ANP  Vol.1 No.3 , November 2012
Lipopolysaccharide Modified Liposomes for Amyotropic Lateral Sclerosis Therapy: Efficacy in SOD1 Mouse Model
ABSTRACT
Activation of microglia is a histological feature observed in neurodegenerative diseases like ALS. The oral administration of minocycline has been demonstrated to have minimal neuroprotection ability in the animal models and is also associated with inadvertent toxicity due to non-specific oral absorption of the drug. Nonetheless, the drug itself shows promise in a number of disease models suggesting it could be effective if delivered optimally. Thus, we utilized LPS modified liposomes to target TLR4 receptor on the microglia in SOD1G93A mice and compared its efficacy with non- targeted nanoliposomes. The in vitro results indicate that targeting the TLR4 receptor on microglia significantly increases (p < 0.01) the uptake of drug by 29% compared to non-targeted liposomes. In the SOD1G93A mouse model of ALS, targeted and non-targeted minocycline treatment significantly increased (p < 0.05) latency to endpoint stages compared to control mice. Targeting liposomes to microglia significantly delayed disease progression. Both targeted and non-targeted liposomes administration in SOD1 mice resulted in decreased TNF-α secretion in activated BV-2 microglial cells as compared to activated cells receiving no treatment. The non-targeted liposomes had a greater effect than the targeted liposomes in reducing the levels of TNF-α released by the BV-2 cells. In SOD1G93A mice, the non- targeted nanovesicles significantly increased the latency to rotarod failure and both targeted and non-targeted nanovesicles significantly delayed disease endpoints.

Cite this paper
Wiley, N. , Madhankumar, A. , Mitchell, R. , Neely, E. , Rizk, E. , Douds, G. , Simmons, Z. and Connor, J. (2012) Lipopolysaccharide Modified Liposomes for Amyotropic Lateral Sclerosis Therapy: Efficacy in SOD1 Mouse Model. Advances in Nanoparticles, 1, 44-53. doi: 10.4236/anp.2012.13007.
References
[1]   M. E. Gurney, H. Pu, A. Y. Chiu, M. C. Dal Canto, C. Y. Polchow, D. D. Alexander, J. Caliendo, A. Hentati, Y. W. Kwon, H. X. Deng, et al., “Motor Neuron Degeneration in Mice That Express a Human Cu,Zn Superoxide Dismutase Mutation,” Science, Vol. 264, No. 5166, 1994, pp. 1772-1775. doi:10.1126/science.8209258

[2]   T. A. Ferguson and L. B. Elman, “Clinical Presentation and Diagnosis of Amyatrophic Lateral Slerosis,” Neurorehabilitation, Vol. 22, No. 6, 2007, pp. 409-416.

[3]   M. E. Alexianu, M. Kozovska and S. H. Appel, Neurology, “Immune Reactivity in a Mouse Model of Familial ALS Correlates with Disease Progression,” Vol. 57, No. 7, 2001, pp. 1282-1289. doi:10.1212/WNL.57.7.1282

[4]   T. Kawamata, H. Akiyama, T. Yamada and P. L. McGeer, “Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue,” American Journal of Pathology, Vol. 140, No. 3, 1992, pp. 691-707.

[5]   T. M. Miller, S. H. Kim, K. Yamanaka, M. Hester, P. Umapathi, H. Arnson, L. Rizo, J. R. Mendell, F. H. Gage, D. W. Cleveland and B. K. Kaspar, “Gene Transfer Demonstrates That Muscle Is Not a Primary Target for Non-Cell-Autonomous Toxicity in Familial Amyotrophic Lateral Sclerosis,” Proceedings of the National Academy of Science of the United States of America, Vol. 103, No. 51, 2006, pp. 19546-19551. doi:10.1073/pnas.0609411103

[6]   S. Boillee, K. Yamanaka, C. S. Lobsiger, N. G. Copeland, N. A. Jenkins, G. Kassiotis, G. Kollias and D. W. Cleveland, “Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia,” Science, Vol. 312, No. 5778, 2006, pp. 1389-1392. doi:10.1126/science.1123511

