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      Squalenoyl Adenosine Nanoparticles provide Neuroprotection after Stroke and Spinal Cord Injury

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          Abstract

          There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, like adenosine, are inefficient upon systemic administration because of their fast metabolisation and rapid clearance from the bloodstream. Here, we show that the conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allow a prolonged circulation of this nucleoside, to provide neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This paper shows, for the first time, that a hydrophilic and rapidly metabolised molecule like adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

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          Most cited references 37

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          Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection.

          Injury reproducibility is an important characteristic of experimental models of spinal cord injuries (SCI) because it limits the variability in locomotor and anatomical outcome measures. Recently, a more sensitive locomotor rating scale, the Basso, Beattie, and Bresnahan scale (BBB), was developed but had not been tested on rats with severe SCI complete transection. Rats had a 10-g rod dropped from heights of 6.25, 12.5, 25, and 50 mm onto the exposed cord at Tl 0 using the NYU device. A subset of rats with 25 and 50 mm SCI had subsequent spinal cord transection (SCI + TX) and were compared to rats with transection only (TX) in order to ascertain the dependence of recovery on descending systems. After 7-9 weeks of locomotor testing, the percentage of white matter measured from myelin-stained cross sections through the lesion center was significantly different between all the groups with the exception of 12.5 vs 25 mm and 25 vs 50 mm groups. Locomotor recovery was greatest for the 6.25-mm group and least for the 50-mm group and was correlated positively to the amount of tissue sparing at the lesion center (p 0.05). Thus, spared descending systems appear to modify segmental systems which produce greater behavioral improvements than isolated cord systems.
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            Degenerative and regenerative mechanisms governing spinal cord injury.

            Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system. The early recruitment of neutrophils and at later stages, macrophages to the site of insult cause exacerbation of injury. However, at more chronic stages, macrophages and recruited T helper cells may potentially be helpful by providing trophic support for neuronal and non-neuronal components of the injured CNS. Within this sea of injurious mechanisms, the oligodendrocytes appear to be highly vulnerable. At chronic stages of SCI, a large number of oligodendrocytes undergo apoptosis at sites that are distant to the vicinity of primary injury. This leads to denudement of axons and deterioration of their conductive abilities, which adds significantly to functional decline. By indulging into the molecular mechanisms that cause oligodendrocyte apoptosis and identifying potential targets for therapeutic intervention, the prevention of this apoptotic wave will be of tremendous value to individuals living with SCI.
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              Adenosine and brain function.

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                Author and article information

                Journal
                101283273
                34218
                Nat Nanotechnol
                Nat Nanotechnol
                Nature nanotechnology
                1748-3387
                1748-3395
                3 November 2014
                24 November 2014
                2014
                18 May 2016
                : 9
                : 12
                : 1054-1062
                Affiliations
                [1 ]Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud XI, 92296 Châtenay-Malabry, France
                [2 ]Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara 06100, Turkey
                [3 ]Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara 06100, Turkey
                [4 ]Department of Neurosurgery, Ankara Ataturk Research & Education Hospital, 06800 Bilkent Ankara, Turkey
                [5 ]Department of Anatomy, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
                [6 ]CEA Saclay, iBiTecS-S/SCBM, Labex LERMIT, 91191 Gif-sur-Yvette, France
                [7 ]NanoBioPhotonics, Institut d’Electronique Fondamentale, University of Paris-Sud XI, 91405, Orsay Cedex, France
                [8 ]EA3544, Faculty of Pharmacy, University of Paris-Sud XI, 92296 Châtenay-Malabry, France
                [9 ]Institut d’Innovation Thérapeutique, IFR141 ITFM, Faculty of Pharmacy, University of Paris-Sud XI, 92296 Châtenay-Malabry, France
                Author notes

                Author contributions

                P.C. and T.D. conceived and designed the research. A.G. designed and performed the nanoparticles preparation, the side-effects and toxicity experiments, the stability and in vivo pharmacokinetic/biodistribution studies and the in vitro experiments. S.L. developed and performed the SQAd synthesis, D.D. helped analysing the chemical results. B.R., S.G.A., G.P. and O.L. developed and performed the radiolabelled compound synthesis. T.D. and M.Y. designed and performed the cerebral ischaemia experiments. B.D.-D. performed the histological stainings and countings for cerebral ischaemia experiments. S.C. and Y.C. were in charge of the nanoparticles preparation for the cerebral ischaemia experiments. H.E., O.F.T. and A.G. designed and performed the spinal cord injury experiments. M.F.Z. performed the ultrastructural evaluation of the spinal cord injury experiments. A.G., O.T. and N.H designed and performed the FRET NAs experiments. Y.L.D and A.G performed the sleep cycle experiments. J.M. performed the HPLC analysis. S.V. performed the complement activation experiments. H.C. helped analysing the radioactivity data and V.N. helped analysing the confocal data. P.C., T.D., K.A., A.G. and M.Y. co-wrote the paper. All authors discussed the results and commented on the manuscript.

                [* ]Correspondence and requests for materials should be adressed to P.C. and K.A. patrick.couvreur@ 123456u-psud.fr , karine.andrieux@ 123456parisdescartes.fr
                Article
                EMS60770
                10.1038/nnano.2014.274
                4351925
                25420034

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                Nanotechnology

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