title: Implantation of genetically modified mesencephalic fetal cells into the rat striatum.
abstract: Transplantation of dopamine (DA) cells into the rat model of hemiparkinsonism induced by intranigral 6-hydroxydopamine (6-OHDA) injections has so far focused mainly on DA replacement via a pump-like mechanism. In the present study, we employed a model of hemiparkinsonism that uses an intrastriatal approach to lesioning the nigrostriatal DA pathway to assess the possibility of using cell transplantation to cause regeneration of that system. Toward that end, we transplanted two types of cells on the side of the 6-OHDA-induced lesions: 1) nonmodified fetal mesencephalic cells and 2) fetal mesencephalic cells that have been infected with a retrovirus vector containing a PKC beta 1 cDNA. Both types of cells cause behavioral improvement although the changes were more prominent and occurred earlier in the PKC-modified groups. Tyrosine hydroxylase (TH) immunocytochemistry revealed significantly cell survival in both groups of animals; in situ hybridization studies confirmed the continuous expression of TH mRNA in both groups. Interestingly, long TH-positive axons were observed only in the striata of animals implanted with PKC-modified cells. More importantly, surviving endogenous nigral TH-positive cell bodies were found only on the lesioned side in the latter group. The observations in these animals were associated with significantly smaller decreases in [3H]mazindol-labeled DA uptake sites in both the striata and substantia nigra pars compacta on the side ipsilateral to the 6-OHDA-induced lesions. Furthermore, immunohistochemical studies revealed increased gliosis in the striata of animals grafted with the PKC-modified cells. When taken together, these results indicate that transplantation of normal fetal mesencephalic cells can cause behavioral improvement by providing DA to the host striata whereas PKC-modified cells can, in addition, prevent the progressive degeneration of or cause regeneration of the dying nigrostriatal DA neurons in this model of hemiparkinsonism. These results are discussed in terms of their support for a role for second messenger systems and glial cells, as well as extracellular matrix molecules in the regeneration of the CNS.
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10032.
authors.forename: S M
authors.initials: SM
authors.lastname: Zhu
authors.forename: K
authors.initials: K
authors.lastname: Kujirai
authors.forename: A
authors.initials: A
authors.lastname: Dollison
authors.forename: J
authors.initials: J
authors.lastname: Angulo
authors.forename: S
authors.initials: S
authors.lastname: Fahn
authors.forename: J L
authors.initials: JL
authors.lastname: Cadet
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D016380:Brain Tissue Transplantation / Q000502:physiology*; D002460:Cell Line; D003342:Corpus Striatum / Q000502:physiology*; D005260:Female; D016332:Fetal Tissue Transplantation / Q000502:physiology*; D005822:Genetic Vectors; D007150:Immunohistochemistry; D008454:Mazindol; D008636:Mesencephalon / Q000637:transplantation*; D009693:Nucleic Acid Hybridization; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000503:physiopathology; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012190:Retroviridae; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D016627:Oxidopamine; D008454:Mazindol; D000661:Amphetamine; D011493:Protein Kinase C