Dataset Information

Pharmacological inhibition of complement C5a-C5a₁ receptor signalling ameliorates disease pathology in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis.

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 hSOD1^G93A mice, the most widely used preclinical model of ALS.

Experimental approach

The selective and orally active C5a₁ receptor antagonist, PMX205, was administered to hSOD1^G93A 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^G93A 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^G93A mice as the disease progressed, in line with augmented blood-brain barrier breakdown. hSOD1^G93A 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 hSOD1^G93A mice, further validating the C5a-C5a₁ receptor signalling axis as a potential therapeutic target to slow disease progression in ALS.

SUBMITTER: Lee JD

PROVIDER: S-EPMC5368046 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Pharmacological inhibition of complement C5a-C5a<sub>1</sub> receptor signalling ameliorates disease pathology in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis.

Lee John D JD Kumar Vinod V Fung Jenny N T JN Ruitenberg Marc J MJ Noakes Peter G PG Woodruff Trent M TM

British journal of pharmacology 20170303 8

<h4>Background and purpose</h4>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<sub>1</sub> receptor (C5aR1). We therefore examined the therapeutic effect of C5a<sub>1</sub> receptor antagonism in hSOD1<sup>G93A</sup> mice, the most widely used preclinical model of ALS.<h4>E ...[more]

PMID: 28128456

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Project description:BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the decline of cognition and the presence of neuropathological changes including neuronal loss, neurofibrillary pathology and extracellular senile plaques. A neuroinflammatory process is also triggered and complement activation has been hypothesized to have a relevant role in this local inflammatory response. C5a, a proinflammatory anaphylatoxin generated after complement activation, exerts its chemotactic and inflammatory functions through the CD88 receptor while the more recently discovered C5L2 receptor has been postulated to have an anti-inflammatory role. Previously, we reported that a CD88 specific antagonist (PMX205) decreased the pathology and improved cognition in transgenic models of AD suggesting that C5a/C5aR interaction has an important role in the progression of the disease. METHODS:The present study characterizes the expression of the two receptors for C5a in human brain with confirmed post mortem diagnosis of vascular dementia (VD) or AD as well as age matched controls by immunohistochemistry and Western blot analysis using several antibodies against different epitopes of the human receptors. RESULTS:The CD88 and C5L2 antibodies revealed increased expression of both receptors in AD samples as compared to age-matched controls or VD brain tissue by Western blot and immunohistochemistry, using multiple antibodies and distinct cohorts of brain tissue. Immunostaining showed that both the C5L2 and CD88 antibodies similarly labeled abundant neurofibrillary tangles, neuropil threads and dystrophic neurites associated with plaques in the hippocampus and frontal cortex of AD cases. In contrast, little or no neuronal staining, tangles or dystrophic neurites associated with plaques were observed in control or VD brains. CD88 and C5L2 receptors are associated with both early (AT8) and mature (PHF1) neurofibrillary tangles and can be found either independently or colocalized with each other. CONCLUSIONS:The observed association of CD88 and C5L2 with neurofibrillary pathology suggests a common altered pathway of degradation.

Dataset Information

Pharmacological inhibition of complement C5a-C5a₁ receptor signalling ameliorates disease pathology in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Pharmacological inhibition of complement C5a-C5a<sub>1</sub> receptor signalling ameliorates disease pathology in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Pharmacological inhibition of complement C5a-C5a<sub>1</sub> receptor signalling ameliorates disease pathology in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pharmacological inhibition of complement C5a-C5a₁ receptor signalling ameliorates disease pathology in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis.