Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

Peter J. Crack, Moses Zhang, Maria C. Morganti-Kossmann, Andrew J. Morris, Jonathan M. Wojciak, Jonathan K. Fleming, Ila Karve, David Wright, Maithili Sashindranath, Yona Goldshmit, Alison Conquest, Maria Daglas, Leigh A. Johnston, Robert L. Medcalf, Roger A. Sabbadini, Alice Pébay

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Background: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.Findings: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.Conclusions: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.

Original languageEnglish
Article number37
JournalJournal of Neuroinflammation
Volume11
DOIs
StatePublished - Feb 27 2014

Bibliographical note

Funding Information:
The authors thank Mr Duncan Crombie (Centre for Eye Research Australia and University of Melbourne) for his technical assistance. This work was supported by a National Health and Medical Research Council of Australia Project Grant 628391 (PJC), a NHMRC Career Development Award Fellowship (AP), a Transport Accident Commission project grant (AP), the ANZ Trustees Program – Medical Research & Technology in Victoria – William Buckland Foundation (AP), the United States National Institutes of Health

Funding Information:
(1R43CA132395-01A2 to RM), an Australian Research Council Future Fellowship (PJC), a University of Melbourne Collaboration Grant and the Victorian State Government’s Department of Innovation, Industry and Regional Development’s Operational Infrastructure Support Program.

Funding Information:
PJC, RAS and AP conceived the experiments. MZ, IK, MS, RLM, and MD performed TBI experiments and behavioral analysis. YG performed immunochemistry. MZ, DW and LAJ performed MRI experiments. RAS developed the anti-LPA mAbs. ACMK and AC collected CSF samples. AM and JMW performed HPLC MS measurements. JKF and JMW performed the KinExA assays. All authors contributed to data analysis and writing of the manuscript. PJC, RAS, and AP contributed financial support for this work. All authors have read and approved the final version of the manuscript.

Keywords

  • Anti-LPA antibody
  • Control cortical impact
  • Human cerebrospinal fluid
  • IL-6
  • Lysophosphatidic acid
  • Magnetic resonance imaging
  • Traumatic brain injury

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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