MS. The purpose of this study was to transplant neurotrophin-3 (NT-3) and retinoic acid (RA) preinduced MSCs (NR-MSCs) into a demyelinated spinal cord induced by ethidium bromide and to investigate whether EA treatment could promote NT-3 secretion in the demyelinated spinal cord. We also sought to determine whether increased NT-3 could further enhance NR-MSCs overexpressing the tyrosine receptor kinase C (TrkC) to differentiate into more oligodendrocyte-like cells, resulting in increased remyelination and nerve conduction in the spinal cord. Our results showed that NT-3 and RA increased transcription of TrkC mRNA in cultured MSCs. EA increased NT-3 levels and promoted differentiation of oligodendrocyte-like cells from grafted NR-MSCs in the demyelinated spinal cord. There was evidence of myelin formation by grafted NR-MSCs. In addition, NR-MSC transplantation combined with EA treatment (the NR-MSCs + EA group) reduced demyelination and promoted remyelination. Furthermore, the conduction of cortical motor-evoked potentials has improved compared to controls. Together, our data suggest that preinduced MSC transplantation combined with EA treatment not only increased MSC differentiation into oligodendrocyte-like cells forming myelin sheaths, but also promoted remyelination and functional improvement of nerve conduction in the demyelinated spinal cord.

Topics: Animals; Cell Differentiation; Electroacupuncture; Male; Mice; Multiple Sclerosis; Neurotrophin 3; Oligodendroglia; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Tretinoin

One suitable approach to enhancing multiple sclerosis (MS) treatment is combination of available medications to provide more desirable outcomes. Immunomodulatory effects of atorvastatin and/or all-trans retinoic acid (ATRA) were determined in previous studies. The present study was set out to investigate the synergistic effects of combination therapy by suboptimal doses of atorvastatin and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE was induced by MOG35-55 in female C57BL/6 mice. Therapies were initiated at day 12 post immunization when the mice developed a disability score and continued throughout the study until the day 33 when animals were sacrificed. Therapeutic treatment with half doses of atorvastatin and ATRA in combination has synergistic benefits causing the regression of clinical and neuropathological features of EAE more favorable than treatment with full doses of either drug alone. Without any advantage in anti-proliferative effect, combination treatment significantly reduced the secretion of pro-inflammatory cytokine interleukin-17 and conversely, increased the production of anti-inflammatory cytokine interleukin-10 more prominent than either drug alone. Furthermore, FoxP3+Treg cells were significantly increased only in combination treatment. In conclusion, combined atorvastatin and ATRA have immunomodulatory synergistic benefits and this pharmacological approach may be as a useful strategy to control MS.

Topics: Animals; Atorvastatin; Brain; Cytokines; Disease Models, Animal; Drug Synergism; Encephalomyelitis, Autoimmune, Experimental; Female; Forkhead Transcription Factors; Heptanoic Acids; Mice; Multiple Sclerosis; Pyrroles; T-Lymphocytes, Regulatory; Tretinoin; Weight Loss

Multiple sclerosis (MS) lesions are characterized by the presence of activated astrocytes, which are thought to actively take part in propagating lesion progression by secreting pro-inflammatory mediators. Conversely, reactive astrocytes may exert disease-dampening effects through the production of trophic factors and anti-inflammatory mediators. Astrocytic control of the blood-brain barrier (BBB) is crucial for normal brain homeostasis and BBB disruption is a well-established early event in MS lesion development. Here, we set out to unravel potential protective effects of reactive astrocytes on BBB function under neuroinflammatory conditions as seen in MS, where we focus on the role of the brain morphogen retinoic acid (RA). Immunohistochemical analysis revealed that retinaldehyde dehydrogenase 2 (RALDH2), a key enzyme for RA synthesis, is highly expressed by reactive astrocytes throughout white matter lesions compared to control and normal appearing white matter. In vitro modeling of reactive astrocytes resulted in increased expression of RALDH2, enhanced RA synthesis, and a protective role for astrocyte-derived RA on BBB function during inflammation-induced barrier loss. Furthermore, RA induces endothelial immune quiescence and decreases monocyte adhesion under inflammatory conditions. Finally, we demonstrated that RA attenuated oxidative stress in inflamed endothelial cells, through activation of the antioxidant transcription factor nuclear factor E2 related factor 2. In summary, RA synthesis by reactive astrocytes represents an endogenous protective response to neuroinflammation, possibly aimed at protecting the BBB against inflammatory insult. A better understanding of RA signaling in MS pathophysiology may lead to the discovery of novel targets to halt disease progression.

Topics: Adult; Aged; Aged, 80 and over; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Astrocytes; Autopsy; Blood-Brain Barrier; Brain; Cells, Cultured; Cytokines; Endothelial Cells; Female; Glial Fibrillary Acidic Protein; HEK293 Cells; Humans; Male; Middle Aged; Multiple Sclerosis; NF-E2-Related Factor 2; Reactive Oxygen Species; Retinal Dehydrogenase; Time Factors; Tretinoin

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology that affects the CNS. While current therapies are primarily directed against the immune system, the new challenge is to address progressive MS with remyelinating and neuroprotective strategies. Here, we develop a highly reproducible protocol to efficiently derive oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes from induced pluripotent stem cells (iPSCs). Key elements of our protocol include adherent cultures, dual SMAD inhibition, and addition of retinoids from the beginning of differentiation, which lead to increased yields of OLIG2 progenitors and high numbers of OPCs within 75 days. Furthermore, we show the generation of viral and integration-free iPSCs from primary progressive MS (PPMS) patients and their efficient differentiation to oligodendrocytes. PPMS OPCs are functional, as demonstrated by in vivo myelination in the shiverer mouse. These results provide encouraging advances toward the development of autologous cell therapies using iPSCs.

Topics: Animals; Axons; Basic Helix-Loop-Helix Transcription Factors; Brain; Cell Differentiation; Cells, Cultured; DNA-Binding Proteins; Female; Hedgehog Proteins; Humans; Induced Pluripotent Stem Cells; Male; Mice; Mice, Knockout; Middle Aged; Multiple Sclerosis; Myelin Sheath; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Smad Proteins; Transplantation, Heterologous; Tretinoin

We recently demonstrated better outcomes in helminth-infected multiple sclerosis (MS) patients, compared with uninfected ones. The present study evaluates the role of TLR2 and retinoic acid (RA) in parasite-driven protection in MS patients. RA serum levels were significantly higher in helminth-infected MS patients than in uninfected MS subjects or healthy controls. Genes involved in RA biosynthesis and metabolism, such as Adh1 and Raldh2, as well as RA receptors and IL-10, were induced in dendritic cells (DCs) via TLR2-dependent ERK signaling. This programmed DCs to induce FOXP3(+) T regulatory cells and suppressed production of proinflammatory cytokines (IL-6, IL-12, IL-23, and TNF-α) via induction of suppressor of cytokine signaling 3 (SOCS3), an effect mediated by soluble egg Ag (SEA) obtained from Schistosoma mansoni, and by RA. SEA-activated DCs also inhibited IL-17 and IFN-γ production through autoreactive T cells. These inhibitory effects were abrogated when SOCS3 gene expression was silenced, indicating that SEA-mediated signaling inhibited production of these cytokines by T cells, through a SOCS3-dependent pathway. Overall, helminth-related immunomodulation observed in MS patients was mediated by TLR2- and RA-dependent pathways, through two different mechanisms, as follows: 1) induction of IL-10 and FOXP3(+) T regulatory cells, and 2) suppression of proinflammatory cytokine production mediated by SOCS3.

Topics: Alcohol Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Antigens, Helminth; Cytokines; Dendritic Cells; Female; Forkhead Transcription Factors; Humans; Inflammation Mediators; Male; Models, Biological; Multiple Sclerosis; Parasitic Diseases; Receptors, Retinoic Acid; Retinal Dehydrogenase; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes, Regulatory; Tretinoin

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.

Topics: Aged; Alitretinoin; Animals; Benzoates; Biphenyl Compounds; Cell Differentiation; Cell Lineage; Cells, Cultured; Central Nervous System; Cerebellum; Demyelinating Diseases; Female; Gene Expression Profiling; Humans; Male; Mice; Mice, Knockout; Middle Aged; Multiple Sclerosis; Myelin Sheath; Nerve Regeneration; Neurotoxins; Oligodendroglia; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; RNA Interference; Stem Cells; Tretinoin

In addressing the question of what seems to prevent multiple sclerosis (MS) in the tropics this paper reviews work done by various researchers and suggests that MS incidence may be affected in the ensemble by the endocrine system's response to environment temperature, the skin's response to sunlight, and by the retina's response to brightness. It shows how the hypouricemia which is a reliable indicator in MS patients can leave the blood-brain barrier unsealed in general but allow retinoids to block their access to the central nervous system. It presents published studies as evidence and suggests a number of straightforward tests of these theories which could allow clinicians to advise their MS patients to take appropriate actions to help slow down or prevent disease progression.

Topics: Age Factors; Blood-Brain Barrier; Demography; Endocrine System; Humans; Incidence; Multiple Sclerosis; Retina; Skin; Sunlight; Temperature; Tretinoin; Tropical Climate; Uric Acid; Vision, Ocular

To determine if retinoids might be beneficial in the treatment of multiple sclerosis (MS), all-trans-retinoic acid (tRA) was tested for its effects on proliferation and cytokine expression in human autoreactive T cells. tRA decreased human lymphocyte proliferation in vitro in a dose-dependent manner. In addition, tRA induced IL-4 gene expression in myelin basic protein (MBP)-specific T cell lines which had previously expressed a Th1-like phenotype. MBP-specific T cell lines generated in the presence of tRA had a Th2-like phenotype. Retinoids have previously been shown to have a similar effect on encephalitogenic T cells in experimental allergic encephalomyelitis (EAE; an animal model for MS) and treatment of EAE with retinoids stabilizes the disease. Since several oral retinoids have been shown to be safe in humans, retinoids may be beneficial in the treatment of MS.

Topics: Autoantigens; Cell Differentiation; Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Interferon-gamma; Interleukin-4; Lymphocyte Activation; Multiple Sclerosis; Myelin Basic Protein; RNA, Messenger; Th1 Cells; Th2 Cells; Tretinoin