Towards retinoid therapy for Alzheimer's disease.

K Shudo,M Nakagomi,H Fukasawa,N Yamagata

doi:10.2174/156720509788486581

K Shudo, M Nakagomi + Show 2 more

Open Access

https://doi.org/10.2174/156720509788486581

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Abstract

Alzheimer’s disease(AD) is associated with a variety of pathophysiological features, including amyloid plaques, inflammation, immunological changes, cell death and regeneration processes, altered neurotransmission, and age-related changes. Retinoic acid receptors (RARs) and retinoids are relevant to all of these. Here we review the pathology, pharmacology, and biochemistry of AD in relation to RARs and retinoids, and we suggest that retinoids are candidate drugs for treatment of AD.

Highlights

The management of Alzheimer’s disease (AD) remains a challenge, even as our knowledge and understanding of AD continue to grow at an unprecedented rate [1,2,3]
The term retinoid is used for substances which may be defined as (1) vitamin A related compounds (including vitamin A and its biological precursor carotenoids, (2) retinoic acid (RA), which activates retinoic acid receptors (RARs), and, and synthetic analogs which bind with RARs with high affinity in an agonistic or antagonistic manner, (3) compounds which activate retinoid X receptors (RXRs), and, which are nuclear receptors different from RARs, (4) compounds which modify the activities of RA by influencing metabolism, biosynthesis or other pathways acting on co-factors, without binding to RARs or RXRs
Much research in AD is still aimed at elucidating basic pathomechanisms, over seventy-five compounds are in clinical development for treatment of AD [39]

Summary

MEDICINAL CHEMISTRY OF RETINOIDS

Retinoids are analogues of retinoic acid, an active metabolite of vitamin A, and are specific modulators of cell. The term retinoid is used for substances which may be defined as (1) vitamin A related compounds (including vitamin A (retinol) and its biological precursor carotenoids, (2) RA (vitamin A metabolite), which activates RAR, , and , and synthetic analogs which bind with RARs with high affinity in an agonistic (similar biological activities to RA) or antagonistic manner, (3) compounds which activate RXR, and , which are nuclear receptors different from RARs, (4) compounds which modify the activities of RA by influencing metabolism, biosynthesis or other pathways acting on co-factors, without binding to RARs or RXRs. We prefer to use the term retinoid in a strict sense, that is, compounds in category (2). Isomeric 13-cis-retinoic acid may be an endogenous retinoid, but is less abundant than RA. 9-cis-Retinoic acid is synthesized from, or in equilibrium with, RA, and it binds to and activates RAR, , and , and in addition RXR , , and. Some act as antagonists which inhibit the activity of RA

BIOLOGICAL AND PHARMACOLOGICAL ACTIVITIES OF RETINOIDS

AUTOIMMUNE FEATURES

REGENERATION OF NEURAL CELLS

LEARNING AND MEMORY

CONCLUSION