Ro 20-1724 Ameliorates Learning Deficit and Long-Term Memory Impairment Secondary to Repeated Ketamine Anesthesia in Young Rats

Sheng Peng, Hai Yan Sun, Gong-Jian Liu, Xia Yang, George Mychaskiw II

Department of Anesthe- siology, Tengzhou Central People’s Hospital, Tengzhou, China;.
Department of Anesthesiology, Nemours Children’s Hospital, Or- lando, USA..
Department of Anesthesiology, Soochow University, Wuxi, China;.
Department of Anesthesiology, Traditional Chinese Medicine Hospital of Zhang Jiang, China;.
Department of Anesthesiology, Xuzhou Medical College, Xuzhou, China;.

DOI: 10.4236/nm.2013.43025                

Abstract

To investigate effects and possible mechanism of Ro 20-1724, a PDE4 inhibitor, on long-time learning and memory ability following repeated ketamine exposure in immature rats. Methods: Sixty 21-day-old SD rats were randomly divided into five groups (n = 12): C: Normal control group, S: Saline control group, K: Ketamine, K + Ro: Ketamine + Ro 20-1724, K + E: Ketamine + ethanol vehicle. Ro 20-1724 (0.5 mg·kg^-1) or its vehicle (ethanol) was administered intraperitoneally 30 minutes after ketamine anesthesia (70 mg·kg^-1), daily for seven days. Nine weeks after birth, the Morris water maze was used to test the ability of learning and spatial localization memory on the rats. Following behavioral testing, animals’ hippocampi were removed for Western blot and electron microscopic examination. Results: In the Morris water maze test, compared with controls, the escape latency in groups exposed to ketamine or ketamine plus the ethanol vehicle were significantly prolonged (P < 0. 05), the ability of spatial localization was lower (P < 0.05), and the expression of p-CREB in the hippocampus was also decreased (P < 0.05), while there was no significant difference between control groups and animals treated with Ro 20-1724 following ketamine exposure (P > 0.05). Electron microscopy demonstrated degenerative changes in hippocampal neurons of animals repetitively exposed to 70 mg·kg^-1 Ketamine, which was ameliorated by Ro 20-1724 (0.5 mg·kg^-1). Conclusion: The PDE-4 inhibitor Ro 20-1724 (0.5 mg·kg^-1

Keywords

Research; Animal; Anesthesia; Neurodegeneration; Phsophodisterase Inhibitors; Memory

