title: Intrastriatal implantation of interleukin-1. Reduction of parkinsonism in rats by enhancing neuronal sprouting from residual dopaminergic neurons in the ventral tegmental area of the midbrain.
abstract: Intrastriatal implantation with dopaminergic of nondopaminergic tissue can elicit behavioral recovery in parkinsonian animals. Because in these animals, especially in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, there are still considerable numbers of dopaminergic neurons left in the mesencephalon, implantation-induced trophic effects on host residual dopaminergic neurons have been suggested as a mechanism underlying the behavioral recovery. Gliosis around the graft is a universal finding in any implantation procedure and is probably mediated by interleukin-1 (IL-1); in addition, activated astrocytes secrete several neurotrophic factors in vitro. Therefore, the authors postulated that trophic effects from IL-1-induced gliosis may be a "final common pathway" for recovery in parkinsonian animals after implantation. Hemiparkinsonism was induced in rats by injection of 6-hydroxydopamine either directly into the substantia nigra or into the median forebrain bundle. The substantia nigra-lesioned rats showed complete depletion of dopaminergic neurons in the substantia nigra but sparing of those in the ventral tegmental area, whereas the median forebrain bundle-lesioned animals had depletion of dopaminergic cells in the substantia nigra and the ventral tegmental area. Polymer pellets containing either slow-released IL-1 alpha and beta or placebo pellets were implanted in the caudate nucleus on the lesioned side in both groups. The rats' rotational response to amphetamine was tested weekly for 8 weeks. Selective substantia nigra-lesioned rats with implantation of IL-1 pellets had a 45% reduction in amphetamine-induced rotation, whereas placebo-implanted substantia nigra-lesioned rats had a 14% reduction in rotation. In the median forebrain bundle-lesioned group, neither IL-1 nor placebo implantation elicited any effect on turning. Immunohistochemical staining for glial fibrillary acidic protein was markedly increased surrounding the IL-1 pellets compared to the placebo pellets. In the selective substantia nigra-lesioned rats with IL-1 pellets implanted in the caudate nucleus, a considerable number of tyrosine hydroxylase immunoreactive (TH-IR) fibers were observed in the medial and middle portions of the caudate nucleus. Fewer TH-IR fibers were seen in the rats with placebo-bearing pellets. These results suggest that neurotrophic activities mediated by IL-1 and reactive astrocytes might be a common path through which tissue trauma and some tissue transplants exert their beneficial effects in parkinsonian animals. Furthermore, most of the sprouted dopaminergic fibers induced by IL-1 in the caudate nucleus come from dopaminergic neurons in the ventral tegmental area.
authors.affiliation: CNS Implantation and Regeneration Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: K S
authors.initials: KS
authors.lastname: Bankiewicz
authors.forename: R J
authors.initials: RJ
authors.lastname: Plunkett
authors.forename: E H
authors.initials: EH
authors.lastname: Oldfield
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D004298:Dopamine / Q000032:analysis; D004343:Drug Implants; D007375:Interleukin-1 / Q000008:administration & dosage*; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000473:pathology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra; D013681:Tegmentum Mesencephali / Q000737:chemistry / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D004343:Drug Implants; D007375:Interleukin-1; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine