TY - JOUR
T1 - Kollidon VA64 Treatment in Traumatic Brain Injury
T2 - Operation Brain Trauma Therapy
AU - Osier, Nicole D.
AU - Bramlett, Helen M.
AU - Shear, Deborah A.
AU - Mondello, Stefania
AU - Carlson, Shaun W.
AU - Dietrich, W. Dalton
AU - Deng-Bryant, Ying
AU - Wang, Kevin K.W.
AU - Hayes, Ronald L.
AU - Yang, Zhihui
AU - Empey, Philip E.
AU - Poloyac, Samuel M.
AU - Lafrenaye, Audrey D.
AU - Povlishock, John T.
AU - Gilsdorf, Janice S.
AU - Kochanek, Patrick M.
AU - Dixon, C. Edward
N1 - Publisher Copyright:
© Copyright 2021, Mary Ann Liebert, Inc.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.
AB - Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.
KW - biomarker
KW - consortium
KW - controlled cortical impact
KW - fluid percussion injury
KW - neuroprotection
KW - penetrating ballistic-like brain injury
KW - rat
KW - therapy
UR - http://www.scopus.com/inward/record.url?scp=85114311236&partnerID=8YFLogxK
U2 - 10.1089/neu.2021.0089
DO - 10.1089/neu.2021.0089
M3 - Article
C2 - 33843262
AN - SCOPUS:85114311236
SN - 0897-7151
VL - 38
SP - 2454
EP - 2472
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
IS - 17
ER -