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	J. H. Krystal, W. Abi-Saab, E. Perry, D. C. D’Souza, N. Liu, R. Gueorguieva, L. McDougall, T. Hunsberger, A. Belger, L. Levine and A. Breier, “Preliminary Evidence of Attenuation of the Disruptive Effects of the NMDA Glutamate Receptor Antagonist Ketamine on Working Memory by Pretreatment with the Group II Metabolic Glutamate Receptor Agonist LY354740 in Healthy Human Subjects,” Psychopharmacology, Vol. 179, No. 1, 2005, pp. 303-309. doi:10.1007/s00213-004-1982-8
[2]	C. J. Morgan, A. Mofeez, B. Brandner and H. V. Curran, “Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers,” Neuropsychopharmacology, Vol. 29, 2004, pp. 208-218. doi:10.1038/sj.npp.1300342
[3]	J. H. Krystal, A. Bennett, D. Abi-Saab, A. Belger, L. P. Karper, D. C. D’Souza, D. Lipschitz, A. Abi-Dargham and D. S. Charney, “Dissociation of Ketamine Effects on Rule Acquisition and Rule Implementation: Possible Relevance to NMDA Receptor Contributions to Executive Cognitive Functions,” Biological Psychiatry, Vol. 47, No. 2, 2000, pp. 137-143. doi:10.1016/S0006-3223(99)00097-9
[4]	S. Peng, Y. Zhang, B. Ren, J. Zhang and J. H. Wang, “Effect of Ketamine Administration on Memory Consolidation, p-CREB and c-fos Expression in the Hippocampal Slices of Minor Rats,” Molecular Biology Reports, Vol. 38, No. 4, 2011, pp. 2401-2407. doi:10.1007/s11033-010-0374-x
[5]	S. Peng, Y. Zhang, H. Wang, B. Ren and J. Zhang, “Anesthetic Ketamine Counteracts Repetitive Mechanical Stress-Induced Learning and Memory Impairment in Developing Mice,” Molecular Biology Reports, Vol. 38, No. 7, 2011, pp. 4347-4351. doi:10.1007/s11033-010-0561-9
[6]	C. G. Vecsey, G. S. Baillie, D. Jaganath, R. Havekes, A. Daniels, M. Wimmer, T. Huang, K. M. Brown, X. Y. Li, G. Descalzi, S. S. Kim, T. Chen, Y. Z. Shang, M. Zhuo, M. D. Houslay and T. Abel, “Sleep Deprivation Impairs cAMP Signalling in the Hippocampus,” Nature, Vol. 461, No. 7267, 2009, pp. 1122-1125. doi:10.1038/nature08488
[7]	C. Wang, X. M. Yang, Y. Y. Zhuo, H. Zhou, H. B. Lin, Y. F. Cheng, J. P. Xu and H. T. Zhang, “The Phosphodiesterase-4 Inhibitor Rolipram Reverses Aβ-Induced Cognitive Impairment and Neuroinflammatory and Apoptotic Responses in Rats,” International Journal of Neuropsychopharmacology, Vol. 15, No. 6, 2012, pp. 749-766. doi:10.1017/S1461145711000836
[8]	V. Sharma, A. Bala, R. Deshmukh, K. L. Bedi and P. L. Sharma, “Neuroprotective Effect of RO-20-1724-a Phosphodiesterase4 Inhibitor against Intracerebroventricular Streptozotocin Induced Cognitive Deficit and Oxidative Stress in Rats,” Pharmacology Biochemistry and Behavior, Vol. 101, No. 2, 2012, pp. 239-245. doi:10.1016/j.pbb.2012.01.004
[9]	L. X. Li, Y. F. Cheng, H. B. Lin, C. Wang, J. P. Xu and H. T. Zhang, “Prevention of Cerebral Ischemia-Induced Memory Deficits by Inhibition of Phosphodiesterase-4 in Rats,” Metabolic Brain Disease, Vol. 26, No. 1, 2011, pp. 37-47. doi:10.1007/s11011-011-9235-0
[10]	V. K. Sharma, “Morris Water Maze: A Versatile Cognitive Tool,” Journal of Bioscience and Technology, Vol. 1, 2009, pp. 15-19.
[11]	R. Slamberová, M. Pometlová, L. Syllabová and M. Mancusková, “Learning in the Place Navigation Task, Not the New-Learning Task, Is Altered by Prenatal Methamphetamine Exposure,” Developmental Brain Research, Vol. 157, No. 2, 2005, pp. 217-219. doi:10.1016/j.devbrainres.2005.04.005
