title: Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress.
abstract: Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphologic, and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze, novel object recognition, and location tasks (object recognition test and/or object location test), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase; MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a protein kinase G inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP, or KT5823. PDE2 inhibition reduced stress-induced extracellular-regulated protein kinase activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and CREB phosphorylation) and plasticity-related proteins (e.g., Egr-1 and brain-derived neurotrophic factor). Pretreatment with inhibitors of NMDA, CaMKII, neuronal nitric oxide synthase, and protein kinase G (or protein kinase A) blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related NMDAR-CaMKII-cGMP/cAMP signaling.
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address: yxu9@buffalo.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Pan
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu Province, China.
authors.forename: Lianshu
authors.initials: L
authors.lastname: Ding
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Ruan
authors.affiliation: Department of Psychology, West Virginia University, Morgantown, WV, USA.
authors.forename: Miranda
authors.initials: M
authors.lastname: Reed
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, WV, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Klabnik
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lin
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.affiliation: Brain Institute, Department of Pharmacy, School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, WV, USA.
authors.forename: Hanting
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics*; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology*; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008813:Mice, Inbred ICR; D009416:Nerve Regeneration / Q000187:drug effects* / Q000235:genetics*; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D000242:Cyclic AMP; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D006152:Cyclic GMP
keywords: Bay 60-7550; Cognition; Neuroplasticity; PDE2; Stress