Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Lee, John D., Kumar, Vinod, Fung, Jenny N. T., Ruitenberg, Marc J., Noakes, Peter G. and Woodruff, Trent M. (2017) Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. British Journal of Pharmacology, 173 8: 689-699. doi:10.1111/bph.13730


Author Lee, John D.
Kumar, Vinod
Fung, Jenny N. T.
Ruitenberg, Marc J.
Noakes, Peter G.
Woodruff, Trent M.
Title Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Formatted title
Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
0007-1188
Publication date 2017-04-01
Year available 2017
Sub-type Article (original research)
DOI 10.1111/bph.13730
Open Access Status Not yet assessed
Volume 173
Issue 8
Start page 689
End page 699
Total pages 11
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Subject 3004 Pharmacology
Abstract Background and Purpose: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. The complement system is up-regulated in ALS, with recent studies indicating that the activation product C5a accelerates disease progression via the C5a receptor (C5aR1). We therefore examined the therapeutic effect of C5a receptor antagonism in hSOD1 mice, the most widely used preclinical model of ALS. Experimental Approach: The selective and orally active C5a receptor antagonist, PMX205, was administered to hSOD1 mice in drinking water, both pre- and post-disease onset. Blood, brain and spinal cord pharmacokinetics were performed using LC–MS/MS methods. Effects of PMX205 on hSOD1 disease progression was determined using body weight, hindlimb grip strength, survival time and blood analysis. Key Results: PMX205 entered the intact CNS at pharmacologically active concentrations, with increased entry observed in hSOD1 mice as the disease progressed, in line with augmented blood–brain barrier breakdown. hSOD1 mice treated with PMX205 before disease onset had significantly improved hindlimb grip strength, slower disease progression and extended survival, compared with vehicle treatment. These improvements were associated with reductions in pro-inflammatory monocytes and granulocytes and increases in T-helper lymphocytes in peripheral blood. PMX205 treatment beginning 3 weeks following disease onset also attenuated disease progression, significantly extending survival. Conclusion and Implications: These results confirm that C5a receptors play a pathogenic role in hSOD1 mice, further validating the C5a-C5a receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.
Formatted abstract
Background and Purpose: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. The complement system is up-regulated in ALS, with recent studies indicating that the activation product C5a accelerates disease progression via the C5a1 receptor (C5aR1). We therefore examined the therapeutic effect of C5a1 receptor antagonism in hSOD1G93A mice, the most widely used preclinical model of ALS.

Experimental Approach: The selective and orally active C5a1 receptor antagonist, PMX205, was administered to hSOD1G93A mice in drinking water, both pre- and post-disease onset. Blood, brain and spinal cord pharmacokinetics were performed using LC-MS/MS methods. Effects of PMX205 on hSOD1G93A disease progression was determined using body weight, hindlimb grip strength, survival time and blood analysis.

Key Results: PMX205 entered the intact CNS at pharmacologically active concentrations, with increased entry observed in hSOD1G93A mice as the disease progressed, in line with augmented blood-brain barrier breakdown. hSOD1G93A mice treated with PMX205 before disease onset had significantly improved hindlimb grip strength, slower disease progression and extended survival, compared with vehicle treatment. These improvements were associated with reductions in pro-inflammatory monocytes and granulocytes and increases in T-helper lymphocytes in peripheral blood. PMX205 treatment beginning 3 weeks following disease onset also attenuated disease progression, significantly extending survival.

Conclusion and Implications: These results confirm that C5a1 receptors play a pathogenic role in hSOD1G93A mice, further validating the C5a-C5a1 receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.
Keyword Motor-Neuron Degeneration
Spinal Cord Barrier
C5A Receptor
Sod1 Mice
Rat Model
Alzheimers-Disease
Als
Antagonists
Activation
Publication
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1082271
Institutional Status UQ

 
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