Systemically Administered Interleukin-10 Reduces Tumor Necrosis Factor-Alpha Production and Significantly Improves Functional Recovery Following Traumatic Spinal Cord Injury in Rats

Abstract

In these studies, we examined the neuroprotective effects of the potent antiinflammatory cytokine interleukin-10 (IL-10) following spinal cord injury (SCI). Neuroprotection was assessed by using behavioral and morphological end points. We hypothesized that injury-induced inflammation contributes to the resulting neuropathology and subsequent loss of function. Therefore, by attenuating injury-induced inflammation, we should promote functional recovery. The New York University device was used to induce moderate SCI and study the resulting inflammatory response and functional consequences of inhibiting this response in rats. We determined that SCI induces the expression of tumor necrosis factor-alpha (TNF-alpha) in the spinal cord and by SCI-activated monocytes isolated from the peripheral circulation. IL-10 (5.0 microg) administered 30 minutes after-injury significantly reduced the expression of TNF-alpha protein in the spinal cord and in vitro by SCI-activated monocytes. Next, we investigated whether IL-10 would improve functional recovery after SCI. Randomized, double-blinded studies demonstrated that a single injection of IL-10 significantly improves hind limb motor function 2 months after injury, as determined by the Basso, Beattie and Bresnahan (BBB) open-field behavioral test. IL-10-treated animals had a mean BBB score of 18.0+/-0.5 (SEM, n = 9) compared with a score of 12.9+/-0.6 (SEM, n = 9) for the saline-treated controls. Morphological analysis demonstrated that IL-10 reduces lesion volume by approximately 49% 2 months after injury. These data suggest that acute administration of IL-10 reduces TNF-alpha synthesis in the spinal cord and by activated macrophages, is neuroprotective, and promotes functional recovery following SCI.

Post-traumatic inflammation following spinal cord injury

“…IL-10 is a potent anti-inflammatory cytokine that supresses the majority of microglial/ macrophage responses. 4,28,93 This cytokine blocks the activation of NF-kB and attenuates the synthesis of various cytokines, chemokines, and matrixproteases. With respect to the CNS, IL-10 reduces the TNF-a production by astrocytes as well as the antigen presentation by both astrocytes and microglia.…”

“…With respect to the CNS, IL-10 reduces the TNF-a production by astrocytes as well as the antigen presentation by both astrocytes and microglia. 4,94 Further, IL-10 is known to act at the BBB preventing adhesion and extravasation of leucocytes. 95 QUIS injection causes excitotoxic SCI.…”

“…[1][2][3][4][5][6][7][8] SCIinduced inflammation may result in further reduction in functional recovery because of the development of scar tissue, as well as necrosis or apoptosis of neurons and oligodendrocytes. However, a potentially beneficial role of the inflammatory process has also been reported, illustrating the dual nature of post-traumatic inflammation.…”

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

“…IL‐10 has been demonstrated to promote functional recovery in SCI models in rats66, 67, 68, 69, 72, 73, 74 and mice 58, 64, 65, 70, 71. IL‐10 affects inflammation through regulation of activation of microglia/macrophages70, 71 and astrocytes,72 as well as reducing the production of TNF‐α,72, 73 IL‐1β, S100β, and inducible nitric oxide synthase (iNOS) 65.…”

Confirming an experimental therapy prior to transfer to humans: What is the ideal?

“…To date, several treatments have been reported to promote a degree of axonal regeneration and functional recovery in the spinal cord [3][4][5][6][7][8][9][10][11][12][13][14]. Also, several neuroprotective strategies administered in the acute injury setting have shown promise in reducing secondary injury mechanisms and promoting recovery [15][16][17][18][19][20][21][22]. Thus, an important question now being discussed in the scientific community is whether these neuroprotective or regenerative strategies are ready for clinical application [23].…”