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

• Published in: Experimental neurology Vol. 161; no. 1; pp. 259 - 272
• Main Authors: Menei, P., Pean, J.M., Nerrière-Daguin, V., Jollivet, C., Brachet, P., Benoit, J.P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2000
• Subjects: Animals; Biodegradation, Environmental; Capsules; Choline O-Acetyltransferase - analysis; Corpus Striatum - drug effects; Corpus Striatum - pathology; Dopamine and cAMP-Regulated Phosphoprotein 32; drug delivery; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; excitotoxic injury; Female; Huntington Disease - drug therapy; Huntington Disease - pathology; Huntington's disease; Iodine Radioisotopes; microsphere; Microspheres; NADPH Dehydrogenase - analysis; nerve growth factor; Nerve Growth Factor - pharmacology; Nerve Tissue Proteins; Neurons - drug effects; Neurons - enzymology; Neuroprotective Agents - pharmacology; Neurotoxins - toxicity; PC12 Cells; Phosphoproteins - analysis; Quinolinic Acid - toxicity; Rats; Rats, Sprague-Dawley; striatum; excitotoxic injury; microsphere; drug delivery; striatum; Huntington's disease; nerve growth factor
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1999.7253

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.