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

T.M. Woodruff, J. W. Crane, L.M. Proctor, K.M. Buller, A.B. Shek, K. De Vos, S. Politt, H.M. Williams, I.A, Shiels

Research output: Contribution to journalArticle

89 Citations (Scopus)

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 up-regulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF-alpha 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.
Original languageEnglish
Pages (from-to)1407-1417
Number of pages11
JournalFASEB Journal
Volume20
Issue number9
DOIs
Publication statusPublished - Jul 2006

Fingerprint

Anaphylatoxin C5a Receptor
Corpus Striatum
Rats
Neurodegenerative diseases
Neutrophil Infiltration
Complement Activation
Ibuprofen
Huntington Disease
Anorexia
Cell death
Infiltration
Neurodegenerative Diseases
Prostaglandins
Weight Loss
Brain
Cell Death
Up-Regulation
Therapeutics
Tumor Necrosis Factor-alpha
Chemical activation

Cite this

Woodruff, T. M., Crane, J. W., Proctor, L. M., Buller, K. M., Shek, A. B., De Vos, K., ... Shiels, I. A. (2006). Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB Journal, 20(9), 1407-1417. https://doi.org/10.1096/fj.05-5814com
Woodruff, T.M. ; Crane, J. W. ; Proctor, L.M. ; Buller, K.M. ; Shek, A.B. ; De Vos, K. ; Politt, S. ; Williams, H.M. ; Shiels, I.A,. / Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. In: FASEB Journal. 2006 ; Vol. 20, No. 9. pp. 1407-1417.
@article{f77e310a8713430cb5d4b961eac1ac3e,
title = "Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration",
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 up-regulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF-alpha 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.",
author = "T.M. Woodruff and Crane, {J. W.} and L.M. Proctor and K.M. Buller and A.B. Shek and {De Vos}, K. and S. Politt and H.M. Williams and I.A, Shiels",
note = "Imported on 12 Apr 2017 - DigiTool details were: month (773h) = July, 2006; Journal title (773t) = The FASEB Journal. ISSNs: 1530-6860;",
year = "2006",
month = "7",
doi = "10.1096/fj.05-5814com",
language = "English",
volume = "20",
pages = "1407--1417",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "9",

}

Woodruff, TM, Crane, JW, Proctor, LM, Buller, KM, Shek, AB, De Vos, K, Politt, S, Williams, HM & Shiels, IA 2006, 'Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration', FASEB Journal, vol. 20, no. 9, pp. 1407-1417. https://doi.org/10.1096/fj.05-5814com

Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. / Woodruff, T.M.; Crane, J. W.; Proctor, L.M.; Buller, K.M.; Shek, A.B.; De Vos, K.; Politt, S.; Williams, H.M.; Shiels, I.A,.

In: FASEB Journal, Vol. 20, No. 9, 07.2006, p. 1407-1417.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration

AU - Woodruff, T.M.

AU - Crane, J. W.

AU - Proctor, L.M.

AU - Buller, K.M.

AU - Shek, A.B.

AU - De Vos, K.

AU - Politt, S.

AU - Williams, H.M.

AU - Shiels, I.A,

N1 - Imported on 12 Apr 2017 - DigiTool details were: month (773h) = July, 2006; Journal title (773t) = The FASEB Journal. ISSNs: 1530-6860;

PY - 2006/7

Y1 - 2006/7

N2 - 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 up-regulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF-alpha 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.

AB - 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 up-regulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF-alpha 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.

U2 - 10.1096/fj.05-5814com

DO - 10.1096/fj.05-5814com

M3 - Article

VL - 20

SP - 1407

EP - 1417

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 9

ER -

Woodruff TM, Crane JW, Proctor LM, Buller KM, Shek AB, De Vos K et al. Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB Journal. 2006 Jul;20(9):1407-1417. https://doi.org/10.1096/fj.05-5814com