New therapeutic target for CNS injury? The role of retinoic acid signaling after nerve lesions

Abstract

Experiments with sciatic nerve lesions and spinal cord contusion injury demonstrate that the retinoic acid (RA) signaling cascade is activated by these traumatic events. In both cases the RA-synthesizing enzyme is RALDH-2. In the PNS, lesions cause RA-induced gene transcription, intracellular translocation of retinoid receptors, and increased transcription of CRBP-I, CRABP-II, and retinoid receptors. The activation of RARbeta appears to be responsible for neurotrophic and neuritogenic effects of RA on dorsal root ganglia and embryonic spinal cord. While the physiological role of RA in the injured nervous system is still under investigation three domains of functions are suggested: (1) neuroprotection and support of axonal growth, (2) modulation of the inflammatory reaction by microglia/macrophages, and (3) regulation of glial differentiation. Few studies have been performed to support nerve regeneration with RA signals in vivo, but a large number of experiments with neuronal and glial cell cultures and spinal cord explants point to beneficial effects of RA, so that future therapeutic approaches will likely focus on the activation of RA signaling.

Prospectively isolated CD133/CD24‐positive ependymal cells from the adult spinal cord and lateral ventricle wall differ in their long‐term in vitro self‐renewal and in vivo gene expression

“…Although RA is largely known as a differentiation inducing agent, it can also promote survival and induce proliferation via binding to PPARb/d, which functions as a heterodimer with RXR (Schug et al, 2007). SC injury is accompanied by an increase of the RA producing enzyme RALDH2 (Mey, 2006), and it will be interesting to learn how RA affects SC ependymal cells in the context of SC injuries.…”

Proteins involved in neuronal differentiation of neuroblastoma cell line N1E‐115

“…The RA system is the best studied and well-documented reproducible and nonsophisticated in vitro model for ND and therefore deserves comparative proteomic testing and can be even used for pharmacological testing of candidate compounds modifying the ND process [14,15].…”

Tamibarotene: A Candidate Retinoid Drug for Alzheimer’s Disease

“…17,18) It is now clear that retinoids play a key role in the differentiation and proliferation of various stem cells and progenitor cells, including nerve cells. 19) Retinoids initially attracted attention in the field of skin science, because they markedly suppress skin keratinization (an effect that stimulates skin rejuvenation). In 1978, Strickland and Madhvi discovered that retinoic acid stimulates differentiation of embryonic stem cells into various types of cells.…”

“…However, neuro-regeneration with retinoids appears to be feasible. 19) The central nervous system contains stem cells whose differentiation undoubtedly involves retinoids. In addition, safety is an absolute requirement, and in this respect, the use of small-molecular drugs may have some advantages.…”

“…19) Goncalves et al 49) reported that differentiation of adult forebrain neural progenitor cells (NPC) into neurons was induced by RA through sequential RARβ and RARα signaling in vivo; RARγ seemed not to be involved. The proliferated embryonic forebrain NPC expressed glial fibrillary acidic protein and were predominantly uni/bipolar, two characteristics of neuronal progenitor cells.…”