PMID- 28366471
OWN - NLM
STAT- MEDLINE
DCOM- 20170817
LR  - 20240327
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 293
DP  - 2017 Jul
TI  - Phosphodiesterase-4 inhibition restored hippocampal long term potentiation after 
      primary blast.
PG  - 91-100
LID - S0014-4886(17)30085-7 [pii]
LID - 10.1016/j.expneurol.2017.03.025 [doi]
AB  - Due to recent military conflicts and terrorist attacks, blast-induced traumatic 
      brain injury (bTBI) presents a health concern for military and civilian personnel 
      alike. Although secondary blast (penetrating injury) and tertiary blast 
      (inertia-driven brain deformation) are known to be injurious, the effects of 
      primary blast caused by the supersonic shock wave interacting with the skull and 
      brain remain debated. Our group previously reported that in vitro primary blast 
      exposure reduced long-term potentiation (LTP), the electrophysiological correlate 
      of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) and 
      that primary blast affects key proteins governing LTP. Recent studies have 
      investigated phosphodiesterase-4 (PDE4) inhibition as a therapeutic strategy for 
      reducing LTP deficits following inertia-driven TBI. We investigated the 
      therapeutic potential of PDE4 inhibitors, specifically roflumilast, to ameliorate 
      primary blast-induced deficits in LTP. We found that roflumilast at 
      concentrations of 1nM or greater prevented deficits in neuronal plasticity 
      measured 24h post-injury. We also observed a therapeutic window of at least 6h, 
      but <23h. Additionally, we investigated molecular mechanisms that could elucidate 
      this therapeutic effect. Roflumilast treatment (1nM delivered 6h post-injury) 
      significantly increased total AMPA glutamate receptor 1 (GluR1) subunit 
      expression, phosphorylation of the GluR1 subunit at the serine-831 site, and 
      phosphorylation of stargazin at the serine-239/240 site upon LTP induction, 
      measured 24h following injury. Roflumilast treatment significantly increased 
      PSD-95 regardless of LTP induction. These findings indicate that further 
      investigation into the translation of PDE4 inhibition as a therapy following bTBI 
      is warranted.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Vogel, Edward W 3rd
AU  - Vogel EW 3rd
AD  - Department of Biomedical Engineering, Columbia University, New York, NY 10027, 
      USA.
FAU - Morales, Fatima N
AU  - Morales FN
AD  - Department of Biomedical Engineering, Columbia University, New York, NY 10027, 
      USA.
FAU - Meaney, David F
AU  - Meaney DF
AD  - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, 
      USA.
FAU - Bass, Cameron R
AU  - Bass CR
AD  - Department of Biomedical Engineering, Duke University, Durham, NC 27705, USA.
FAU - Morrison, Barclay 3rd
AU  - Morrison B 3rd
AD  - Department of Biomedical Engineering, Columbia University, New York, NY 10027, 
      USA. Electronic address: bm2119@columbia.edu.
LA  - eng
GR  - R01 NS088176/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20170331
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Aminopyridines)
RN  - 0 (Benzamides)
RN  - 0 (Cyclopropanes)
RN  - 0 (Disks Large Homolog 4 Protein)
RN  - 0 (Dlg4 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, AMPA)
RN  - 0P6C6ZOP5U (Roflumilast)
RN  - DAA13NKG2Q (Papaverine)
RN  - EC 2.7.4.8 (Guanylate Kinases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
RN  - M0TTH61XC5 (ibudilast)
RN  - TE7660XO1C (Glycine)
RN  - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1)
SB  - IM
MH  - Aminopyridines/therapeutic use
MH  - Animals
MH  - Animals, Newborn
MH  - Benzamides/therapeutic use
MH  - Blast Injuries/*pathology
MH  - Cell Death
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4/*metabolism
MH  - Cyclopropanes/therapeutic use
MH  - Disease Models, Animal
MH  - Disks Large Homolog 4 Protein
MH  - Gene Expression Regulation/drug effects
MH  - Glycine/pharmacology
MH  - Guanylate Kinases/metabolism
MH  - Hippocampus/drug effects/*physiology
MH  - In Vitro Techniques
MH  - Long-Term Potentiation/drug effects/*physiology
MH  - Membrane Proteins/metabolism
MH  - Papaverine/pharmacology/therapeutic use
MH  - Phosphodiesterase 4 Inhibitors/pharmacology/therapeutic use
MH  - Pyridines/pharmacology/therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/metabolism
MH  - Time Factors
PMC - PMC6016024
MID - NIHMS975150
OTO - NOTNLM
OT  - Blast injury
OT  - Electrophysiology
OT  - Hippocampus
OT  - In vitro
OT  - Long-term potentiation
OT  - Memory
OT  - Military injury
OT  - Phosphodiesterase
OT  - Therapeutic
OT  - Traumatic brain injury
COIS- Conflict of interest The authors declare no competing financial interests.
EDAT- 2017/04/04 06:00
MHDA- 2017/08/18 06:00
PMCR- 2018/06/25
CRDT- 2017/04/04 06:00
PHST- 2016/11/01 00:00 [received]
PHST- 2017/03/08 00:00 [revised]
PHST- 2017/03/30 00:00 [accepted]
PHST- 2017/04/04 06:00 [pubmed]
PHST- 2017/08/18 06:00 [medline]
PHST- 2017/04/04 06:00 [entrez]
PHST- 2018/06/25 00:00 [pmc-release]
AID - S0014-4886(17)30085-7 [pii]
AID - 10.1016/j.expneurol.2017.03.025 [doi]
PST - ppublish
SO  - Exp Neurol. 2017 Jul;293:91-100. doi: 10.1016/j.expneurol.2017.03.025. Epub 2017 
      Mar 31.