NM  Vol.2 No.4 , December 2011
The PARF Antagonist AChE Inhibitor PMS777 Attenuates LPS-Induced Acute Neuroinflammation
Abstract: When injected into the fourth ventricle, the proinflammagen lipopolysaccharide (LPS) induces acute neuroinflammation in the whole brain of rats. The new compound PMS777 is a novel platelet-activating factor receptor (PAFR) antagonist and acetylcholinesterase (AChE) inhibitor. The current study determined whether PMS777 could provide neuroprotection from the cytotoxic effects associated with LPS-induced neuroinflammation. Acute LPS infusions impaired recognition in rats as measured by the Morris water maze. In addition, LPS infusions decreased the number of AChE positive cells, and increased the number of OX-42 immunoreactive microglia and GFAP immunoreactive astrocytes in the hippocampus, the cortex and the basal nuclei. Furthermore, acute infusions of LPS also impaired organelles associated with protein synthesis. Peripheral administration of PMS777 (i.e., intraperitoneal injection) protected against the impairment in recognition, and attenuated the cytotoxic effects of the acute inflammatory processes upon cholinergic cells, microglia, astrocytes and ultrastructure of hippocampal cells. Here, we propose that the cytotoxic effects of acute neuroinflammation may involve the release of PAF and loss of cholinergic neurons, and this mechanism leads to neuronal dysfunction and spatial memory impairment. The PAFR antagonist inhibitor and AChE inhibitor PMS777 could provide neuroprotection from the cytotoxic effects induced by LPS.
Cite this paper: nullJ. Hu, J. Li, Z. Wei, H. Gu, B. Shao, D. Long and H. Chen, "The PARF Antagonist AChE Inhibitor PMS777 Attenuates LPS-Induced Acute Neuroinflammation," Neuroscience and Medicine, Vol. 2 No. 4, 2011, pp. 355-362. doi: 10.4236/nm.2011.24047.

[1]   H. Dou, J. Morehead, J. Bradley, et al., “Neuropathologic and Neuroinflammatory Activities of HIV-1-Infected Human Astrocytes in Murine Brain,” Glia, Vol. 54, No. 2, 2006, pp. 81-93. doi:10.1002/glia.20358

[2]   H. Dou, J. D. Kingsley, R. L. Mosley, et al., “Neuroprotective Strategies for HIV-1 Associated Dementia,” Neurotoxicity Research, Vol. 6, No. 7-8, 2004, pp. 503-521. doi:10.1007/BF03033447

[3]   J. J. Hoozemans, R. Veerhuis, I. Janssen, et al., “Interleukin-1beta Induced Cyclooxygenase 2 Expression and Prostaglandin E2 Secretion by Human Neuroblastoma Cells: Implications for Alzheimer’s Disease,” Experimental Gerontology, Vol. 36, No. 3, 2001, pp. 559-570. doi:10.1016/S0531-5565(00)00226-6

[4]   R. M. Bluthe, R. Dantzer and K. W. Delley, “Effects of Interleukin-1 Receptor Antagonist on the Behavioral Effects of Lipopolysaccharide in Rat,” Brain Research, Vol. 573, No. 2, 1992, pp. 318-320. doi:10.1016/0006-8993(92)90779-9

[5]   N. Quan, S. K. Sundar and J. M. Weiss, “Induction of Interleukin-1 in Various Brain Regions after Peripheral and Central Injections of Lipopolysaccharide,” Journal of Neuroimmunology, Vol. 49, No. 1-2, 1994, pp. 125-134. doi:10.1016/0165-5728(94)90188-0

[6]   C. Sherwin and R. Fern, “Acute Lipopolysaccharide-Mediated Injury in Neonatal White Matter Glia: Role of TNF-alpha, IL-1beta, and Calcium,” Journal of Immunology, Vol. 175, No. 1, 2005, pp. 155-161.

[7]   W. E. Zink, E. Anderson, J. Boyle, et al., “Impaired Spatial Cognition and Synaptic Potentiation in a Murine Model of Human Immunodeficiency Virus Type 1 Encephalitis,” Journal of Neuroscience, Vol. 22, No. 6, 2002, pp. 2096-2105.

[8]   Y. Huang, N. Erdmann, J. Zhao, et al., “The Signaling and Apoptotic Effects of TNF-Related Apoptosis-Inducing Ligand in HIV-1 Associated Dementia,” Neurotoxicity Research, Vol. 8, No. 1-2, 2005, pp. 135-148. doi:10.1007/BF03033825

[9]   H. W. Beatrice, G. V. Maria and L. W. Gary, “Behavioral and Ultrastructural Changes Induced by Chronic Beuroinflammation in Young Rats,” Brain Research, Vol. 859, 2000, pp. 157-166. doi:10.1016/S0006-8993(00)01999-5

[10]   B. Hauss-Wegizyniak, L. Lukovic, M. Bigaud, et al., “Brain Inflammatory Response Induced by Intracerebroventricular Infusion of Lipopolysaccharide: An Immunohistochemical Study,” Brain Research, Vol. 794, No. 2, 1998, pp. 211-224. doi:10.1016/S0006-8993(98)00227-3

[11]   M. F. Ezoulin, C. Z. Dong, Z. Liu, J. Li, H. Z. Chen, et al., “Study of PMS777, a New Type of Acetylcholinesterase Inhibitor, in Human HepG2 Cells, Comparison with Tacrine and Galanthamine on Oxidative Stress and Mitochondrial Impairment,” Toxicology in Vitro, Vol. 20, No. 6, 2006, pp. 824-831. doi:10.1016/j.tiv.2006.01.002

[12]   J. Li, H. Huang, J. M. Miezan Ezoulin, et al., “Pharmacological Profile of PMS777, a New AChE Inhibitor with PAF Antagonistic Activity,” International Journal of Neuropsychopharmacology, Vol. 10, No. 1, 2007, pp. 21-29. doi:10.1017/S1461145705006425

[13]   M. J. Ezoulin, J. Li, G. Wu, et al., “Differential Effect of PMS777, a New Type of Acetylcholinesterase Inhibitor, and Galanthamine on Oxidative Injury Induced in Human Neuroblastoma SK-N-SH Cells,” Neuroscience Letters, Vol. 389, No. 2, 2005, pp. 61-65. doi:10.1016/j.neulet.2005.07.026

[14]   R. L. Richardson, E. M. Kim, T. Gardiner and E. O’Hare “Chronic Intracerebroventricular Infusion of Lipopolysaccharide: Effects of Ibuprofen Treatment and Behavioural and Histopathological Correlates,” Behavioural Pharmacology, Vol. 16, No. 7, 2005, pp. 531-541. doi:10.1097/01.fbp.0000179278.03868.96

[15]   Y. Persidsky, J. Limonges, J. Rasmussen, et al., “Reduction in Glial Immunity and Neuropathology by a PAF Antagonist and an MMP and TNFalpha Inhibitor in SCID Mice with HIV-1 Encephalitis,” Journal of Neuroimmunology, Vol. 114, No. 1-2, 2001, pp. 57-68. doi:10.1016/S0165-5728(00)00454-9

[16]   T. Pung, B. Klein, D. Blodgett, et al., “Examination of Concurrent Exposure to Repeated Stress and Chlorpyrifos on Cholinergic, Glutamatergic, and Monoamine Neurotransmitter Systems in Rat Forebrain Regions,” International Journal of Toxicology, Vol. 25, No. 1, 2006, pp. 65-80. doi:10.1080/10915810500527119

[17]   M. Hartlage-Rubsamen, R. Lemke and R. Schliebs, “Interleukin-1beta, Inducible Nitric Oxide Synthase, and Nuclear Factor-KappaB Are Induced in Morphologically Distinct Microglia after Rat Hippocampal Lipopolysaccharide/Interferon-Gamma Injection,” Journal of Neuroscience Research, Vol. 57, No. 3, 1999, pp. 388-398. doi:10.1002/(SICI)1097-4547(19990801)57:3<388::AID-JNR11>3.0.CO;2-2

[18]   C. G. Ballard, “Advances in the Treatment of Alzheimer’s Disease: Benefits of Dual Cholinesterase Inhibition,” European Neurology, Vol. 47, No. 1, 2002, pp. 64-70. doi:10.1159/000047952

[19]   S. H. Wang, J. Li and M. Y. Geng, “Inflammatory Pathology and the Anti-Inflammation of Saccharide Substances in Alzheimer’s Disease,” Sheng Li Ke Xue Jin Zhan, Vol. 36, No. 1, 2005, pp. 67-70.

[20]   M. B. H. Youdim and J. J. Buccafusco, “Multi-Functional Drugs for Various CNS Targets in the Treatment of Neurodegenerative Disorders,” Trends in Pharmacology Science, Vol. 26, 2005, pp. 27-35. doi:10.1016/