Is the modulation of retinoid and retinoid‐associated signaling a future therapeutic strategy in neurological trauma and neurodegeneration?

Abstract

The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels. Finally, we summarize the potential therapeutic avenues based on the modulation of retinoid targets undergoing reactivation under conditions of acute injury and chronic degeneration in the central nervous system, and discuss some of the unresolved issues linked to this treatment strategy.

All-trans-retinoic Acid Reduces BACE1 Expression under Inflammatory Conditions via Modulation of Nuclear Factor κB (NFκB) Signaling

“…These effects were largely reversed by the administration of RA (29,30). Taken together, these data provide strong rationale investigating RA-based therapy in AD (31)(32)(33)(34).…”

Towards Retinoid Therapy for Alzheimers Disease

“…Development of retinoids that are highly selective for individual RARs may contribute to the treatment of AD and other neurodegenerative diseases. Recently there came out a review emphasizing significant roles of retinoids for treatment of neurodegenerative diseases such as ALS, AD and schizophrenia [153]. We did not cover RXRs and RXR ligands here, though these may have a role in increasing the selectivity of retinoids, and they seem to have important roles in mental activities such as sleep regulation, reward-related behaviors [154-158].…”

The human G93A-SOD1 mutation in a pre-symptomatic rat model of amyotrophic lateral sclerosis increases the vulnerability to a mild spinal cord compression

“…A link between the vitamin-A down-stream effects and the pathological changes observed in ALS has already been suggested [35-38]. Early vitamin-A deprivation, for example, causes motor cell loss in rodents [35].…”

“…Early vitamin-A deprivation, for example, causes motor cell loss in rodents [35]. RBP1 and CRABP2 are over-expressed in spinal cord from the end-stage G93A-SOD1 rat, whilst surviving small motor neurons show selective immunostaining for specific retinoid receptors [36-38]. Our observations in the acute post-injury phase may inspire potential neuroprotective therapeutic strategies, since both the alteration of ion current regulation and the activation of retinoid signalling can be pharmacologically modified.…”