Intracerebral implantation of NGF-releasing biodegradable microspheres protects striatum against excitotoxic damage.
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.
Menei
P
P
Department of Neurosurgery, University Hospital, Angers, France.
Pean
J M
JM
Nerrière-Daguin
V
V
Jollivet
C
C
Brachet
P
P
Benoit
J P
JP
D000818:Animals; D001673:Biodegradation, Environmental; D002214:Capsules; D002795:Choline O-Acetyltransferase / Q000032:analysis; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy / Q000473:pathology; D007457:Iodine Radioisotopes; D008863:Microspheres; D009252:NADPH Dehydrogenase / Q000032:analysis; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D016716:PC12 Cells; D010750:Phosphoproteins / Q000032:analysis; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D002214:Capsules; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D007457:Iodine Radioisotopes; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010750:Phosphoproteins; D020932:Nerve Growth Factor; D009252:NADPH Dehydrogenase; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid