title: Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice.
abstract: Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.
authors.affiliation: 1] Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China [2] State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica &Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Wang
authors.affiliation: 1] Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China [2] Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Yang
authors.affiliation: Department of Anatomy, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: Liu
authors.affiliation: School of Pharmacy &Pharmaceutical Sciences, The State University of New York at Buffalo, New York, NY 14260, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilson
authors.affiliation: School of Pharmacy &Pharmaceutical Sciences, The State University of New York at Buffalo, New York, NY 14260, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: O'Donnell
authors.affiliation: Departments of Behavioral Medicine &Psychiatry and Physiology &Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV26506, USA.
authors.forename: Han-Ting
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000188:drug therapy / Q000209:etiology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D058988:Phosphodiesterase 4 Inhibitors; D034741:RNA, Small Interfering; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D003345:Corticosterone