NM  Vol.2 No.2 , June 2011
A Nucleotide-based Drug Protects Against Glutamate- and MPP+- Induced Neurotoxicity
Abstract: Nucleo CMP Forte® is a nucleotide-based drug consisting of cytidinemonophosphate, uridinemonophosphate, uridin-ediphosphate and uridinetriphosphate. It has been prescribed for peripheral nervous system disorders, such as lum-bosciatalgia, diabetic or alcoholic polyneuropathy, or trigeminal neuralgia. Its effects on brain pathologies has re-ceived little attention. We examined its neuroprotective effects on cell toxicity induced by glutamate excitotoxicity or by 1-methyl-4-phenyl-pyridinium (MPP+), an in vitro cell model of Parkinson’s disease. We used the human dopaminergic cell line SH-SY5Y and a primary culture of rat cortical cells pre-treated with the drug for 24 hours and then exposed to MPP+ or glutamate at a range of concentrations. Cell viability was measured at different times. Nucleo CMP Forte® pre-treatment significantly increased the rate of cell division in SH-SY5Y cells, as well as the synthesis of triglycerides and phospholipids. More interestingly, drug pre-treatment significantly reduced MPP+- and glutamate-induced cell death in SH-SY5Y cells and in rat cortical cells. These results indicate that the nucleotides included in Nucleo CMP Forte® are promising therapeutic molecules for the prevention of neuronal death in brain caused by focal ischemia, Parkinson’s disease or other neurodegenerative pathologies.
Cite this paper: nullA. Gella, T. Martiañez, A. Lamarca and C. Gutierrez, "A Nucleotide-based Drug Protects Against Glutamate- and MPP+- Induced Neurotoxicity," Neuroscience and Medicine, Vol. 2 No. 2, 2011, pp. 154-160. doi: 10.4236/nm.2011.22022.

[1]   D.W. Choi, S.M. Rothman, “The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death” Neurosci, Vol. 13, 1990, pp. 171-182.

[2]   R.L. Hayes, L.W. Jenkins, BG. Lyeth, “Neurotransmitter-mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids” J TraumaSuppl, Vol. 1, 1992, pp. S173-S187.

[3]   S.M. Rothman, J.W. Olney, “Excitotoxicity and the NMDA receptor--still lethal after eight years” Trends Neurosci, Vol. 10,1995, pp. 299-302.

[4]   B.B. Meldrum, J. Garthwaita, “Excitatory amino acid neurotoxicity and neurodegenerative disease” Trends PharmacolSci, Vol. 11, No. 9,1990, pp. 379-387.

[5]   D.W. Choi, “Enhancement of outward potassium current may participate in beta-amyloid peptide-induced cortical neuronal death” Neuron, Vol. 1, 1998, pp. 623-634.

[6]   Y. Zhang, B.R. Bhavnani, “Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens” BMC Neurosci, Vol.7, 2006,pp. 49.

[7]   M.J. Zigmond, E.M. Stricker, “Animal models of parkinsonism using selective neurotoxins: clinical and basic implications” Int Rev Neurobiol, Vol. 31,1989, pp. 1-79.

[8]   O. Eberhardt, J.B. Schulz, “Apoptotic mechanisms and antiapoptotic therapy in the MPTP model of Parkinson's disease” ToxicolLett, Vol. 139,2003,pp. 135-151.

[9]   V. Gallai, G. Mazzotta, S. Montesi, P. Sarchelli, F. Del Gatto, “Effects of uridine in the treatment of diabetic neuropathy: an electrophysiological study”ActaNeurol Scand, Vol. 86, No.1, 1992, pp. 3-7.

[10]   L. Cartier, J.L. Castillo, R. Verdugo, “Effect of the Nucleus CMP forte in 46 patients with progressive spastic paraparesis. Randomized and blind study” Rev Med Chil, Vol. 124, No. 5,1996, pp. 583-587.

[11]   C. Kretschmar, S. Kaumeier, W. Hasse, “Medicamentous therapy of alcoholic polyneuropathy. Randomized double-blind study comparing 2 vitamin B preparations and a nucleotide preparation” Fortschr Med, Vol. 114, No. 32, 1996,pp.439-443.

[12]   B. Watting, G. Schalow, F. Heydenreich, R. Warzok, J. Cervós-Navarro “Enhancement of nerve fibre regeneration by nucleotides after peripheral nerve crush damage” Electrophysiologic and morphometric investigations. Arzeinmittelforshung, Vol. 42, 1992, pp.1075-1078.

[13]   W. Araki and R.J. Wurtman, “How is membrane phospholipid biosynthesis controlled in neural tissues?”J Neurosci Res, Vol. 51, No. 6,1998, pp. 667-674.

[14]   J.R. Marszalek, H.F. Lodish, “Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you” Annu Rev Cell Dev Biol, Vol. 21, 2005, pp. 633-657.

[15]   S.I. Rapoport, “In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling” J Mol Neurosci, Vol. 16, 2001, pp. 234-261.

[16]   E.S. Haugaard, K.B. Frantz, N. Haugaard, “Effect of uridine on cellular UTP and glycogen synthesis in skeletal muscle: stimulation of UTP formation by insulin” Proc NatlAcadSci USA, Vol. 74, No. 6,1977, pp. 2339-2342.

