Elsevier

Experimental Neurology

Volume 161, Issue 1, January 2000, Pages 259-272
Experimental Neurology

Regular Article
Intracerebral Implantation of NGF-Releasing Biodegradable Microspheres Protects Striatum against Excitotoxic Damage

https://doi.org/10.1006/exnr.1999.7253Get rights and content

Abstract

Intrastriatal implantation of genetically modified cells synthesizing nerve growth factor (NGF) constitutes one way to obtain a long-term supply of this neurotrophic factor and a neuronal protection against an excitotoxic lesion. We have investigated if NGF-loaded poly(d,l-lactide-co-glycolide) microspheres could represent an alternative to cell transplantations. These microspheres can be implanted stereotaxically and locally release the protein in a controlled and sustained way. In order to test this paradigm, the NGF release kinetics were characterized in vitro using radiolabeled NGF, immunoenzymatic assay, and PC-12 cells bioassay and then in vivo after implantation in the intact rat striatum. These microspheres were thus implanted into the rat striatum 7 days prior to infusing quinolinic acid. Control animals were either not treated or implanted with blank microspheres. The extent of the lesion and the survival of ChAT-, NADPH-d-, and DARPP-32-containing neurons were analyzed. In vitro studies showed that microspheres allowed a sustained release of bioactive NGF for at least 1 month. Microspheres implanted in the intact striatum still contained NGF after 2.5 months and they were totally degraded after 3 months. After quinolinic acid infusion, the lesion size in the group treated with NGF-releasing microspheres was reduced by 40% when compared with the control groups. A marked neuronal sparing was noted, principally concerning the cholinergic interneurons, but also neuropeptide Y/somatostatin interneurons and GABAergic striatofuge neurons. These results indicate that implantation of biodegradable NGF-releasing microspheres can be used to protect neurons from a local excitotoxic lesion and that this strategy may ultimately prove to be relevant for the treatment of various neurological diseases.

References (73)

  • Y. Kawaguchi et al.

    Striatal interneurons: Chemical, physiological and morphological characterization

    TINS

    (1995)
  • J.H. Kordower et al.

    Intrastriatal implants of polymer encapsulated cells genetically modified to secrete human nerve growth factor: Trophic effects upon cholinergic and noncholinergic striatal neurons

    Neuroscience

    (1996)
  • J.H. Kou et al.

    Bioerosion and biocompatibility of poly(d,l-lactic-co-glycolic acid) implants in brain

    J. Control. Release

    (1997)
  • N.W. Kowall et al.

    Neuropeptide Y, somatostatin and reduced nicotinamide adenine dinucleotide phosphate diaphorase in the human striatum: A combined immunocytochemical and enzyme histochemical study

    Neuroscience

    (1987)
  • C.E. Krewson et al.

    Transport and elimination of recombinant human NGF during long-term delivery to the brain

    Brain Res.

    (1996)
  • M. Levivier et al.

    Time course of the neuroprotective effect of transplantation on quinolinic acid-induced lesion of the striatum

    Neurosciences

    (1995)
  • D. Maysinger et al.

    Microencapsulated nerve growth factor: Effect on the forebrain neurons following devascularizing cortical lesions

    Neurosci. Lett.

    (1992)
  • D. Maysinger et al.

    Microencapsulation of genetically engineered fibroblasts secreting nerve growth factor

    Neurochem. Int.

    (1993)
  • P. Menei et al.

    Biodegradation and brain tissue reaction to poly(d-l lactide-co-glycolide) microspheres

    Biomaterials

    (1993)
  • G. Nistico et al.

    NGF restores decrease in catalase activity and increase superoxide dismutase and glutathione peroxidase activity in the brain of aged rats

    Free Rad. Biol. Med.

    (1992)
  • J.M. Pean et al.

    Optimization of HSA and NGF encapsulation yields in PLGA microparticles

    Int. J. Pharm.

    (1998)
  • J.M. Pean et al.

    NGF release from poly(d,l-lactide-co-glycolide) microspheres: Effect of some formulation parameters on encapsulated NGF stability

    J. Contr. Release

    (1998)
  • E.M. Powell et al.

    Controlled release of nerve growth factor from a polymeric implant

    Brain Res.

    (1990)
  • J.M. Schumacher et al.

    Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids

    Neuroscience

    (1991)
  • G. Spenlehauer et al.

    In vitro and in vivo degradation of poly(d,l-lactide:glycolide) type microspheres made by solvent evaporation method

    Biomaterials

    (1989)
  • T.L. Steininger et al.

    High-affinity nerve growth factor receptor (Trk) immunoreactivity is localised in cholinergic neurons of the basal forebrain and striatum in the adult rat brain

    Brain Res.

    (1993)
  • J.L. Venero et al.

    Intrastriatal infusion of nerve growth factor after quinolinic acid prevents reduction of cellular expression of choline acetyltransferase messenger RNA and trkA messenger RNA, but not glutamate decarboxylase messenger RNA

    Neuroscience

    (1994)
  • L.R. Williams

    Hypophagia is induced by intracerebroventricular administration of nerve growth factor

    Exp. Neurol.

    (1991)
  • S.R. Winn et al.

    Polymer-encapsulated genetically modified cells continue to secrete human nerve growth factor for ever one year in rat ventricles: behavioral and anatomical consequences

    Exp. Neurol.

    (1996)
  • S. Yamamoto et al.

    Protective effect of NGF atelocollagen mini-pellet on the hippocampal delayed neuronal death in gerbils

    Neurosci. Lett.

    (1992)
  • K.D. Anderson et al.

    Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington's disease

    Proc. Natl. Acad. Sci. USA

    (1996)
  • M.F. Beal et al.

    Chronic quinolinic acid lesions in rats closely resemble Huntington's disease

    J. Neurosci.

    (1991)
  • M.F. Beal et al.

    Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid

    Nature

    (1986)
  • M. Boisdron-Celle et al.

    Preparation and characterization of 5-fluorouracil-loaded microparticles as biodegradable anticancer drug carriers

    J. Pharm. Pharmacol.

    (1995)
  • P.J. Camarata et al.

    Sustained release of nerve growth factor from biodegradable polymer microspheres

    Neurosurgery

    (1992)
  • J.T. Coyle et al.

    Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea

    Nature

    (1976)
  • Cited by (0)

    1

    To whom reprint requests should be addressed at Service de Neurochirurgie, CHU d'Angers, 49033 Angers Cedex 01, France. Fax: (33) 241 354 508.

    View full text