title: Phosphodiesterase inhibition rescues chronic cognitive deficits induced by traumatic brain injury.
abstract: Traumatic brain injury (TBI) modulates several cell signaling pathways in the hippocampus critical for memory formation. Previous studies have found that the cAMP-protein kinase A signaling pathway is downregulated after TBI and that treatment with a phosphodiesterase (PDE) 4 inhibitor rolipram rescues the decrease in cAMP. In the present study, we examined the effect of rolipram on TBI-induced cognitive impairments. At 2 weeks after moderate fluid-percussion brain injury or sham surgery, adult male Sprague Dawley rats received vehicle or rolipram (0.03 mg/kg) 30 min before water maze acquisition or cue and contextual fear conditioning. TBI animals treated with rolipram showed a significant improvement in water maze acquisition and retention of both cue and contextual fear conditioning compared with vehicle-treated TBI animals. Cue and contextual fear conditioning significantly increased phosphorylated CREB levels in the hippocampus of sham animals, but not in TBI animals. This deficit in CREB activation during learning was rescued in TBI animals treated with rolipram. Hippocampal long-term potentiation was reduced in TBI animals, and this was also rescued with rolipram treatment. These results indicate that the PDE4 inhibitor rolipram rescues cognitive impairments after TBI, and this may be mediated through increased CREB activation during learning.
authors.affiliation: Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Titus
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakurai
authors.forename: Yuan
authors.initials: Y
authors.lastname: Kang
authors.forename: Concepcion
authors.initials: C
authors.lastname: Furones
authors.forename: Stanislava
authors.initials: S
authors.lastname: Jergova
authors.forename: Rosmery
authors.initials: R
authors.lastname: Santos
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sick
authors.forename: Coleen M
authors.initials: CM
authors.lastname: Atkins
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002908:Chronic Disease; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D058988:Phosphodiesterase 4 Inhibitors; D000242:Cyclic AMP; D020889:Rolipram