The Effect of Am-80, a Synthetic Retinoid, on Spinal Cord Injury-Induced Motor Dysfunction in Rats

Takenaga, Mitsuko; Ohta, Yuki; Tokura, Yukie; Hamaguchi, Akemi; Shudo, Koichi; Igarashi, Rie

doi:10.1248/bpb.32.225

Cited by 17 publications

(9 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results suggest that Am80 may be a useful candidate for applying to novel therapeutic strategies for neurodegenerative diseases such as Parkinson's disease. Very recently, Takenaga et al has reported that Am80 induces TrkB expression and increased BDNF sensitivity in SH-SY5Y human neuroblastoma cells (25). Our findings agree with their data.…”

Section: Discussionsupporting

confidence: 93%

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Shiohira

Kitaoka²,

Shirasawa³

et al. 2010

Int J Mol Med

View full text Add to dashboard Cite

Abstract. Retinoids including natural vitamin A, its derivatives and synthetic compounds work as transcription factors through the retinoic acid receptors (RAR, RXR). All-trans retinoic acid (ATRA), a family of retinoids, is an internal ligand of RAR and well known as a useful differentiation inducer to treat acute promyelocytic leukemia (APL). ATRA therapy is now established as an initial treatment for APL. Recently, to improve therapeutic potency and reduce adverse effects of ATRA, a novel synthetic selective agonist for RAR· and ß, Am80, was developed and applied to APL treatment.In this study, we tested whether Am80 was capable of inducing neuronal differentiation in a human neuroblastoma cell line, NH-12 and compared the differentiation effects between Am80 and ATRA. Morphological studies demonstrated that Am80 induced more potent neurite outgrowth and also proved lesser cell toxicity than ATRA. Am80 upregulated the expression of tropomyosin-related kinase B as well as ATRA. Moreover, Am80 increased the expression of the neuronal marker, growth-associated protein 43. These findings suggest that Am80 induces neuronal differentiation to a greater extent than ATRA and thus may help establishing therapeutic strategies against neuronal degenerative disorders such as Parkinson's disease. IntroductionAll-trans retinoic acid (ATRA), a natural derivative of vitamin A, is known as a differentiation inducer and has been utilized for the initial therapy to successfully treat acute promyelocytic leukemia (APL) by itself or in combination with other chemotherapies (1-3). A number of synthetic retinoids have been developed to improve its therapeutic potency. Among them, Am80 (Tamibarotene), which is a retinoic acid receptor · (RAR·)-and RARß-specific synthetic agonist, exhibits greater potency than ATRA in differentiation assays of tumor cells in vitro (4,5) and a clinical trial (6).ATRA-induced cell differentiation effect is dependent on the RARs and retinoid X receptor (RXR) pathways (7). RARs and RXRs are members of the nuclear hormone receptor superfamily acting as transcription factors and can regulate gene transcription associated with neuronal differentiation (8-10). Therefore, ATRA is commonly used to induce neuronal differentiation (11)(12)(13)(14). RARß pathway has been shown to be involved in neuronal differentiation (15,16). More specifically, ATRA has been shown to induce the expression of tropomyosin-related kinase B (TrkB) and to increase sensitivity against brain-derived neurotrophic factor (BDNF) as well as neuronal markers such as growth-associated protein-43 (GAP43) (17)(18)(19). In this study, we investigated whether Am80 could induce neuronal differentiation in NH-12 human neuroblastoma cells. We also compared the effect of Am80 with that of ATRA in morphological and biochemical cell differentiation analyses. Materials and methodsCell lines and cell culture. Human neuroblastoma cell line, NH-12, was kindly provided by the Cell Resource Center for Biomedical Research Institute of Development Aging and ...

show abstract

Section: Discussionsupporting

confidence: 93%

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Shiohira

Kitaoka²,

Shirasawa³

et al. 2010

Int J Mol Med

View full text Add to dashboard Cite

show abstract

“…9cis retinoic acid is an RXR ligand, while all trans retinoic acid activates RARs. 9-cis retinoic acid and all trans retinoic acid both reduce infarct size in ischemia models (Choi et al, 2009; Shen et al, 2009), and oral and subcutaneous administration of Am-80, a synthetic retinoid, increased expression of TrkB, the neurotrophin receptor and MBP, while reducing lesion cavity in a model of spinal cord injury (Takenaga et al, 2009). Retinoic acid receptor B activation inhibited Nogo receptor signaling and repression of LINGO resulting in increased neurite outgrowth in cerebellar cultures and in a model of axon regeneration (Puttagunta et al, 2011).…”

