Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration

Woodruff, Trent M.; Crane, James W.; Proctor, Lavinia M.; Buller, Kathryn M.; Shek, Annie; Vos, Kurt J. De; Pollitt, Sandra; Williams, Hua M.; Shiels, Ian A.; Monk, Peter N.; Taylor, Stephen M.

doi:10.1096/fj.05-5814com

Cited by 133 publications

(135 citation statements)

References 43 publications

(49 reference statements)

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“…In concordance with the notion that C5a contributes to pathogenic processes within the CNS, we have previously demonstrated C5aR up-regulation on degenerating striatal neurons in an acute model of Huntington's disease (18). Given that C3/C3b up-regulation occurs in these SOD1-transgenic rodents (indicating increased complement activation in the lumbar spinal cord), locally produced C5a could be interacting with C5aR-expressing motor neurons and astrocytes of ALS animals.…”

Section: Expression Of Complement Factors and Receptors For C5a Are Asupporting

confidence: 81%

“…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: 66%

“…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%

“…C5a is also produced locally in the CNS and the C5aR (CD88) is present on neurons and glia (17). Consistent with its presence in the CNS, this anaphylatoxin is implicated in the pathology of neurodegenerative diseases in vivo (17,18). C5a also binds to another recently described receptor, the C5a-like receptor 2 (C5L2; GPR77) (19).…”

mentioning

confidence: 93%

“…We found significant deposition of complement factor C3/C3b and an up-regulation of the C5aR and C5L2 in the diseased spinal cord. We then used a potent and selective C5aR antagonist (PMX205) that we had previously found to reduce striatal neurodegeneration in 3-nitropropionic acid intoxication in rats (18). Chronic oral administration of PMX205 to SOD1 G93A transgenic rats significantly reduced end-stage (ES) motor-deficit scores and enhanced survival times.…”

mentioning

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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139

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: Expression Of Complement Factors and Receptors For C5a Are Asupporting

confidence: 81%

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

confidence: 66%

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

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

See 3 more Smart Citations

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

139

177

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Success in Navigating Hurdles to Oral Delivery of a Bioactive Peptide Complement Antagonist through Use of Nanoparticles to Increase Bioavailability and In Vivo Efficacy

Kumar

Cui

et al. 2022

Advanced Therapeutics

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Substantial preclinical data have validated cyclic hexapeptide complement C5a receptor 1 antagonists (C5aRAs) that target immune cells, as novel therapies for a range of inflammatory diseases that currently have limited effective treatment options. However, like most small‐molecule peptides, their poor oral bioavailability and short circulation half‐life are major hurdles that have limited their clinical translation. Here, a single emulsion technique is employed to produce poly(lactic‐co‐glycolic) acid nanoparticles (NPs) with exceptionally high peptide C5aRA (PMX205) loading efficiency (over 50%). Strikingly, the PMX205‐NPs not only facilitate prolonged release of the encapsulated PMX205 but also dramatically increase its oral bioavailability (from ≈25% to ≈50%), and therapeutic potential (≈95% inhibition of C5a induces neutrophilia in mice and maintenance of neuroprotective barrier integrity). The enhanced in vivo pharmacological activity of PMX205 in the form of NPs opens an exciting opportunity for the clinical application of peptide C5aRAs and possibly other therapeutic peptides.

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Complement: Bridging the innate and adaptive immune systems in sterile inflammation

Woodruff

2020

Journal of Leukocyte Biology

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The complement system is a collection of soluble and membrane‐bound proteins that together act as a powerful amplifier of the innate and adaptive immune systems. Although its role in infection is well established, complement is becoming increasingly recognized as a key contributor to sterile inflammation, a chronic inflammatory process often associated with noncommunicable diseases. In this context, damaged tissues release danger signals and trigger complement, which acts on a range of leukocytes to augment and bridge the innate and adaptive immune systems. Given the detrimental effect of chronic inflammation, the complement system is therefore well placed as an anti‐inflammatory drug target. In this review, we provide a general outline of the sterile activators, effectors, and targets of the complement system and a series of examples (i.e., hypertension, cancer, allograft transplant rejection, and neuroinflammation) that highlight complement's ability to bridge the 2 arms of the immune system.

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Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration

Cited by 133 publications

References 43 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

Success in Navigating Hurdles to Oral Delivery of a Bioactive Peptide Complement Antagonist through Use of Nanoparticles to Increase Bioavailability and In Vivo Efficacy

Complement: Bridging the innate and adaptive immune systems in sterile inflammation

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