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An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury

Spinal Cord Injury Laboratory, BioTherapeutics Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, PO Box 5015, 100 Perth Drive, London, Ontario Canada.
Experimental Neurology (Impact Factor: 4.62). 10/2008; 214(2):160-7. DOI: 10.1016/j.expneurol.2008.09.006
Source: PubMed

ABSTRACT Our previous studies have shown that treatment with an alpha4beta1 integrin blocking antibody after spinal cord injury (SCI) in rats decreases intraspinal inflammation and oxidative damage, improving neurological function. Here, we studied effects of a high affinity small molecule alpha4beta1 inhibitor, BIO5192. First, rats were treated intravenously with BIO5192 (10 mg/kg) or with vehicle (controls) to assess effects of integrin blockade for 24 h or 72 h after thoracic clip-compression SCI. BIO5192 treatment significantly decreased the MPO enzymatic activity (neutrophil infiltration) and ED-1 expression (macrophage density) by 40% and 38% at 24 h and by 52% and 25% at 72 h post injury, respectively. In cord homogenates, BIO5192 treatment decreased expression of the oxidative enzymes gp91(phox), inducible nitric oxide and cyclooxygenase-2 by approximately 40% at both times of analysis. Free radical concentration decreased by 30% and lipid peroxidation decreased by 34% and 46%, respectively, at 24 h and 72 h after SCI. Next, after blockade by BIO5192 for 72 h, neurological outcomes were analyzed for 1-6 weeks after SCI. Motor function significantly improved when assessed by an open-field test. Treated rats planter placed their hind paws and/or dorsal stepped, with weight support, whereas controls only swept their hindlimbs. BIO5192 treatment also decreased mechanical allodynia elicited from the trunk and hind paw by up to 35%. This improved function correlated with decreased lesion size and spared myelin-containing white matter. The neurological improvement offered by this neuroprotective strategy supports the potential for an anti-integrin treatment for SCI.

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    • "important. The CS-1 fragment is much smaller than full-length fibronectin, which suggests that CS-1: (1) more easily diffuses away from the injected sites to exert its effects, (2) is more biologically stable because of fewer digestive sites for proteases , (3) is less likely to produce side effects because of the lack of binding sites for interaction, and (4) is more specific because the CS-1 fragment binds specifically to integrin a4b1, which is present on multiple cell types, including endothelium (Hamill 1987; Milner and Campbell, 2002), inflammatory cells (Bao et al., 2008), glia, and neurons (Lefcort et al., 1992; Su et al., 2008; Tomaselli et al., 1993; Werner et al., 2000). It is likely that the combined participation of all of these cell types upon fibronectin stimulation provides a more favorable microenviroment for later functional recovery (Kadoya et al., 2009). "
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    • "However, further studies will be needed to address the involvement of specific subtypes of macrophages in the injured cord. A number of studies using antibody blockade (Fleming et al., 2008; Gris et al., 2004; Mabon et al., 2000), and pharmacological (Bao et al., 2008; Noble et al., 2002) and genetic (Letellier et al., 2010) strategies to block the early infiltration of leukocytes, report an improvement in long-term neurological outcomes. In the present study, improved neurological recovery and white matter sparing were limited to those animals that had been depleted of both neutrophils and monocytes. "
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    • "Infiltrating inflammatory cells have been significantly correlated with the amount of damaged tissue after injury [5]. These observations have been the basis for the design of different strategies directed towards eliminating immune cells from the injury site [3] [18]. However, recent findings have suggested that the presence and function of these cells are essential for CNS-tissue protection and regeneration [14] [21] [22] [26]. "
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