Retinoic acid synthesis by a population of NG2‐positive cells in the injured spinal cord

Abstract

Retinoic acid (RA) promotes growth and differentiation in many developing tissues but less is known about its influence on CNS regeneration. We investigated the possible involvement of RA in rat spinal cord injury (SCI) using the New York University (NYU) impactor to induce mild or moderate spinal cord contusion injury. Changes in RA at the lesion site were determined by measuring the activity of the enzymes for its synthesis, the retinaldehyde dehydrogenases (RALDHs). A marked increase in enzyme activity occurred by day 4 and peaked at days 8-14 following the injuries. RALDH2 was the only detectable RALDH present in the control or injured spinal cord. The cellular localization of RALDH2 was identified by immunostaining. In the noninjured spinal cord, RALDH2 was detected in oligodendroglia positive for the markers RIP and CNPase. Expression was also intense in the arachnoid membrane surrounding the spinal cord. After SCI the increase in RALDH2 was independent of the RIP- and CNPase-positive cells, which were severely depleted. Instead, RALDH2 was present in a cell type not previously identified as capable of synthesizing RA, that expressed NG2 and that was negative for markers of astrocytes, oligodendroglia, microglia, neurons, Schwann cells and immature lymphocytes. We postulate that the RALDH2- and NG2-positive cells migrate into the injured sites from the adjacent arachnoid membrane, where the RALDH2-positive cells proliferate substantially following SCI. These findings indicate that close correlations exist between RA synthesis and SCI and that RA may play a role in the secondary events that follow acute SCI.

The Effect of Am-80, a Synthetic Retinoid, on Spinal Cord Injury-Induced Motor Dysfunction in Rats

“…Mey et al 21) reported that SCI induced retinoic acid (RA) production over time with a peak of from 7 to 14 d after injury, indicating that the response to spinal cord damage involves RA. Wyatt et al 35) and Arrieta et al 36) have proposed that RA binds to its receptors to stimulate neurotrophic factor production and differentiation of stem cells into mature neurons, astrocytes, and oligodendrocytes to reform the neural network, thus leading to an improvement of performance.…”

“…21,22) In addition, retinoiddeficient rats have been reported to develop motor neuron disease. 23) Therefore, retinoids seem to be deeply involved in regeneration of the spinal cord after injury.…”

Fenretinide Promotes Functional Recovery and Tissue Protection after Spinal Cord Contusion Injury in Mice

“…After SCI, activated microglia express the retinoic acid receptor (Mey et al, 2005). Studies in vitro have shown that retinoic acid mediates antiinflammatory effects on microglia cells, reducing the release of TNF-␣ (Dheen et al, 2005).…”

“…This can be explained, in part, by a reduction in AA levels. However, since fenretinide is an analog of retinoic acid and reactive microglia expresses its receptors after SCI (Mey et al, 2005), we examined whether fenretinide could also exert a direct effect on microglial cells. To assess this, we activated microglial cells in vitro by the addition of LPS (10 ng/ml) and determined whether fenretinide was able to reduce the release of TNF-␣ into the culture supernatant.…”

Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons

“…Moreover, cultured embryonic midbrains selectively activated RAR-lacZ but not RXRlacZ constructs, indicative of the presence of endogenous all-trans-RA (here referred to as RA) (de Urquiza et al, 2000). RA is an essential molecule for embryonic brain development for its involvement in cellular differentiation (Mey et al, 2005;Maden, 2007) and has the ability to induce differentiation of the embryonic ventral midbrain-derived dopaminergic cell line MN9D (Eom et al, 2005;Castro et al, 2001). Furthermore, RA is an essential factor in ES-cell differentiation protocols for the generation of DA neurons .…”