Xian-Feng Huang1, Wen-Tao Jiang1, Li Liu1, Fang-Chen Song1, Xia Zhu2, Gui-Lan Shi3, Shu-Ming Ding1, Heng-Ming Ke4, Wei Wang5, James M O'Donnell6, Han-Ting Zhang7, Hai-Bin Luo8, Yi-Qian Wan9, Guo-Qiang Song1, Ying Xu6. 1. School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu, China. 2. Department of Pharmacology, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China. 3. Zibo Vocational Institute, Zibo, Shandong, China. 4. Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA. 5. Department of Chemistry, University of New Mexico, Albuquerque, NM, USA. 6. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA. 7. Departments of Behavioral Medicine & Psychiatry and Physiology, Pharmacology& Neuroscience, The Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, USA. 8. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. 9. School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, China.
Abstract
BACKGROUND: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. METHODS: We examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice. RESULTS: C36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp-8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. CONCLUSION: Our results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.
BACKGROUND: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. METHODS: We examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice. RESULTS: C36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp-8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. CONCLUSION: Our results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.
Authors: Peter Filipcik; Petr Novak; Boris Mravec; Katarina Ondicova; Gabriela Krajciova; Michal Novak; Richard Kvetnansky Journal: Cell Mol Neurobiol Date: 2012-01-06 Impact factor: 5.046
Authors: F Josef van der Staay; Kris Rutten; Lars Bärfacker; Jean Devry; Christina Erb; Heike Heckroth; Dagmar Karthaus; Adrian Tersteegen; Marja van Kampen; Arjan Blokland; Jos Prickaerts; Klaus G Reymann; Ulrich H Schröder; Martin Hendrix Journal: Neuropharmacology Date: 2008-07-12 Impact factor: 5.250
Authors: Boris Birmaher; David Brent; William Bernet; Oscar Bukstein; Heather Walter; R Scott Benson; Allan Chrisman; Tiffany Farchione; Laurence Greenhill; John Hamilton; Helene Keable; Joan Kinlan; Ulrich Schoettle; Saundra Stock; Kristin Kroeger Ptakowski; Jennifer Medicus Journal: J Am Acad Child Adolesc Psychiatry Date: 2007-11 Impact factor: 8.829