[12]	R. G. M. Morris, “Morris Water Maze,” 2012. http://www.scholarpedia.org/article/Morris_water_maze
[13]	R. E. Featherstone, Y. Liang, J. A. Saunders, V. M. Tatard-Leitman, R. S. Ehrlichman and S. J. Siegel, “Subchronic Ketamine Treatment Leads to Permanent Changes in EEG, Cognition and the Astrocytic Glutamate Transporter EAA T2 in Mice,” Neurobiology of Disease, Vol. 47, No. 3, 2012, pp. 338-346. doi:10.1016/j.nbd.2012.05.003
[14]	M. G. Paule, M. Li, R. R. Allen, F. Liu, X. Zou, C. Hotchkiss, J. P. Hanig, T. A. Patterson, W. Slikker Jr. and C. Wang, “Ketamine Anesthesia during the First Week of Life Can Cause Long-Lasting Cognitive Deficits in Rhesus Monkeys,” Neurotoxicology and Teratology, Vol. 33, No. 2, 2011, pp. 220-230. doi:10.1016/j.ntt.2011.01.001
[15]	E. R. Kandel and J. H. Schwartz, “Molecular Biology of Learning: Modulation of Transmitter Release,” Science, Vol. 29, No. 4571, 1982, pp. 433-443. doi:10.1126/science.6289442
[16]	E. R. Kandel, “The Molecular Biology of Memory Storage: A Dialogue between Genes and Synapses,” Science, Vol. 294, No. 5544, 2001, pp. 1030-1038. doi:10.1126/science.1067020
[17]	X. Wang, L. Liu, S. Xia, C. Feng and A. Guo, “Relationship between Visual Learning/Memory Ability and Brain cAMP Level in Drosophila,” Science in China Series C: Life Sciences, Vol. 4, 1998, pp. 503-511. doi:10.1007/BF02882888
[18]	Y. F. Li, Y. Huang, S. L. Amsdell, L. Xiao, J. M. O’Donnell and H. T. Zhang, “Antidepressant-and Anxiolytic-Like Effects of the Phosphodiesterase-4 Inhibitor Rolipram on Behavior Depend on Cyclic AMP Response Element Binding Protein-Mediated Neurogenesis in the Hippocampus,” Neuropsychopharmacology, Vol. 34, 2009, pp. 2404-2419. doi:10.1038/npp.2009.66
[19]	D. Jancic, M. Lopez de Armentia, L. M. Valor, R. Olivares and A. Barco, “Inhibition of cAMP Response Element-Binding Protein Reduces Neuronal Excitability and Plasticity, and Triggers Neurodegeneration,” Cerebral Cortex, Vol. 19, No. 11, 2009, pp. 2535-2547. doi:10.1093/cercor/bhp004
[20]	B. S. Skalhegg and K. Tasken, “Specificity in the cAMP/ PKA Signaling Pathway. Differential Expression Regulation, and Subcellular Localization of Subunit of PKA,” Frontiers in Bioscience, Vol. 5, 2000, pp. 678-693. doi:10.2741/Skalhegg
[21]	O. V. Vitolo, A. Sant’Angelo, V. Costanzo, F. Battaglia, O. Arancio and M. Shelanski, “Amyloid β-Peptide Inhibition of the PKA/CREB Pathway and Long-Term Potentiation: Reversibility by Drugs That Enhance cAMP Signaling,” Proceedings of the National Academy of Sciences of USA, Vol. 99, No. 20, 2002, pp. 13217-13221. doi:10.1073/pnas.172504199
[22]	A. Ghavami, W. D. Hirst and T. J. Novak, “Selective Phosphodiesterase (PDE)-4 Inhibitors: A Novel Approach to Treating Memory Deficit?” Drugs in R&D, Vol. 7, 2006, pp. 63-71. doi:10.2165/00126839-200607020-00001
[23]	V. Boswell-Smith, M. Cazzola and C. P. Page, “Are Phosphodiesterase 4 Inhibitors Just More Theophylline?” The Journal of Allergy and Clinical Immunology, Vol. 117, No. 6, 2006, pp. 1237-1243. doi:10.1016/j.jaci.2006.02.045
[24]	M. C. Yu, J. H. Chen, C. Y. Lai, C. Y. Han and W. C. Ko, “Luteolin, a Non-Selective Competitive Inhibitor of Phosphodiesterases 1-5, Displaced [3H]-Rolipram from High-Affinity Rolipram Binding Sites and Reversed Xylazine/ Ketamine-Induced Anesthesia,” European Journal of Pharmacology, Vol. 627, No. 1-3, 2010, pp. 269-275. doi:10.1016/j.ejphar.2009.10.031