Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

Abstract

Summary: 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.

Lack of galectin-3 improves the functional outcome and tissue sparing by modulating inflammatory response after a compressive spinal cord injury

“…Understanding of the changes in the spinal cord environment after a trauma is necessary, in order to develop strategies that aim to promote proper functional recovery. During the last few decades, evidence has accumulated showing that the inflammatory response elicited after SCI plays a pivotal role during the course of the initial trauma (Caroleo et al, 2001;David and Kroner, 2011;Elkabes and Black, 1996;Gensel and Zhang, 2015;Kigerl et al, 2009;Lee et al, 2010Lee et al, , 2011Ousman and Kubes, 2012;Popovich et al, 1999;Shechter et al, 2009;Stirling et al, 2009;Taoka et al, 1997).…”

Immune-Based Therapies for Spinal Cord Injury

“…Spinal cord injury is first induced by a mechanical insult supporting secondary biochemical and physiological damage that ultimately promotes permanent loss of sensory and motor function (Pajoohesh-Ganji and Byrnes, 2011). The secondary damage initiates a series of degenerative events that results in further tissue destruction, massive cellular death, disrupted vasculature, increased permeability of the blood-spinal cord barrier, axonal demyelination, glial scar formation and neuroinflammation (Fehlings and Nguyen, 2010;Pajoohesh-Ganji and Byrnes, 2011;Jaerve and Muller, 2012).…”

“…The secondary damage initiates a series of degenerative events that results in further tissue destruction, massive cellular death, disrupted vasculature, increased permeability of the blood-spinal cord barrier, axonal demyelination, glial scar formation and neuroinflammation (Fehlings and Nguyen, 2010;Pajoohesh-Ganji and Byrnes, 2011;Jaerve and Muller, 2012). Because the secondary damage is so widespread, the prevention or a reduction in one or several of these secondary events post-SCI could potentially initiate spinal cord tissue repair and promote the overall improvement in functional outcomes.…”

Emerging Concepts in Myeloid Cell Biology after Spinal Cord Injury

“…These various experiments, including the use of clodronate liposomes [64,65], anti-CD11d antibodies [92][93][94][95], minocycline [96], silica dust [1,97,98], colchicine and chloroquine [98,99], activated protein C [49], and nitrogen mustard [100,101] have been reviewed previously [1,5,98] and will not be discussed further. Additionally, because 2 other review articles in this issue provide an overview of the use of MMP inhibitors for SCI [80] and provide new strategies to manipulate microglia (and macrophage) metabotropic glutamate receptors [102], we will not discuss these topics any further. Instead, we will focus on newer approaches in which blockade or infusion of select cytokines has been shown to modify the composition and phenotype of the responding myeloid cells.…”