TY - JOUR
T1 - Nervous system delivery of antilysophosphatidic acid antibody by nasal application attenuates mechanical allodynia after traumatic brain injury in rats
AU - Eisenried, Andreas
AU - Meidahl, Anders C.N.
AU - Klukinov, Michael
AU - Tzabazis, Alexander Z.
AU - Sabbadini, Roger A.
AU - Clark, J. David
AU - Yeomans, David C.
N1 - Funding Information:
Supported by Grant number MR141271 from the Department of Defense (CDMRP) and by the Department of Anesthesia, Pain and Perioperative Medicine, Stanford University, USA. In addition, the antibodies used in this study were provided by Lpath Inc.
Publisher Copyright:
© 2017 International Association for the Study of Pain.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Lysophosphatidic acid (LPA) is a bioactive lipid that impacts neurological outcomes after neurotrauma by inhibiting neuroregeneration, promoting inflammation, and contributing to behavioral deficits. Blocking LPA signaling with a novel anti-LPA monoclonal antibody (mAb) is neuroprotective after traumatic brain injury (TBI) if given to injured animals whose blood-brain barrier (BBB) has been compromised. It is hypothesized that the anti-LPA mAb could improve chronic pain initiated by TBI. However, poor brain penetration after systemic application of the antibody makes access to the central nervous system (CNS) problematic in situations where the BBB is intact. Our experiments investigated whether intranasal delivery of the anti-LPA mAb could bypass the BBB, allowing for direct entry of the antibody to certain areas of the CNS. When the humanized anti-LPA mAb, LT3114, was intranasally applied to injured rats within 30 minutes after mild TBI using the central lateral percussion model, enzyme-linked immunospecific assay and immunohistochemistry demonstrated antibody uptake to several areas in the CNS, including the area of cortical injury, the corpus callosum, cerebellum, and the subventricular region. Compared with control rats that received LT3114 but no TBI, TBI rats demonstrated significantly higher concentrations of intranasally administered LT3114 antibody in some tissues. In behavioral studies, a significant attenuation of mechanical allodynia after TBI was observed in the anti-LPA treatment group (P = 0.0079), when compared with vehicle controls within 14 days after TBI. These results suggest that intranasal application of the anti-LPA antibody directly accesses CNS sites involved in TBI-related pain and that this access attenuates pain sequelae to the neurotrauma.
AB - Lysophosphatidic acid (LPA) is a bioactive lipid that impacts neurological outcomes after neurotrauma by inhibiting neuroregeneration, promoting inflammation, and contributing to behavioral deficits. Blocking LPA signaling with a novel anti-LPA monoclonal antibody (mAb) is neuroprotective after traumatic brain injury (TBI) if given to injured animals whose blood-brain barrier (BBB) has been compromised. It is hypothesized that the anti-LPA mAb could improve chronic pain initiated by TBI. However, poor brain penetration after systemic application of the antibody makes access to the central nervous system (CNS) problematic in situations where the BBB is intact. Our experiments investigated whether intranasal delivery of the anti-LPA mAb could bypass the BBB, allowing for direct entry of the antibody to certain areas of the CNS. When the humanized anti-LPA mAb, LT3114, was intranasally applied to injured rats within 30 minutes after mild TBI using the central lateral percussion model, enzyme-linked immunospecific assay and immunohistochemistry demonstrated antibody uptake to several areas in the CNS, including the area of cortical injury, the corpus callosum, cerebellum, and the subventricular region. Compared with control rats that received LT3114 but no TBI, TBI rats demonstrated significantly higher concentrations of intranasally administered LT3114 antibody in some tissues. In behavioral studies, a significant attenuation of mechanical allodynia after TBI was observed in the anti-LPA treatment group (P = 0.0079), when compared with vehicle controls within 14 days after TBI. These results suggest that intranasal application of the anti-LPA antibody directly accesses CNS sites involved in TBI-related pain and that this access attenuates pain sequelae to the neurotrauma.
UR - http://www.scopus.com/inward/record.url?scp=85040780298&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000001019
DO - 10.1097/j.pain.0000000000001019
M3 - Journal articles
C2 - 29028747
AN - SCOPUS:85040780298
SN - 0304-3959
VL - 158
SP - 2181
EP - 2188
JO - Pain
JF - Pain
IS - 11
ER -