[7]   S. Zhu, I. G. Stavrovskaya, M. Drozda, B. Y. Kim, V. Ona, M. Li, S. Sarang, A. S. Liu, D. M. Hartley, D. C. Wu, S. Gullans, R. J. Ferrante, S. Przedborski, B. S. Kristal and R. M. Friedlander, “Minocycline Inhibits Cytochrome C Release and Delays Progression of Amyotrophic Lateral Sclerosis in Mice,” Nature, Vol. 417, No. 6884, 2002, pp. 74-78. doi:10.1038/417074a

[8]   H. Manev and R. Manev, “Interactions with GluR1 AMPA Receptors Could Influence the Therapeutic Usefulness of Minocycline in ALS,” Amyotroph Lateral Scler, Vol. 10, No. 5-6, 2009, pp. 416-417. doi:10.3109/17482960802702288

[9]   J. Yrjanheikki, R. Keinanen, M. Pellikka, T. Hokfelt and J. Koistinaho, “Tetracyclines Inhibit Microglial Activation and Are Neuroprotective in Global Brain Ischemia,” Proceedings of the National Academy of Science of the United States of America, Vol. 95, No. 26, 1998, pp. 15769-15774. doi:10.1073/pnas.95.26.15769

[10]   K. L. Arvin, B. H. Han, Y. Du, S. Z. Lin, S. M. Paul and D. M. Holtzman, “Minocycline Markedly Protects the Neonatal Brain against Hypoxic-Ischemic Injury,” Annals of Neurology, Vol. 52, No. 1, 2002, pp. 54-61. doi:10.1002/ana.10242

[11]   R. O. Sanchez Mejia, V. O. Ona, M. Li and R. M. Friedlander, “Minocycline Reduces Traumatic Brain Injury-mediated Caspase-1 Activation, Tissue Damage, and Neurological Dysfunction,” Neurosurgery, Vol. 48, No. 6, 2001, pp. 1393-1399.

[12]   J. E. Wells, R. J. Hurlbert, M. G. Fehlings and V. W. Yong, “Neuroprotection by Minocycline Facilitates Significant Recovery from Spinal Cord Injury in Mice,” Brain, Vol. 126, No. 7, 2003, pp. 1628-1637. doi:10.1093/brain/awg178

[13]   V. Brundula, N. B. Rewcastle, L. M. Metz, C. C. Bernard and V. W. Yong, “Targeting Leukocyte MMPs and Transmigration Minocycline as a Potential Therapy for Multiple Sclerosis,” Brain, Vol. 125, No. 6, 2002, pp. 1297-1308. doi:10.1093/brain/awf133

[14]   Y. Du, Z. Ma, S. Lin, R. C. Dodel, F. Gao, K. R. Bales, L. C. Triarhou, E. Chernet, K. W. Perry, D. L. Nelson, S. Luecke, L. A. Phebus, F. P. Bymaster and S. M. Paul, “Minocycline Prevents Nigrostriatal Dopaminergic Neurodegeneration in the MPTP Model of Parkinson’s Disease,” Proceedings of the National Academy of Science of the United States of America, Vol. 98, No. 25, 2001, pp. 14669-14674. doi:10.1073/pnas.251341998

[15]   D. C. Wu, V. Jackson-Lewis, M. Vila, K. Tieu, P. Teismann, C. Vadseth, D. K. Choi, H. Ischiropoulos and S. Przedborski, “Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetra- hydropyridine Mouse Model of Parkinson Disease,” The Journal of Neuroscience, Vol. 22, No. 5, 2002, pp. 1763- 1771.

[16]   Y. He, S. Appel and W. Le, “Minocycline Inhibits Microglial Activation and Protects Nigral Cells after 6-Hy- droxydopamine Injection into Mouse Striatum,” Brain Research, Vol. 909, No. 1-2, 2001, pp. 187-193. doi:10.1016/S0006-8993(01)02681-6

[17]   M. Chen, V. O. Ona, M. Li, R. J. Ferrante, K. B. Fink, S. Zhu, J. Bian, L. Guo, L. A. Farrell, S. M. Hersch, W. Hobbs, J. P. Vonsattel, J. H. Cha and R. M. Friedlander, “Minocycline Inhibits Caspase-1 and Caspase-3 Expression and Delays Mortality in a Transgenic Mouse Model of Huntington disease,” Nature Medicine, Vol. 6, No. 7, 2000, pp. 797- 801. doi:10.1038/80538

