Novel neuroinflammatory targets in the chronically injured spinal cord

Abstract

Injury to the spinal cord is known to result in inflammation. To date, the preponderance of research has focused on the acute neuroinflammatory response, which begins immediately and is believed to terminate within hours to (at most) days after the injury. However, recent studies have demonstrated that postinjury inflammation is not restricted to the first few hours or days after injury, but can last for months to years after a spinal cord injury (SCI). These chronic studies have revealed that increased numbers of inflammatory cells, such as microglia and macrophages, and inflammatory factors, including cytokines, chemokines, and enzyme products are found at markedly delayed times after injury. Here we review experimental work on a selection of the novel inflammatory factors observed chronically after SCI, including the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase enzyme and galectin-3. We will discuss the role of these proteins in inflammation with regard to both detrimental and beneficial effects of neuroinflammation after injury. Finally, the potential of these proteins to serve as therapeutic targets will be considered, and a novel therapeutic approach (i.e., the agonist for metabotropic glutamate receptor 5 [mGluR5], [RS]-2-Chloro-5-hydroxyphenylglycine [CHPG]) will be discussed. This review will demonstrate the expression and activity profiles, roles in potentiation of injury, and therapy studies of these inflammatory factors suggest that not only are these chronically expressed factors viable targets for SCI treatment, but that the therapeutic window is broader than has previously been thought.

Figures

FIG. 1

Diagram of the the input of the novel chronic neuroinflammatory factors NADPH oxidase and galectin-3 on cell death, and the input of the novel anti-inflammatory treatment (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG). Trauma results in microglial activation, including NADPH oxidase activity and galectin-3 expression. These proteins then act to both enhance inflammation and neurotoxicity, as well as promote their own expression and activity. The metabotropic glutamate receptor 5 (mGluR5) agonist CHPG has activities to block this neuroinflammation and may operate as a viable anti-inflammatory agent for chronic inflammation. (IL = interleukin; TGF = transforming growth factor; TNF = tumor necrosis factor.)

FIG. 2

Diagram of the mechanism of NADPH oxidase-induced cell death. NADPH oxidase activation by aggregation of all components to the cell membrane results in production of superoxide (O2-). Superoxide can then combine with nitric oxide (NO) to produce peroxynitrite (ONOO-), which interferes within mitochondrial activity and can induce cell death. Superoxide can also interact with the cell membrane to produce reactive aldehydes, which also induce cell death. ATP = adenosine triphosphate.

FIG. 3

Gene expression of the novel neuroinflammatory targets after spinal cord injury (SCI). Microarray data from http://pepr.cnmcresearch.org was mined to determine the expression of (a) galectin-3, (b) p22PHOX, and (c) gp91PHOX. Expression is significantly elevated, chronically after moderate SCI in mice for each marker in comparison with sham-injured tissue. (d) Sham-injured tissue and spinal cord-injured tissue stained with gp91 (red) and ToPro (blue) at 28 days after a moderate contusion injury in mice indicates elevation of this protein corresponding to the gene expression measurements. (Bar = 200 μm).