PMID- 28887487 OWN - NLM STAT- MEDLINE DCOM- 20190611 LR - 20200930 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 IP - 1 DP - 2017 Sep 8 TI - TrkB-enhancer facilitates functional recovery after traumatic brain injury. PG - 10995 LID - 10.1038/s41598-017-11316-8 [doi] LID - 10995 AB - Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma. FAU - Marshall, John AU - Marshall J AD - Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, 02912, USA. John_Marshall@Brown.edu. FAU - Szmydynger-Chodobska, Joanna AU - Szmydynger-Chodobska J AD - Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI, 02903, USA. FAU - Rioult-Pedotti, Mengia S AU - Rioult-Pedotti MS AD - Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, 02912, USA. FAU - Lau, Kara AU - Lau K AD - Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, 02912, USA. FAU - Chin, Andrea T AU - Chin AT AD - Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI, 02903, USA. FAU - Kotla, Siva K Reddy AU - Kotla SKR AD - Center for Targeted Drug Delivery, Department of Biomedical & Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA. FAU - Tiwari, Rakesh Kumar AU - Tiwari RK AD - Center for Targeted Drug Delivery, Department of Biomedical & Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA. FAU - Parang, Keykavous AU - Parang K AD - Center for Targeted Drug Delivery, Department of Biomedical & Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA. FAU - Threlkeld, Steven W AU - Threlkeld SW AD - Department of Neuroscience, Regis College, Weston, MA, 02493, USA. FAU - Chodobski, Adam AU - Chodobski A AD - Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI, 02903, USA. LA - eng GR - R01 NS094440/NS/NINDS NIH HHS/United States GR - R15 HD077544/HD/NICHD NIH HHS/United States GR - R21 MH104252/MH/NIMH NIH HHS/United States GR - R21 NS099605/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 - 20170908 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Biomarkers) RN - 0 (CN2097) RN - 0 (Peptides, Cyclic) RN - EC 2.7.10.1 (Ntrk2 protein, rat) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Behavior, Animal MH - Biomarkers MH - Brain Injuries, Traumatic/*metabolism/pathology/physiopathology/*rehabilitation MH - Cerebral Cortex/drug effects/metabolism/pathology/physiopathology MH - Hippocampus/metabolism/pathology/physiopathology MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Male MH - Maze Learning MH - Peptides, Cyclic/pharmacology MH - Rats MH - Receptor, trkB/*metabolism MH - Recovery of Function PMC - PMC5591207 COIS- The authors declare that they have no competing interests. EDAT- 2017/09/10 06:00 MHDA- 2019/06/14 06:00 PMCR- 2017/09/08 CRDT- 2017/09/10 06:00 PHST- 2017/03/27 00:00 [received] PHST- 2017/08/22 00:00 [accepted] PHST- 2017/09/10 06:00 [entrez] PHST- 2017/09/10 06:00 [pubmed] PHST- 2019/06/14 06:00 [medline] PHST- 2017/09/08 00:00 [pmc-release] AID - 10.1038/s41598-017-11316-8 [pii] AID - 11316 [pii] AID - 10.1038/s41598-017-11316-8 [doi] PST - epublish SO - Sci Rep. 2017 Sep 8;7(1):10995. doi: 10.1038/s41598-017-11316-8.