Journal of Neuroimmunology 213 (2009) 20–25
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Journal of Neuroimmunology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m
Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis Pablo Kizelsztein a,1, Haim Ovadia b,1, Olga Garbuzenko a, Alex Sigal a, Yechezkel Barenholz a,⁎ a b
Laboratory of Membrane and Liposome Research, Department of Biochemistry, The Hebrew University-Hadassah Medical School, Jerusalem, Israel Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah University Hospital, Jerusalem, Israel
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Reactive oxygen species are involved in the pathogenesis of multiple sclerosis (MS), Parkinson's disease and neurodegenerative diseases. Here we report that Tempamine (TMN), a stable radical with antioxidant and proapoptotic activities, when encapsulated in the intraliposome aqueous phase of pegylated (b 100 nm) nanoliposomes (nSSL), is efﬁcient in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice. The TMN is remote-loaded into nSSL by an intraliposome high/extraliposome low transmembrane ammonium sulfate gradient. Biodistribution studies of nSSL–TMN labeled with the liposome non transferable non metabolizable 3H-cholesteryl hexadecyl ether show that almost 3% of the injected dose of liposomes reached the brain of the EAE mice, compared with less than 1% in the control healthy mice. This accumulation in the brain, combined with the fact that TMN demonstrates a controlled slow release out of the nSSL, may explain the superior therapeutic activity of nSSL–TMN over free TMN. Our results suggest that the study of nSSL–TMN for therapy of MS, and other neurodegenerative diseases involving oxidative damage, is worth pursuing. © 2009 Published by Elsevier B.V.
Article history: Received 29 September 2008 Received in revised form 25 May 2009 Accepted 26 May 2009 Keywords: Liposomes Antioxidants Tempamine EAE MS Neurodegeneration
1. Introduction There is signiﬁcant evidence that at least part of the pathogenesis of autoimmune demyelinative diseases, such as multiple sclerosis (MS) and various other neurodegenerative diseases, may involve the generation of reactive oxygen species (ROS) (Borlongan et al., 1996; Ebadi et al., 1996; Ferrante et al., 1997; Halliwell, 2001; Lu et al., 2000; Markesbery and Carney, 1999; Sarsero et al., 2003). ROS include molecules that are not themselves free radicals, but are capable of formation of free radicals such as hydrochlorous acid (HOCl), singlet oxygen ('O2), hydrogen peroxide (H2O2), and nitroxide (HNNO). While free radicals are essential for the body for achieving a balance between oxidative and reductive compounds (redox state) inside the cell, impairing this balance in favor of oxidative compounds leads to oxidative stress. Therefore, antioxidants may act to diminish tissue damage and attenuate inﬂammation (Calabrese et al., 2007). There were many attempts to use natural antioxidants such as vitamin E (tocopherol), carotenoids, ﬂavonoids and the enzyme superoxide dismutase (SOD) for the treatment of central nervous system diseases (Halliwell, 2001). Unfortunately, most of them do not readily cross the blood–brain barrier. In addition, most antioxidants in
⁎ Corresponding author. Department of Biochemistry, The Hebrew UniversityHadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel. Tel.: +972 2 6758507; fax: +972 2 6757499. E-mail address: email@example.com (Y. Barenholz). 1 Equal senior authors. 0165-5728/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.jneuroim.2009.05.019
their free form undergo fast clearance due to rapid chemical degradation in plasma, and in order to achieve an effect they must be administered in very high doses. To overcome some of these obstacles, we have used a piperidine...
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