Increased Potency of a Novel Complement Factor 5a Receptor Antagonist in a Rat Model of Inflammatory Bowel Disease

Woodruff, Trent M.; Pollitt, Sandra; Proctor, Lavinia M.; Stocks, Shelli Z.; Manthey, Helga D.; Williams, Hua M.; Mahadevan, I. B.; Shiels, Ian A.; Taylor, Stephen M.

doi:10.1124/jpet.105.086835

Cited by 67 publications

(81 citation statements)

References 26 publications

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“…We have previously shown that PMX205 reduces C5a-mediated pathology in several inflammatory models (25), including an acute model of Huntington's disease (18). The present study provides compelling evidence that the complement system and, in particular C5a, is involved in the disease progression seen in our rat model of ALS.…”

Section: Treatment With a C5ar Antagonist Extends Survival Times And supporting

confidence: 56%

“…This orally active compound (25) crosses the blood-brain barrier and has been shown to have a protective effect in an acute model of striatal degeneration (18). Furthermore, PMX205 displays little detectable affinity for C5L2 (36).…”

Section: Treatment With a C5ar Antagonist Extends Survival Times And mentioning

confidence: 99%

“…Following this, in a separate group of experiments, we examined whether blocking the C5aR with the selective C5aR antagonist PMX205 would provide protective effects in SOD1 G93A rats. PMX205 (hydrocinnamate-[OP(D-Cha)WR]) was synthesized as previously described (25). Three experimental groups were chosen: untreated, PMX205 treated from day 28 onward, and PMX205 treated from day 70 onward.…”

Section: Experimental Designmentioning

confidence: 99%

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The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff¹,

Costantini²,

Crane

et al. 2008

The Journal of Immunology

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141

177

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Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1G93A transgenic rats). With end-stage disease, SOD1G93A rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.

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Section: Treatment With a C5ar Antagonist Extends Survival Times And supporting

confidence: 56%

Section: Treatment With a C5ar Antagonist Extends Survival Times And mentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

See 1 more Smart Citation

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff¹,

Costantini²,

Crane

et al. 2008

The Journal of Immunology

Self Cite

141

177

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“…PMX-53 is a peptidic C5aR antagonist and has proven to be advantageous in experimental animal studies for neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion and inflammatory bowel disease (102,166,167). It is currently being evaluated in clinical trials, but a recent study in humans failed to show significant effects on synovial inflammation (168).…”

Section: Immunomodulation Of Complementmentioning

confidence: 99%

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Ehrnthaller

Ignatius

Gebhard

et al. 2010

Mol Med

188

154

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The complement system was discovered a century ago as a potent defense cascade of innate immunity. After its first description, continuous experimental and clinical research was performed, and three canonical pathways of activation were established. Upon activation by traumatic or surgical tissue damage, complement reveals beneficial functions of pathogen and danger defense by sensing and clearing injured cells. However, the latest research efforts have provided a more distinct insight into the complement system and its clinical subsequences. Complement has been shown to play a significant role in the pathogenesis of various inflammatory processes such as sepsis, multiorgan dysfunction, ischemia/reperfusion, cardiovascular diseases and many others. The three well-known activation pathways of the complement system have been challenged by newer findings that demonstrate direct production of central complement effectors (for example, C5a) by serine proteases of the coagulation cascade. In particular, thrombin is capable of producing C5a, which not only plays a decisive role on pathogens and infected/damaged tissues, but also acts systemically. In the case of uncontrolled complement activation, "friendly fire" is generated, resulting in the destruction of healthy host tissue. Therefore, the traditional research that focuses on a mainly positive-acting cascade has now shifted to the negative effects and how tissue damage originated by the activation of the complement can be contained. In a translational approach including structure-function relations of this ancient defense system, this review provides new insights of complement-mediated clinical relevant diseases and the development of complement modulation strategies and current research aspects.

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“…It was reported that C5a contributed to the initiation and/or amplification of various pathological conditions such as ischemia-reperfusion injury, inflammatory bowel disease, arthritis, antiglomerular basement membrane nephritis, septic shock, Alzheimer's disease, and hemodialysis in animal models and humans (1,5,7,14,16,27,40,41,44) Therefore, C5a might be a target as an anti-C therapy as a way to prevent inflammatory tissue injury. There are numerous agents for inhibition of C5a, such as C5aR antagonists (C5aRA) and monoclonal anti-C5a IgG (10,28,42).…”

mentioning

confidence: 99%

Anti-C5a complementary peptide ameliorates acute peritoneal injury induced by neutralization of Crry and CD59

Mizuno

Imai

et al. 2013

American Journal of Physiology-Renal Physiology

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Increased Potency of a Novel Complement Factor 5a Receptor Antagonist in a Rat Model of Inflammatory Bowel Disease

Abstract: We have previously shown that complement factor 5a (C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective,

Cited by 67 publications

References 26 publications

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Anti-C5a complementary peptide ameliorates acute peritoneal injury induced by neutralization of Crry and CD59

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