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

Abstract

The inflammatory response is thought to contribute to secondary damage after spinal cord injury (SCI). Polyunsaturated fatty acids (PUFAs) play an important role in the onset and resolution of inflammation. Arachidonic acid (AA), an -6 PUFA, contributes to the initiation of inflammatory responses, whereas docosahexaenoic acid (DHA), an -3 PUFA, has antiinflammatory effects. Therefore, decreasing AA and increasing DHA levels after SCI might be expected to attenuate inflammation after SCI and promote tissue protection and functional recovery. We show here that daily oral administration of fenretinide after spinal cord contusion injury led to a significant decrease in AA and an increase in DHA levels in plasma and injured spinal cord tissue. This was accompanied by a significant reduction in tissue damage and improvement in locomotor recovery. Fenretinide also reduced the expression of proinflammatory genes and the levels of oxidative stress markers after SCI. In addition, in vitro studies demonstrated that fenretinide reduced TNF-␣ (tumor necrosis factor-␣) expression by reactive microglia. These results demonstrate that fenretinide treatment after SCI can reduce inflammation and tissue damage in the spinal cord and improve locomotor recovery. These beneficial effects may be mediated via the ability of fenretinide to modulate PUFA homeostasis. Since fenretinide is currently in clinical trials for the treatment of cancers, this drug might be a good candidate for the treatment of acute SCI in humans.

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

“…A previous study ( 21 ) demonstrated that long-term (18 h) treatment with fenretinide inhibited TNF-␣ in microglial cell culture induced by LPS stimulation. In our study, Raw 264.7 cells pretreated with fenretinide for 16 h and stimulated with immune signaling transduction.…”

“…Previous study has shown that fenretinide inhibited chemokine ( 18 ) and chemokine receptor expression ( 19 ) and suppressed infl ammatory response in animal models ( 20,21 ). We hypothesized that fenretinide had an by guest, on May 11, 2018 www.jlr.org Downloaded from the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) (also called Akt) pathway ( 28,29 ), the PI3K-PKC pathway ( 30,31 ), and the mitogen-activated protein kinase (MAPK) signaling pathways ( 32,33 ).…”

“…Fenretinide inhibited chemokine ( 18 ) and chemokine receptor expression ( 19 ) in vitro. In animal studies, fenretinide suppressed chronic arthritis induced by administration of streptococcal cell wall ( 20 ) and decreased the mRNA levels of proinfl ammatory mediators in the spinal cord after a spinal cord injury ( 21 ). However, the underlying mechanisms related to the anti-infl ammatory effect of fenretinide were not elucidated.…”

Salvianolic Acid B Ameliorates Motor Dysfuntion in Spinal Cord Injury Rats

“…Inflammation is one of the major secondary pathologies following SCI [23], and severe inflammatory responses in the injured spinal cord destroy neurons, leading to exacerbate neurodegeneration [24]. Inflammation contributes to secondary damage partly through over-release of cytokines, such as TNF-α, which enhance permeability of endothelial cells and facilitate trans-endothelial migration of activated leukocytes to the injured area [25,26]. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages are potent producers of IL-1, IL-6, and TNF-α [27].…”

Nanomedicine strategies for treatment of secondary spinal cord injury

“…26 Upon uncontrolled release, though, many of these molecules and enzymes, specifically reactive oxygen species and reactive nitrogen species (Figure 1), travel to neighboring cells, including healthy ones, and cause secondary damage through effects such as lipid peroxidation and inflammation. [31][32][33] Biochemical targets of SCI In SCI, inflammation plays a role in the health and progres sion of CNS neurons. In vitro, activated microglial cells induce oxidative stress when cultured with neuronal cells.…”