Tamibarotene: A Candidate Retinoid Drug for Alzheimer’s Disease

Abstract

Tamibarotene (Am80), a synthetic retinoid approved in Japan for treatment of acute promyelocytic leukemia (APL), is a retinoic acid receptor (RAR) agonist with high specificity for RARα and RARβ over RARγ. Temporarily and spatially specific expression of RARs suggests their pivotal roles in the adult brain. Am80 is considered to be a promising candidate drug for treatment of Alzheimer's disease (AD) because of its transcriptional controls of multiple target genes involved in etiology and pathology of AD. In APP23 AD model mice, administration of Am80 decreased the deposition of insoluble amyloid-β(42). In senescence-accelerated mice (SAMP8), Am80 ameliorated the decrease of cortical acetylcholine, as well as reducing anxiety in behavioral tests and improving the sleep deficit. Am80 also effected a significant improvement of memory in the rat scopolamine-induced memory deficit model. Like other retinoids, Am80 also has an immunomodulatory effect and reduces secretion of proinflammatory cytokines and chemokines by astrocytes and microglia surrounding amyloid-β plaques. In a rat experimental autoimmune encephalomyelitis model, Am80 reduced inflammatory cytokines and showed significant efficacy. Retinoids also promote differentiation of neural stem cells, and Am80 improved the recovery of spinal cord-injured rats. Am80 may also improve vascular factors involved in onset and/or progression of AD. Am80 has been in clinical use for treatment of APL in Japan since 2005, and has been reported to have fewer side effects than other retinoids. We have recently started a clinical study to evaluate the efficacy and safety of Am80 for the treatment of Alzheimer's disease.