[18]   X. Wang, S. Zhu, M. Drozda, W. Zhang, I. G. Stavrovskaya, E. Cattaneo, R. J. Ferrante, B. S. Kristal and R. M. Friedlander, “Minocycline Inhibits Caspase-independent and -Dependent Mitochondrial Cell Death Pathways in Models of Huntington’s Disease,” Proceedings of the National Academy of Science of the United States of America, Vol. 100, No. 18, 2003, pp. 10483-10487. doi:10.1073/pnas.1832501100

[19]   J. Kriz, M. D. Nguyen, and J. P. Julien, “Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis,” Neurobiology of Disease, Vol. 10, No. 3, 2002, pp. 268-278. doi:10.1006/nbdi.2002.0487

[20]   L. Van Den Bosch, P. Tilkin, G. Lemmens and W. Robberecht, “Minocycline Delays Disease Onset and Mortality in a Transgenic Model of ALS,” Neuroreport, Vol. 13, No. 8, 2002, pp. 1067-1070. doi:10.1097/00001756-200206120-00018

[21]   P. N. Leigh, V. Meininger, G. Bensimon, M. Cudkowicz and W. Robberecht, “Minocycline for Patients with ALS,” Lancet Neurol, Vol. 7, No. 2, 2008, pp. 119-120.

[22]   A. Milane, L. Tortolano, C. Fernandez, G. Bensimon, V. Meininger and R. Farinotti, “Brain and Plasma Riluzole Pharmacokinetics: Effect of Minocycline Combination,” Journal of Pharmacy and Pharmaceutical Sciences, Vol. 12, No. 2, 2009, pp. 209-217.

[23]   H. Manev and R. Manev, “Interactions with GluR1 AMPA Receptors Could Influence the Therapeutic Usefulness of Minocycline in ALS,” Amyotroph Lateral Scler, Vol. 10 No. 5-6, 2009, pp. 1-2. doi:10.1080/17482960802702288

[24]   P. H. Gordon, D. H. Moore, R. G. Miller, J. M. Florence, J. L. Verheijde, C. Doorish, J. F. Hilton, G. M. Spitalny, R. B. MacArthur, H. Mitsumoto, H. E. Neville, K. Boylan, T. Mozaffar, J. M. Belsh, J. Ravits, R. S. Bedlack, M. C. Graves, L. F. McCluskey, R. J. Barohn and R. Tandan, “Efficacy of Minocycline in Patients with Amyotrophic Lateral Sclerosis: A Phase Iii Randomised Trial,” The Lancet Neurology, Vol. 6, No. 12, 2007, pp. 1045-1053. doi:10.1016/S1474-4422(07)70270-3

[25]   W. Zhang, Narayanan, M., and Friedlander, R. M. “Additive Neuroprotective Effects of Minocycline with Creatine in a Mouse Model of ALS,” Annals of Neurology, Vol. 53, No. 2, 2003, pp. 267-270. doi:10.1002/ana.10476

[26]   C. Gurley, J. Nichols, S. Liu, N. K. Phulwani, N. Esen and T. Kielian, “Microglia and Astrocyte Activation by Toll-Like Receptor Ligands: Modulation by PPAR-Agonists,” PPAR Research, Vol. 2008, 2008, pp. 1-15. doi:10.1155/2008/453120

[27]   J. C. Chow, D. W. Young, D. T. Golenbock, W. J. Christ and F. Gusovsky, “Toll-Like Receptor-4 Mediates Lipopolysaccharide-Induced Signal Transduction,” The Journal of Biological Chemistry, Vol. 274, No. 16, 1999, pp. 10689-10692. doi:10.1074/jbc.274.16.10689

[28]   D. W. Chung, K. Y. Yoo, I. K. Hwang, D. W. Kim, J. Y. Chung, C. H. Lee, J. H. Choi, S. Y. Choi, H. Y. Youn, I. S. Lee and M. H. Won, “Systemic Administration of Lipopolysaccharide Induces Cyclooxygenase-2 Immunoreactivity in Endothelium and Increases Microglia in the Mouse Hippocampus,” Cell Mol Neurobiol, Vol. 30, No. 4, 2009.

[29]   K. Hoshino, O. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Akeda and S. Akira, “Cutting Edge: Toll-Like Receptor 4 (TLR4)-Deficient Mice Are Hyporesponsive to Lipopolysaccharide: Evidence for TLR4 as the Lps Gene Product,” The Journal of Immunology, Vol. 162, No. 7, 1999, pp. 3749-3752.

