PMID- 30639321 OWN - NLM STAT- MEDLINE DCOM- 20200221 LR - 20200401 IS - 1090-2430 (Electronic) IS - 0014-4886 (Print) IS - 0014-4886 (Linking) VI - 314 DP - 2019 Apr TI - EPPS treatment attenuates traumatic brain injury in mice by reducing Abeta burden and ameliorating neuronal autophagic flux. PG - 20-33 LID - S0014-4886(18)30463-1 [pii] LID - 10.1016/j.expneurol.2019.01.002 [doi] AB - Beta-amyloid (Abeta) burden and impaired neuronal autophagy contribute to secondary brain injury after traumatic brain injury (TBI). 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) treatment has been reported to reduce Abeta aggregation and rescue behavioral deficits in Alzheimer's disease-like mice. Here, we investigated neuroprotective effects of EPPS in a mouse model of TBI. Mice subjected to controlled cortical impact (CCI) were treated with EPPS (120 mg/kg, orally) immediately after CCI and thereafter once daily for 3 or 7 days. We found that EPPS treatment profoundly reduced the accumulation of beta-amyloid precursor protein (beta-APP) and Abeta over a widespread area detected in the pericontusional cortex, external capsule (EC), and hippocampal CA1 and CA3 at 3 days after TBI, accompanied by significant reduction in the TBI-induced diffuse axonal injury identified by increased immunoreactivity of SMI-32 (an indicator for axonal damage). We also found that EPPS treatment ameliorated the TBI-induced synaptic damage (as reflected by enhanced postsynaptic density 95, PSD-95), and impairment of autophagy flux in the neurons as reflected by reduced autophagy markers (LC3-II/LC3-I ratio and p62/SQSTM1) and increased lysosomal enzyme cathepsin D (CTSD) in neurons detected in the cortex and hippocampal CA1. As a result, EPPS treatment significantly reduced the TBI-induced early neuronal apoptosis (assessed by active caspase-3), and eventually prevented cortical tissue loss and hippocampal neuronal loss at 28 days after TBI. Additionally, we found that inhibition of autophagic flux with chloroquine by decreasing autophagosome-lysosome fusion significantly reversed the decreased expressions of neuronal p62/SQSTM1 and apoptosis by EPPS treatment. These data suggest that the neuroprotection by EPPS is, at least in part, related to improved autophagy flux. Finally, we found that EPPS treatment significantly improved the cortex-dependent motor and hippocampal-dependent cognitive deficits associated with TBI. Taken together, these findings support the further investigation of EPPS as a treatment for TBI. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Anthony Jalin, Angela Melinda A AU - Anthony Jalin AMA AD - Department of Neurosurgery, Neuroscience Institute, Penn State Hershey Medical Center, Hershey 17033, USA. Electronic address: aanthonyjalin@pennstatehealth.psu.edu. FAU - Jin, Rong AU - Jin R AD - Department of Neurosurgery, Neuroscience Institute, Penn State Hershey Medical Center, Hershey 17033, USA. Electronic address: rjin@pennstatehealth.psu.edu. FAU - Wang, Min AU - Wang M AD - Department of Neurosurgery, Neuroscience Institute, Penn State Hershey Medical Center, Hershey 17033, USA. Electronic address: mwang2@pennstatehealth.psu.edu. FAU - Li, Guohong AU - Li G AD - Department of Neurosurgery, Neuroscience Institute, Penn State Hershey Medical Center, Hershey 17033, USA. Electronic address: guohongli@pennstatehealth.psu.edu. LA - eng GR - R01 NS088719/NS/NINDS NIH HHS/United States GR - R01 NS089991/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190109 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Amyloid beta-Peptides) RN - 0 (N(2-hydroxythyl)piperazine-N'-(3-propanesulfonic acid)) RN - 0 (Neuroprotective Agents) RN - 0 (Piperazines) RN - EC 3.4.14.1 (Cathepsin C) RN - EC 3.4.14.1 (Ctsc protein, mouse) SB - IM MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Apoptosis/drug effects MH - Autophagy/*drug effects MH - Axons/drug effects/pathology MH - Brain Chemistry/drug effects MH - Brain Injuries, Traumatic/*drug therapy/pathology/psychology MH - Cathepsin C/metabolism MH - Cognition/drug effects MH - Hippocampus/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotective Agents/*therapeutic use MH - Piperazines/*therapeutic use MH - Psychomotor Performance/drug effects MH - Synapses/drug effects/pathology PMC - PMC6457462 MID - NIHMS1518852 OTO - NOTNLM OT - Autophagy OT - Axonal injury OT - Beta-amyloid OT - Neuroprotection OT - Traumatic brain injury COIS- AUTHOR DISCLOSURE STATEMENT The authors declare that no competing financial interests exist. EDAT- 2019/01/15 06:00 MHDA- 2020/02/23 06:00 PMCR- 2020/04/01 CRDT- 2019/01/15 06:00 PHST- 2018/09/12 00:00 [received] PHST- 2019/01/02 00:00 [revised] PHST- 2019/01/03 00:00 [accepted] PHST- 2019/01/15 06:00 [pubmed] PHST- 2020/02/23 06:00 [medline] PHST- 2019/01/15 06:00 [entrez] PHST- 2020/04/01 00:00 [pmc-release] AID - S0014-4886(18)30463-1 [pii] AID - 10.1016/j.expneurol.2019.01.002 [doi] PST - ppublish SO - Exp Neurol. 2019 Apr;314:20-33. doi: 10.1016/j.expneurol.2019.01.002. Epub 2019 Jan 9.