PMID- 29940352 OWN - NLM STAT- MEDLINE DCOM- 20190906 LR - 20190906 IS - 1873-4596 (Electronic) IS - 0891-5849 (Print) IS - 0891-5849 (Linking) VI - 124 DP - 2018 Aug 20 TI - The cysteine-rich whey protein supplement, Immunocal(R), preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact. PG - 328-341 LID - S0891-5849(18)31117-1 [pii] LID - 10.1016/j.freeradbiomed.2018.06.026 [doi] AB - Traumatic brain injury (TBI) is a major public health problem estimated to affect nearly 1.7 million people in the United States annually. Due to the often debilitating effects of TBI, novel preventative agents are highly desirable for at risk populations. Here, we tested a whey protein supplement, Immunocal(R), for its potential to enhance resilience to TBI. Immunocal(R) is a non-denatured whey protein preparation which has been shown to act as a cysteine delivery system to increase levels of the essential antioxidant glutathione (GSH). Twice daily oral supplementation of CD1 mice with Immunocal((R)) for 28 days prior to receiving a moderate TBI prevented an ~ 25% reduction in brain GSH/GSSG observed in untreated TBI mice. Immunocal(R) had no significant effect on the primary mechanical injury induced by TBI, as assessed by MRI, changes in Tau phosphorylation, and righting reflex time or apnea. However, pre-injury supplementation with Immunocal(R) resulted in statistically significant improvements in motor function (beam walk and rotarod) and cognitive function (Barnes maze). We also observed a significant preservation of corpus callosum width (axonal myelination), a significant decrease in degenerating neurons, a reduction in Iba1 (microglial marker), decreased lipid peroxidation, and preservation of brain-derived neurotrophic factor (BDNF) in the brains of Immunocal(R)-pretreated mice compared to untreated TBI mice. Taken together, these data indicate that pre-injury supplementation with Immunocal(R) significantly enhances the resilience to TBI induced by a moderate closed head injury in mice. We conclude that Immunocal(R) may hold significant promise as a preventative agent for TBI, particularly in certain high risk populations such as athletes and military personnel. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Ignowski, Elizabeth AU - Ignowski E AD - University of Denver, Department of Biological Sciences, Denver, CO 80208, United States. Electronic address: lizignowski@gmail.com. FAU - Winter, Aimee N AU - Winter AN AD - University of Denver, Department of Biological Sciences, Denver, CO 80208, United States. Electronic address: aimee.n.winter@gmail.com. FAU - Duval, Nathan AU - Duval N AD - University of Denver, Knoebel Institute for Healthy Aging, Denver, CO 80208, United States. Electronic address: ng.duval@gmail.com. FAU - Fleming, Holly AU - Fleming H AD - University of Denver, Knoebel Institute for Healthy Aging, Denver, CO 80208, United States. Electronic address: holly.fleming@du.edu. FAU - Wallace, Tyler AU - Wallace T AD - University of Denver, Department of Biological Sciences, Denver, CO 80208, United States. Electronic address: tywall28@gmail.com. FAU - Manning, Evan AU - Manning E AD - University of Denver, Department of Biological Sciences, Denver, CO 80208, United States. Electronic address: evan.manning@ucdenver.edu. FAU - Koza, Lilia AU - Koza L AD - University of Denver, Department of Biological Sciences, Denver, CO 80208, United States. Electronic address: koza.lilia@gmail.com. FAU - Huber, Kendra AU - Huber K AD - University of Colorado Cancer Center, Aurora, CO 80045, United States. Electronic address: kendra.huber@ucdenver.edu. FAU - Serkova, Natalie J AU - Serkova NJ AD - University of Colorado Cancer Center, Aurora, CO 80045, United States. Electronic address: natalie.serkova@ucdenver.edu. FAU - Linseman, Daniel A AU - Linseman DA AD - University of Denver, Department of Biological Sciences and Knoebel Institute for Healthy Aging, 2155 E. Wesley Ave., Denver, CO 80208, United States. Electronic address: daniel.linseman@du.edu. LA - eng GR - P30 CA046934/CA/NCI NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180627 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Neuroprotective Agents) RN - 0 (Whey Proteins) RN - GAN16C9B8O (Glutathione) RN - K848JZ4886 (Cysteine) SB - IM MH - Animals MH - Brain/metabolism/*pathology MH - Brain Injuries, Traumatic/metabolism/*pathology MH - Cysteine MH - *Dietary Supplements MH - Disease Models, Animal MH - Glutathione/metabolism MH - Male MH - Mice MH - Neuroprotective Agents/*pharmacology MH - Recovery of Function MH - Whey Proteins/*pharmacology PMC - PMC6211803 MID - NIHMS1509421 OTO - NOTNLM OT - Cognitive function OT - Glutathione OT - Motor function OT - Neuroprotection OT - Traumatic brain injury COIS- Conflicts of Interest The authors have received funding from Immunotec Inc. (Quebec, Canada) to support research on the therapeutic effects of Immunocal(R) in pre-clinical mouse models of TBI. EDAT- 2018/06/26 06:00 MHDA- 2019/09/07 06:00 PMCR- 2019/08/20 CRDT- 2018/06/26 06:00 PHST- 2018/03/09 00:00 [received] PHST- 2018/06/08 00:00 [revised] PHST- 2018/06/22 00:00 [accepted] PHST- 2018/06/26 06:00 [pubmed] PHST- 2019/09/07 06:00 [medline] PHST- 2018/06/26 06:00 [entrez] PHST- 2019/08/20 00:00 [pmc-release] AID - S0891-5849(18)31117-1 [pii] AID - 10.1016/j.freeradbiomed.2018.06.026 [doi] PST - ppublish SO - Free Radic Biol Med. 2018 Aug 20;124:328-341. doi: 10.1016/j.freeradbiomed.2018.06.026. Epub 2018 Jun 27.