ABSTRACT The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase activity in vitro, could attenuate memory deficits in the mu-p-75 saporin injected mouse model of Alzheimer’s disease (AD). Seventy-one, seven-week old C57/BL6 mice received daily oral intubation of 10, 15, or 20 mg/kg CXB-909, or vehicle (0.5% methylcellulose solution), which continued for 32 days. At postnatal week nine, mice received bilateral intra-cerebroventricular injections of mu-p-75 saporin, or sterile phosphate buffered saline. Seven days after surgery, mice were trained for two days, on a cued-platform version of the Morris water maze task, and then tested on a four-day hidden-platform version, followed by a one-day probe version of this task. Mice injected with mu-p-75 saporin, had increased latency to find the hidden-platform compared to sham mice. Furthermore, mice treated with CXB-909 at the 10, and 15 mg/kg doses, significantly reduced their latency to reach the hidden-platform, compared to vehicle-treated mice given mu-p-75 saporin. These results suggest that CXB-909 can attenuate memory deficits in the mu-p-75 saporin injected mouse model of AD.
Cite this paper
S. Lowrance, J. Matchynski, J. Rossignol, N. Dekorver, M. Sandstrom and G. Dunbar, "CXB-909 Attenuates Cognitive Deficits in the Mu-P-75 Saporin Mouse Model of Alzheimer’s Disease," Neuroscience and Medicine, Vol. 3 No. 1, 2012, pp. 65-68. doi: 10.4236/nm.2012.31010.
 Z. S. Khachaturian, “Diagnosis of Alzheimer’s Disease,” Archives of Neurology, Vol. 42, No. 11, 1985, pp. 1097-1105. doi:10.1001/archneur.1985.04060100083029
 R. T. Bartus, “On Neurodegenerative Diseases, Models, and Treatment Strategies: Lessons Learned and Lessons Forgotten a Generation Following the Cholinergic Hypothesis,” Experimental Neurology, Vol. 163, No. 2, 2000, pp. 495-529. doi:10.1006/exnr.2000.7397
 J. Berger-Sweeney, N. A. Stearns, S. L. Murg, et al., “Selective Immunolesions of Cholinergic Neurons in Mice: Effects on Neuroanatomy, Neuroche-mistry, and Behavior,” Journal of Neuroscience, Vol. 21, No. 20, 2001, pp. 8164-8173.
 P. H. Moreau, B. Cosquer, H. Jeltsch, et al., “Neuroanatomical and Behavioral Effects of a Novel Version of the Cholinergic Immunotoxin mu-p-75-Saporin in Mice”. Hippocampus, Vol. 18, No. 6, 2008, pp. 610-622.
 M. H. Tuszynski, “Intraparenchymal NGF Infusions Rescue Degenerating Cholinergic Neu-rons,” Cell Transplant, Vol. 9, No. 9, 2000, pp. 629-636.
 A. C. Cuello, M. A. Bruno and K. F. Bell, “NGF-Cholinergic Dependency in Brain Aging, MCI and Alzheimer’s Disease,” Current Alzheimers Research, Vol. 4, No. 4, 2007, pp. 351-358. doi:10.2174/156720507781788774
 V. Di Fausto, M. Fiore, P. Tirassa, A. Lambiase and L. Aloe, “Eye Drop NGF Administration Promotes the Recovery of Chemically Injured Cholinergic Neurons of Adult Mouse forebrain,” European Journal of Neuroscience, Vol. 26, No. 9, 2007, pp. 2473-2480.
 H. Kewitz, K. L. Rost, O. Pleul and A. Handke, “Dose-Related Effects of Nerve Growth Factor (NGF) on Choline Acetyltransferase (ChAT), Acetylcholine (ACh) Content and ACh Turnover in the Brain of Newborn Rats,” Neurochemistry International, Vol. 17, No. 2, 1990, pp. 239-244. doi:10.1016/0197-0186(90)90146-K
 A. H. Nagahara, T. Bernot, R. Moseanko, et al., “Long- Term Reversal of Cholinergic Neuronal Decline in Aged Non-Human Primates by Lentiviral NGF Gene Delivery,” Experimental Neurology, Vol 215, No. 1, 2009, pp. 153-159. doi:10.1016/j.expneurol.2008.10.004
 A. Salehi, J. D. Delcroix and D. F. Swaab, “Alzheimer’s Disease and NGF Signaling,” Journal of Neural Transmission, Vol. 111, No. 3, 2004, pp. 323-345.
 G. L. Dunbar, M. I. Sandstrom, J. Rossignol and L. Lescaudron, “Eurotrophic Enhancers as Therapy for Behavioral Deficits in Rodent Models of Huntington’s Disease: Use of Gangliosides, Substituted Pyrimidines, and Mesenchymal Stem Cells,” Behavioral Cognitive Neuroscience Reviews, Vol. 5, No. 2, 2006, pp. 63-79.
 J. A. Fyfe, L. M. Beauchamp and A. O. Caggiano, “P544 Amplifies the Effects of Nerve Growth Factor on Cell Differentiation and Is Neuroprotective,” Drug Development Research, Vol. 62, No. 1, 2004, pp. 49-59.
 M. A. Geist, C. Volbracht, J. Podhorna, et al., “Wide Spectrum Modulation by KP-544 in Models Relevant for Neuronal Survival,” Vol. 16, No. 6, 2007, pp. 571-575.
 T. A. Krenitsky, J. Dillberger, E. Zotova, et al., “KP544, a Nerve Growth Factor Amplifier: Pharmacokinetics, Safety, and Efficacy in the Rat,” Vol. 62, 2004, pp. 50-60.
 N. D. Dey, A. J. Boersen, R. A. Myers, et al., “The Novel Substituted Pyrimidine, KP544, Reduces Motor Deficits in the R6/2 Transgenic Mouse Model of Huntington’s Disease,” Restorative Neurology and Neuroscience, Vol. 25, No. 5-6, 2007, pp. 485-492.
 R. Morris “Developments of a Water-Maze Procedure for Studying Spatial Learning in the Rat,” Journal of Neuro- science Methods, Vol. 11, No. 1, 1984, pp. 47-60.
 F. Papaleo, J. L. Silverman, J. Aney, et al., “Working Memory Deficits Increased Anxiety-Like Traits and Seizure Susceptibility in BDNF Over-expressing Mice,” Learning & Memory, Vol. 18, No. 8, 2011, pp. 534-544.
 A. M. Fortress, M. Buhusi, K. L. Helke and A. C. Granholm, “Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats,” Journal of Aging Research, Vol. 2011, 2011, p. 1-10.