Oral Administration of Synthetic Retinoid Am80 (Tamibarotene) Decreases Brain .BETA.-Amyloid Peptides in APP23 Mice

Kawahara, Kohichi; Nishi, Kentaro; Suenobu, Michita; Ohtsuka, Hideyuki; Maeda, Akira; Nagatomo, Kenichiro; Kuniyasu, Akihiko; Staufenbiel, Matthias; Nakagomi, Madoka; Shudo, Koichi; Nakayama, Hitoshi

doi:10.1248/bpb.32.1307

Cited by 35 publications

(24 citation statements)

References 25 publications

(24 reference statements)

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“…Control animals received the same volume of 0.5% (w/v) carboxymethylcellulose solution orally, without the other compounds. We set the 0.5 mg/kg/d dose for Am80 on the basis that this had been found effective in other in vivo studies, such as those by Kawahara et al [15] and Ishido and Shudo [37]. Higher doses of Am80 (3 mg/kg/d and 6 mg/kg/d) were also orally administered to mice for 17 consecutive days.…”

Section: Drug Administrationmentioning

confidence: 99%

“…The MWM test was performed as described previously [15,38]. For this test, administered during the 12 h dark period, a circular, 150-cm-diameter pool (40 cm high) was filled with water maintained at 23.0 ± 1 • C. A 12-cm-diameter round platform was placed in one quadrant and was kept 1 cm below the water surface.…”

Section: Morris Water Maze (Mwm) Testmentioning

confidence: 99%

“…Clinical evidence has indicated that late-onset AD brains have a defect in retinoid transport function [12]. Therefore, RA or synthetic retinoids may be candidates for treatment of AD [5,[13][14][15][16][17]. We previously demonstrated that oral administration of Am80 (0.5 mg/kg/d, for 14 weeks) reduced levels of Tris-buffered saline (TBS)-insoluble A␤ 42 in brains of 5-month-old A␤PP23 mice, an AD model [15].…”

Section: Introductionmentioning

confidence: 99%

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Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Kawahara

Suenobu

Ohtsuka

et al. 2014

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-␤ (A␤) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)␣,␤ agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-␤ protein precursor 23 (A␤PP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in A␤PP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble A␤ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble A␤ peptide in 8.5-month-old A␤PP23 mice requires co-activation of RAR␣,␤ and RXRs. RAR␣-positive microglia accumulated A␤ plaques in the A␤PP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A␤ 1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to A␤ clearance in Am80/HX630-treated A␤PP23 mice. Am80/HX630 also increased IL-4R␣ expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated A␤PP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric A␤ peptides by restoring impaired IL-4 signaling in A␤PP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

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Section: Drug Administrationmentioning

confidence: 99%

Section: Morris Water Maze (Mwm) Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Kawahara

Suenobu

Ohtsuka

et al. 2014

JAD

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“…Furthermore, Am80-PEG-NLC resulted in a higher drug accumulation in brain compared with Am80-NLC (p50.05), which may be explained by the fact that the RES removal of the nanoparticles can be prevented by surface coating with hydrophilic polymers, such as PEG and F68, to increase their availability at brain (Kaur et al, 2008). Except for the treatment of APL, Am80 has been reported to have potential for the treatment of some neurological disorders as well, such as Alzheimer's disease, age-related dementia, and Parkinson's disease (Shudo et al, 2004;Kawahara et al, 2009). So the higher Am80 concentration in brain may contribute to the treatment of these neurological disorders.…”

Section: Biodistribution Studymentioning

confidence: 99%

Novel PEG-grafted nanostructured lipid carrier for systematic delivery of a poorly soluble anti-leukemia agent Tamibarotene: characterization and evaluation

et al. 2014

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The School of Pharmaceutical Science, Shandong University, Ji'nan, Shandong Province, PR China Abstract Tamibarotene (Am80), a poorly water-soluble drug for the treatment of acute promyelocytic leukemia (APL), loaded nanostructured lipid carrier (Am80-NLC) was developed and characterized previously. The purpose of the present work was to develop PEGylated nanostructured lipid carrier (PEG-NLC) for intravenous delivery of Am80, with the aim to further extend the circulation in blood and decrease the adverse events. Am80-loaded PEG-NLC (Am80-PEG-NLC) modified with PEG-40 stearate (PEG40-SA, molecular weight 2000 Da) was formulated by the method of melt-emulsification and low temperature-solidification technique. Am80-NLC was developed as well as control. Based on the optimized results of single-factor screening experiment, the average drug entrapment efficiency, the mean particle size, and zeta potential of Am80-NLC and Am80-PEG-NLC were found to be 89.8-94.3%, 178.9-201.6 nm, and À37.74 to À20.1 mV, respectively. In vitro drug release of Am80-NLC and Am80-PEG-NLC possessed a sustained release characteristic and their release behavior was in accordance with the Ritger-Peppas equation. In vivo, after intravenous (i.v.) injection to rats, the mean residence time (MRT) of Am80-PEG-NLC group was significantly prolonged and the AUC value was improved as well compared with the Am80-NLC group. Furthermore, the biodistribution in mice showed that Am80-PEG-NLC preferentially decreased the accumulation of Am80 in kidney and increased the drug concentration in brain after i.v. injection. In conclusion, Am80-PEG-NLC may be a potential delivery system for Am80 in the treatment of APL.

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“…32) This decrease of insoluble Aβ(42) may be an outcome of retinoid-induced potentiation of either α-secretase transcription or phagocytosis by alternatively activated (= phagocytic) microglia (vide infra). 33,34) Although Am80 had no significant effect on the learning deficit of APP23 mice in the Morris water maze (MWM) test, coadministration of Am80 with a specific RXR agonist HX630, which strongly enhances the biological effects of RARs in the presence of RAR agonist, resulted in a highly significant improvement in the MWM test concomitantly with a decrease of Aβ production (Kawahara, unpublished).…”

Section: Amyloid β Etchamendy Et Almentioning

confidence: 99%

Tamibarotene: A Candidate Retinoid Drug for Alzheimer’s Disease

Fukasawa

Nakagomi

Yamagata

et al. 2012

Biological & Pharmaceutical Bulletin

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Oral Administration of Synthetic Retinoid Am80 (Tamibarotene) Decreases Brain .BETA.-Amyloid Peptides in APP23 Mice

Abstract: The purpose of this study is to investigate whether a synthetic retinoid Am80 (tamibarotene) exhibits any improving effects on amyloid precursor protein (

Cited by 35 publications

References 25 publications

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Novel PEG-grafted nanostructured lipid carrier for systematic delivery of a poorly soluble anti-leukemia agent Tamibarotene: characterization and evaluation

Tamibarotene: A Candidate Retinoid Drug for Alzheimer’s Disease

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