Ian A. Shiels

Ischemia-reperfusion (I/R) injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient. Interruption of blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury. I/R is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. The use of specific inhibitors to block complement activation has been shown to prevent local tissue injury after I/R. Clinical and experimental studies in gut, kidney, limb, and liver have shown that I/R results in local activation of the complement system and leads to the production of the complement factors C3a, C5a, and the membrane attack complex. The novel inhibitors of complement products may find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

ABSTRACT The complement system is thought to be involved in the pathogenesis of numerous neurological diseases, although its precise role remains controversial. In this study we used orally active C5a receptor antagonists (PMX53 and PMX205) developed in our laboratories in a rat model of 3‐nitropropionic acid (3‐NP) ‐induced Huntington's disease. Administration of the C5a antagonists (10 mg/kg/day, oral) either 48 h pre‐ or 48 h post‐toxin significantly reduced body weight loss, anorexia, and behavioral and motor deficits associated with 3‐NP intoxication. Striatal lesion size, apoptosis, neutrophil infiltration, and hemorrhage were also significantly reduced in C5a antagonist‐treated rats. Immunohistochemical analysis demonstrated marked deposition of C3 and C9, and upregulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF‐α with ibuprofen or infliximab had no effect in this model. The C5a antagonists did not affect 3‐NP‐induced cell death when added directly to rat striatal neuronal cultures, indicating a secondary mechanism of action in vivo . Our findings demonstrate for the first time that complement activation in the brain, particularly C5a, is a key event in the pathogenesis of this disease model, and suggest a future role for inhibitors of C5a in the treatment of neurodegenerative diseases.—Woodruff, T. M., Crane, J. W., Proctor, L. M., Buller, K. M., Shek, A. B., de Vos, K., Pollitt, S., Williams, H. M., Shiels, I. A., Monk, P. N., Taylor, S. M. Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB J. 20, 1407–1417 (2006)

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.