A neutrophil elastase inhibitor (ONO‐5046) reduces neurologic damage after spinal cord injury in rats

Abstract

In view of a cytoprotective effect of elastase inhibitor on chemokine-mediated tissue injury, we examined the neuroprotective effect of ONO-5046, a speci®c inhibitor of neutrophil elastase, in rats with spinal cord injury. Standardized spinal cord compression markedly increased cytokine-induced neutrophil chemo-attractant (CINC)-1 mRNA and protein.Their increases correlated with neurologic severity of injured rats. Immunohistochemically, CINC-1 protein was detected sequentially in vascular endothelial cells at 4 h, in perivascular neutrophils at 8 h, and in neutrophils in®ltrating into cord substance at 12 h. Pretreatment with ONO-5046 (50 mg/kg) markedly ameliorated motor disturbance in injured rats, and reduced CINC-1 protein and mRNA expression. ONO-5046 also signi®cantly reduced the increase of neutrophil accumulation or in®ltration estimated by myeloperoxidase activity, and the extent of vascular permeability by Evans blue extravasation in the injured cord segment in comparison to control animals receiving vehicle. These results suggest that CINC-1 contributed to in¯ammation in rat spinal cord injury and ONO-5046 attenuated neurologic damage partly by blocking CINC-1 production of the chemoattractant, preventing neutrophil activation and vascular endothelial cell injury.

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

“…The latter effect may underlie the marked reduction in neutrophil influx into the spinal cord of MK2-null mice at 12 h after contusion injury, as TNF-␣, IL-12 and CCL3/MIP-1␣ have previously been shown to stimulate neutrophil recruitment and activation (Lukacs et al, 1995;Ramos et al, 2005;Moreno et al, 2006). These observations are of relevance since several studies suggest that neutrophils may to contribute to secondary damage in SCI (Taoka et al, 1997;Tonai et al, 2001;Gris et al, 2004), although a recent study with neutrophil depletion showed contrary results (Stirling et al, 2009). …”

“…This loss is permanent after SCI because of the limited capacity of the CNS for regeneration and self-renewal. The localized immune response after SCI, involving neutrophils, microglia/macrophages, and reactive astrocytes, contributes to this secondary damage (Giulian and Robertson, 1990;Taoka et al, 1997;Popovich et al, 1999Popovich et al, , 2002Tonai et al, 2001;Gris et al, 2004). Under such conditions, these cells release various cytotoxic mediators, including proinflammatory chemokines/cytokines (McTigue et al, 1998;Rice et al, 2007), reactive oxygen species (Bao et al, 2004), and proteases (Noble et al, 2002;Wells et al, 2003b).…”

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

“…1,2, 15 In this situation, activated neutrophils can cause neurovascular injury by releasing free radicals, inflammatory cytokines or destructive enzymes. 3,4,16 Among them, NE, one of the proteases from neutrophils, induces not only systemic harmful reaction via humoral mechanism 4 but also local damages such as neuronal cell death [17][18][19] and increase in BBB permeability. 20,21 Therefore, NE inhibition can be beneficial to attenuate these inflammatory damages.…”

Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds

“…Different types of elastase inhibitors have been characterized from human skin (Lammers et al, 1986), parotid secretions, and bronchial mucus (Hochstrasser et al, 1981), as well as from other sources such as soybean (Odani and Ikenaka, 1978), turkey ovomucoid and leech (Seemuller et al, 1980) and suggested that the innate elastase inhibitors may play an important role for the protection of organs and tissues (Ashcroft et al, 2000;O'Blenes et al, 2000;Tonai et al, 2001;Ueno et al, 2001;Waugh et al, 2001). Furthermore, the leukocyte elastase inhibitors were considered as potential therapeutic agents for preventing number of chronic inflammatory diseases.…”