hx-630 and tamibarotene

Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)α,β 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-β protein precursor 23 (AβPP23) 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 AβPP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble Aβ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble Aβ peptide in 8.5-month-old AβPP23 mice requires co-activation of RARα,β and RXRs. RARα-positive microglia accumulated Aβ plaques in the AβPP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125I-labeled oligomeric Aβ1-42 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 Aβ clearance in Am80/HX630-treated AβPP23 mice. Am80/HX630 also increased IL-4Rα expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated AβPP23 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 Aβ peptides by restoring impaired IL-4 signaling in AβPP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Antipsychotic Agents; Benzazepines; Benzoates; Brain; Cells, Cultured; Disease Models, Animal; Drug Therapy, Combination; Gene Expression Regulation; Humans; Insulysin; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Mutation; Rats; Rats, Wistar; Receptors, Retinoic Acid; Retinoid X Receptors; Tetrahydronaphthalenes; Time Factors

Memory deficit in rats treated with scopolamine was rescued by several synthetic retinoids, RAR-ligands (Am80, Am555S, Tp80) and an RXR-ligand (HX630). These results may have implications for the treatment of Alzheimer's disease, age-related dementia, Parkinson's disease, and other neurological disorders.

Topics: Animals; Antibodies, Monoclonal; Avoidance Learning; Benzazepines; Benzoates; Dose-Response Relationship, Drug; Male; Memory Disorders; Nootropic Agents; Platelet Glycoprotein GPIIb-IIIa Complex; Rats; Rats, Wistar; Retinoids; Scopolamine; Tetrahydronaphthalenes; Time Factors; Trimethylsilyl Compounds

In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.

Topics: Azepines; Benzoates; Binding, Competitive; Cell Differentiation; Dibenzazepines; Dimerization; Drug Synergism; HL-60 Cells; Humans; Molecular Structure; Protein Binding; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Tetrahydronaphthalenes; Transcription Factors