A Possible Role for Platelet-Activating Factor Receptor in Amyotrophic Lateral Sclerosis Treatment.

Marcelo R. S. Briones,James R. Broach,Elizabeth B. Neely,James R. Connor,Renata C. Ferreira,Amanda M. Snyder

doi:10.3389/fneur.2018.00039

Abstract

Amyotrophic lateral sclerosis (ALS) is the third most prevalent neurodegenerative disease affecting upper and lower motor neurons. An important pathway that may lead to motor neuron degeneration is neuroinflammation. Cerebrospinal Fluids of ALS patients have increased levels of the inflammatory cytokine IL-18. Because IL-18 is produced by dendritic cells stimulated by the platelet-activating factor (PAF), a major neuroinflammatory mediator, it is expected that PAF is involved in ALS. Here we show pilot experimental data on amplification of PAF receptor (PAFR) mRNA by RT-PCR. PAFR is overexpressed, as compared to age matched controls, in the spinal cords of transgenic ALS SOD1-G93A mice, suggesting PAF mediation. Although anti-inflammatory drugs have been tested for ALS before, no clinical trial has been conducted using PAFR specific inhibitors. Therefore, we hypothesize that administration of PAFR inhibitors, such as Ginkgolide B, PCA 4248 and WEB 2086, have potential to function as a novel therapy for ALS, particularly in SOD1 familial ALS forms. Because currently there are only two approved drugs with modest effectiveness for ALS therapy, a search for novel drugs and targets is essential.

Highlights

Amyotrophic lateral sclerosis (ALS), a motor neuron disease, is the third most prevalent neurodegenerative disease (4 cases per 100,000 people), being Alzheimer’s disease and Parkinson’s disease the first and second, respectively [1]
Previous observations have established that only 10% of ALS patients have a family history of the disease, which means that 90% of patients have no near relatives who have presented with the disease
All animal experiments were performed in accordance with protocol #46763 approved by the IACUC of Pennsylvania State University

Summary

INTRODUCTION

Amyotrophic lateral sclerosis (ALS), a motor neuron disease, is the third most prevalent neurodegenerative disease (4 cases per 100,000 people), being Alzheimer’s disease and Parkinson’s disease the first and second, respectively [1]. This group was defined as patients with diagnostic of definite or probable ALS according to El Escorial, disease onset within two years and greater-efficacy-expected subpopulation within the efficacyexpected population with% forced vital capacity of ≥80%, and ≥2 points for all item scores in the revised ALSFRS-R score before treatment [28] In another phase 3, randomized, doubleblind, parallel-group study with this post hoc subgroup only a small subset of people showed a smaller decline of ALSFRS-R score compared with placebo suggesting that edaravone may not be effective in all ALS patients [29]. We hypothesize a possible role for PAF receptor inhibitors as a novel therapy for ALS, in SOD1-familial forms

PILOT STUDY RESULTS

DISCUSSION

ETHICS STATEMENT