Section: Strategies For Improving Protection and Repairmentioning

confidence: 99%

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

Chew

DeBoy

2016

Neuropharmacology

View full text Add to dashboard Cite

White matter disease afflicts both developing and mature central nervous systems. Both cell intrinsic and extrinsic dysregulation result in profound changes in cell survival, axonal metabolism and functional performance. Experimental models of developmental white matter (WM) injury and demyelination have not only delineated mechanisms of signaling and inflammation, but have also paved the way for the discovery of pharmacological approaches to intervention. These reagents have been shown to enhance protection of the mature oligodendrocyte cell, accelerate progenitor cell recruitment and/or differentiation, or attenuate pathological stimuli arising from the inflammatory response to injury. Here we highlight reports of studies in the CNS in which compounds, namely peptides, hormones, and small molecule agonists/antagonists, have been used in experimental animal models of demyelination and neonatal brain injury that affect aspects of excitotoxicity, oligodendrocyte development and survival, and progenitor cell function, and which have been demonstrated to attenuate damage and improve WM protection in experimental models of injury. The molecular targets of these agents include growth factor and neurotransmitter receptors, morphogens and their signaling components, nuclear receptors, as well as the processes of iron transport and actin binding. By surveying the current evidence in non-immune targets of both the immature and mature WM, we aim to better understand pharmacological approaches modulating endogenous oligodendroglia that show potential for success in the contexts of developmental and adult WM pathology.

show abstract

“…Inflammatory cytokine release from astrocytes was reduced by RA [61]. In a model of spinal cord injury, treatment of rats with the synthetic retinoid AM80 resulted in greater recovery of spinal cord injury related motor function, and the authors demonstrated that the ability of AM80 to promote regeneration/repair was via promotion of differentiation of neural stem cells by increasing TrkB expression [62]. Stable RARβ 2 expression in dorsal root ganglia neurons in vitro enabled their axons to regenerate across the inhibitory dorsal root entry zone and project into the gray matter of the spinal cord in an in vivo model.…”

Section: Retinoids Are Stored In Cells and Active Retinoids Are Genermentioning

confidence: 99%

Emerging roles for retinoids in regeneration and differentiation in normal and disease states

Gudas¹

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

139

159

View full text Add to dashboard Cite

The vitamin A (retinol) metabolite, all-trans retinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells. In this review the physiological and pathophysiological roles of retinoids (retinol and related metabolites) in mature animals are discussed. Both in the developing embryo and in the adult, RA signaling via combinatorial Hox gene expression is important for cell positional memory. The genes that require RA for the maturation/differentiation of T cells are only beginning to be catalogued, but it is clear that retinoids play a major role in expression of key genes in the immune system. An exciting, recent publication in regeneration research shows that ALDH1a2 (RALDH2), which is the rate-limiting enzyme in the production of RA from retinaldehyde, is highly induced shortly after amputation in the regenerating heart, adult fin, and larval fin in zebrafish. Thus, local generation of RA presumably plays a key role in fin formation during both embryogenesis and in fin regeneration. HIV transgenic mice and human patients with HIV-associated kidney disease exhibit a profound reduction in the level of RARβ protein in the glomeruli, and HIV transgenic mice show reduced retinol dehydrogenase levels, concomitant with a greater than 3-fold reduction in endogenous RA levels in the glomeruli. Levels of endogenous retinoids (those synthesized from retinol within cells) are altered in many different diseases in the lung, kidney, and central nervous system, contributing to pathophysiology.

show abstract

The Effect of Am-80, a Synthetic Retinoid, on Spinal Cord Injury-Induced Motor Dysfunction in Rats

Cited by 17 publications

References 41 publications

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Am80 induces neuronal differentiation in a human neuroblastoma NH-12 cell line

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

Emerging roles for retinoids in regeneration and differentiation in normal and disease states

Contact Info

Product

Resources

About