Time course of the neuroprotective effect of transplantation on quinolinic acid-induced lesions of the striatum.
Injection of quinolinic acid in the rat striatum mimics neurochemical changes observed in Huntington's disease. We previously demonstrated that intrastriatal transplantation of fetal striatum or gelfoam protects against toxicity induced by a subsequent intrastriatal injection of quinolinic acid performed one week later. Herein, we examined whether fetal striatum or sham transplantation provides protection against quinolinic acid that lasts up to four weeks. Intrastriatal quinolinic acid injection produces neuronal loss and gliosis in Nissl staining, loss of cytochrome oxidase histochemical staining, decrease in autoradiographic binding of [3H]SCH 23390-labeled dopamine D1 and [3H]CGS 21680-labeled adenosine A2 receptors, and increase in autoradiographic binding of [3H]PK 11195-labeled peripheral benzodiazepine binding sites. None of these changes was observed in rats transplanted with fetal striatum one, two or four weeks before quinolinic acid injection. In animals transplanted with fetal striatal tissue, Nissl staining showed healthy grafts located in normal appearing striata. Although sham transplantation performed one week before quinolinic acid injection also protected against histological, histochemical and binding changes, sham transplantation performed two or four weeks before quinolinic acid injection was less effective in attenuating quinolinic acid-induced striatal toxicity. Thus, sham transplantation provides transient protection against quinolinic acid-induced striatal toxicity, whereas implantation of tissue such as fetal striatum seems to be required for long-lasting protection. Our study suggests that intracerebral transplantation may also act through other mechanisms than restoration of deficient neurotransmitters or damaged pathways, a finding which may have significant clinical implications in assessing the potential benefit of this approach for the treatment of neurodegenerative disorders such as Huntington's disease.
Levivier
M
M
Department of Neurosurgery, Université Libre de Bruxelles-Hôpital Erasme, Belgium.
Gash
D M
DM
Przedborski
S
S
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced / Q000517:prevention & control; D003342:Corpus Striatum / Q000187:drug effects* / Q000196:embryology / Q000473:pathology*; D003576:Electron Transport Complex IV / Q000378:metabolism; D016332:Fetal Tissue Transplantation; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D009417:Nerve Tissue / Q000637:transplantation*; D010627:Phenethylamines / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013997:Time Factors
D001552:Benzazepines; D007546:Isoquinolines; D010627:Phenethylamines; D017447:Receptors, Dopamine D1; D011963:Receptors, GABA-A; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D003576:Electron Transport Complex IV; D017378:Quinolinic Acid; D000241:Adenosine; C037850:PK 11195