[17]   N.N. Suzuki, K. Koizumi, M. Fukushima, A. Matasuda, F. Inagaki, “Structural basis for the specificity, catalysis, and regulation of human uridine-cytidinekinase”Structure, Vol. 12,2004, pp. 751-764.

[18]   A. Gella, J. Ponce, R. Cussó, N. Durany, “Effect of the nucleotides CMP and UMP on exhaustion in exercise rats”J Physiol Biochem, Vol. 64, No.1,2008, pp. 9-17.

[19]   M. Okada, T. Nakagawa, M. Minami, M. Satoh, “Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats”J Pharmacol Exp Ther, Vol. 303, No. 1,2002, pp. 66-73.

[20]   LA. Teather, RJ. Wurtman, “Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats”J Nutr,Vol.136, No.11,2006, pp. 2834-2837.

[21]   T. Sakamoto, M. Cansev, RJ. Wurtman, “Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus”Brain Res, Vol. 28, 2007, pp.50-59.

[22]   L. Wang, MA. Albrecht, R.J. Wurtman, “Dietary supplementation with uridine-5'-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat”Brain Res, Vol. 1133, No. 1,2007, pp. 42-48.

[23]   M.L. Tian, Z. Zou, H.B. Yuan, CC. Wang, Q.F. Zhu, H.T. Xu, X. Gao, XY. Shi, “Uridine 5'-triphosphate (UTP) protects against cerebral ischemia reperfusion injury in rats”Neurosci Lett, Vol. 465, No. 1,2009, pp. 55-60.

[24]   M.B Hansen, SE. Nielsen, K. Berg, “Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill” J Immunol Methods, Vol. 119, No. 2,1989, pp. 203-210.

[25]   S.M. Weissman, “Human pyrimidine metabolism”JAMA, Vol. 195, No. 1,1966, pp. 27-30.

[26]   D. Lecca, S. Ceruti, “Uracil nucleotides: from metabolic intermediates to neuroprotection and neuroinflammation” Biochemical Pharmacology, Vol. 75,2008, pp. 1869-1881.

[27]   W. Fischer, U. Krügel, “P2Y receptors: focus on structural, pharmacological and functional aspects in the brain”Curr Med Chem, Vol. 14, No. 23,2007, pp. 2429-1455.

[28]   A. Brunschweiger, CE. Müller, “P2 receptors activated by uracil nucleotides--an update.” Curr Med Chem, Vol.13, No. 3, 2006, pp. 289-312.

[29]   H.R. Xie, LS. Hu, G.Y. Li, “SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson's disease”Chin Med J, Vol. 123, No. 8, 2010, pp. 1086-1092.

[30]   A. Cuppelo, A. Dierich, P. Mandel, M. Wintzerith, “In vitro protein synthesis activity of poly(A) RNA from neuroblastoma cells” Neurochem Res, Vol. 5,1980, pp. 271-279.

[31]   T. Ming-Tzeu, L. Shue-Feno, W. Chuan-Chawng, C. Chin-Sung, C.H. Chi-Tso, L. Chih-Chung, Y. Chuen-Mang, “P2Y2 receptor mediated proliferation of C6 glioma cells via activation of Ras/Raf/MEK/MAPK pathway” Br J Pharmacol, Vol. 129, No. 7,2000, pp. 1481-1489.

[32]   J.T. Nearg, Y. Kang, Y. Bu, E. Yu, K. Akong, C.M. Peters, “ Mitogenic signaling by ATP/P2Y purinergic receptors in astrocytes: involvement of a calcium-independent protein kinase C, extracellular signal-regulated protein kinase pathway distinct from the phosphatidylinositol-specific phospholipase C/calcium pathway” JNeuroscience, Vol. 19, No. 11, 1999, pp. 4211-4220.

[33]   F. Cavaliere, V. Nestola, S. Amadio, N. D'Ambrosi, DF. Angelini, G. Sancesario, G. Bernardi, C. Volonté, “The metabotropic P2Y4 receptor participates in the commitment to differentiation and cell death of human neuroblastoma SH-SY5Y cells”Neurobiol Dis., Vol. 18, No. 1,2005,pp. 100-109.

[34]   J. Milosevic, A. Brandt, U. Roemuss, A. Arnold, F. Wegner, S.C. Schwarz, A. Storch, E. Zimmermann, J. Schwarz, “Uracil nucleotides stimulate human neural precursor cell proliferation and dopaminergic differentiation: involvement of MEK/ERK signaling” J Neurochem, Vol.99, No. 3,2006, pp. 913-923.

[35]   S. Yitzhaki, E. Hochhauser, E. Porat, A. Shainberg, “Uridine-5’-triphosphate (UTP) maintains cardiac mitochondrial function following chemical and hypoxic stress” J Mol Cell Cardiol, Vol. 43, No. 5,2007, pp. 653-662.

[36]   H.Y. Cheng, M.T. Hsieh, C.R. Wu, FH. Tsai, T.C. Lu, C.C. Hsieh, W.C. Li, Y.T. Lin, W.H. Peng, “Schizandrin protects primary cultures of rat cortical cells from glutamate-induced excitotoxicity” Journal of Pharmacological Science, Vol. 107, No. 1,2008, pp. 21-31.