title: Phosphodiesterase-4 inhibition restored hippocampal long term potentiation after primary blast.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Vogel
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
authors.forename: Fatima N
authors.initials: FN
authors.lastname: Morales
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27705, USA.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Bass
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Electronic address: bm2119@columbia.edu.
authors.forename: Barclay
authors.initials: B
authors.lastname: Morrison
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000627:therapeutic use; D001753:Blast Injuries / Q000473:pathology*; D016923:Cell Death; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003521:Cyclopropanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000494:pharmacology; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology / Q000627:therapeutic use; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D013997:Time Factors; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes; D000076122:Disks Large Homolog 4 Protein; D005998:Glycine; D051528:Guanylate Kinases; D008565:Membrane Proteins; D010208:Papaverine; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; D018091:Receptors, AMPA; C501447:Dlg4 protein, mouse; C424423:Roflumilast; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
keywords: Blast injury; Electrophysiology; Hippocampus; In vitro; Long-term potentiation; Memory; Military injury; Phosphodiesterase; Therapeutic; Traumatic brain injury