[30]   S. Lehnardt, C. Lachance, S. Patrizi, S. Lefebvre, P. L. Follett, F. E. Jensen, P. A. Rosenberg, J. J. Volpe and T. Vartanian, “The Toll-Like Receptor TLR4 Is Necessary for Lipopolysaccharide-Induced Oligodendrocyte Injury in the CNS,” The Journal of Neuroscience, Vol. 22, No. 7, 2002, pp. 2478-2486.

[31]   E. Blasi, R. Barluzzi, V. Bocchini, R. Mazzolla and F. Bistoni, “Immortalization of Murine Microglial Cells by a V-Raf/V-Myc Carrying Retrovirus,” Journal of Neuroimmunology, Vol. 27, No. 2-3, 1990, pp. 229-237. doi:10.1016/0165-5728(90)90073-V

[32]   S. G. Kremlev, R. L. Roberts, and C. Palmer, “Differential Expression of Chemokines and Chemokine Receptors during Microglial Activation and Inhibition,” Journal of Neuroimmunology, Vol. 149, No. 1, 2004, pp. 1-9. doi:10.1016/j.jneuroim.2003.11.012

[33]   M. Nikodemova, I. D. Duncan, and J. J. Watters, “Minocycline Exerts Inhibitory Effects on Multiple Mitogen- Activated Protein Kinases and IκBα Degradation in a Stimulus-Specific Manner in Microglia,” Journal of Neurochemistry, Vol. 96, No. 2, 2006, pp. 314-323. doi:10.1111/j.1471-4159.2005.03520.x

[34]   M. E. Gurney, F. B. Cutting, P. Zhai, A. Doble, C. P. Taylor, P. K. Andrus and E. D. Hall, “Benefit of Vitamin E, Riluzole, And Gababapentin in a Transgenic Model of Familial Amyotrophic Lateral Sclerosis,” Annals of Neurology, Vol. 39, No. 2, 1996, pp. 147-157. doi:10.1002/ana.410390203

[35]   M. Molina-Hernandez, N. P. Tellez-Alcantara, J. Perez- Garcia, J. I. Olivera-Lopez and M. T. Jaramillo-Jaimes, “Antidepressant-Like Actions of Minocycline Combined with Several Glutamate Antagonists,” Progress in Neuro- Psychopharmacology and Biological Psychiatry, Vol. 32, No. 2, 2008, pp. 380-386. doi:10.1016/j.pnpbp.2007.09.004

[36]   T. Miyaoka, R. Yasukawa, H. Yasuda, M. Hayashida, T. Inagaki and J. Horiguchi, “Possible Antipsychotic Effects of Minocycline in Patients with Schizophrenia,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 31, No. 1, 2007, pp. 304-307. doi:10.1016/j.pnpbp.2006.08.013

[37]   G. Bensimon, L. Lacomblez and V. Meininger, “A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis,” The New England Journal of Medicine, Vol. 330, No. 9, 1994, pp. 585-591. doi:10.1056/NEJM199403033300901

[38]   L. Lacomblez, G. Bensimon, P. N. Leigh, P. Guillet and V. Meininger, “Dose-Ranging Study of Riluzole in Amyotrophic Lateral Sclerosis,” Lancet, Vol. 347, No. 9013, 1996, pp. 1425- 1431.

[39]   C. Scherfler, T. Sather, E. Diguet, N. Stefanova, Z. Puschban, F. Tison, W. Poewe and G. K. Wenning, “Riluzole Improves Motor Deficits and Attenuates Loss of Striatal Neurons in a Sequential Double Lesion Rat Model of Striatonigral Degeneration (Parkinson Variant of Multiple System Atrophy),” Journal of Neural Transmission, Vol. 112, No. 18, 2005, pp. 1025-1033. doi:10.1007/s00702-004-0245-5

[40]   J. A. Rocha, C. Reis, F. Simoes, J. Fonseca and J. Mendes Ribeiro, “Diagnostic Investigation and Multidisciplinary Management in Motor Neuron Disease,” Journal of Neuroimmunology, Vol. 252, No. 12, 2005, pp. 1435-1447. doi:10.1007/s00415-005-0007-9

 
 
Top