Motor function, graft survival and gliosis in rats with 6-OHDA lesions and foetal ventral mesencephalic grafts chronically treated with L-dopa and carbidopa.
In rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway, foetal ventral mesencephalic grafts implanted into the 6-OHDA-lesioned striatum produced a reduction in apomorphine-induced contralateral rotation, and complete abolition of (+)-amphetamine-induced ipsilateral rotation. The graft-induced reduction of apomorphine and (+)-amphetamine-induced rotation was not affected by chronic 27 week administration of L-DOPA and carbidopa to rats receiving foetal grafts. TH-immunohistochemistry revealed greater than 96% loss of dopamine cells in the substantia nigra ipsilateral to the 6-OHDA lesion in all animals, but cell loss in the ipsilateral ventral tegmental area was more variable (21-46% of the intact side). TH-positive cells in the intact substantia nigra and ventral tegmental area were not affected by chronic treatment with L-DOPA and carbidopa. In the lesioned striatum of rats receiving sham grafts, no TH-positive cells or fibres were seen. In the 6-OHDA-lesioned striatum of animals receiving foetal grafts, many TH-positive cells were seen in the grafts and chronic treatment with L-DOPA and carbidopa did not reduce cell survival. GFA-P immunohistochemistry revealed that a unilateral 6-OHDA lesion followed by a sham graft was not associated with a reactive gliosis reaction in the striatum at the time of study (38 weeks after lesion surgery and 30 weeks after sham-graft), and treatment of such rats with L-DOPA and carbidopa was also without effect on glia. In contrast there was a marked gliosis in the striatum surrounding foetal grafts which was unaffected by chronic treatment with L-DOPA and carbidopa. The grafts themselves were surrounded by a rim of glial cells, and the glial density within the grafts was higher in animals receiving chronic L-DOPA and carbidopa treatment. However, there was no obvious relationship between the number of TH-positive cells within the grafts, or graft volume, and glial cell density within the grafts. These results suggest that long-term treatment with L-DOPA and carbidopa does not impair either the behavioural recovery produced by foetal ventral mesencephalic grafts in rats or the long-term survival of grafts as revealed by TH-immunohistochemistry. The presence of a foetal graft is associated with a reactive gliosis in the implanted striatum, which was not altered by long-term treatment with L-DOPA and carbidopa. However such treatment did result in an increase in glial density within the grafts themselves.
Blunt
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SB
Parkinson's Disease Society Experimental Research Laboratories, King's College, London, UK.
Jenner
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P
Marsden
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CD
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D016380:Brain Tissue Transplantation / Q000502:physiology; D002230:Carbidopa / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology; D005260:Female; D016332:Fetal Tissue Transplantation / Q000502:physiology; D005911:Gliosis / Q000139:chemically induced*; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D007980:Levodopa / Q000494:pharmacology*; D008636:Mesencephalon / Q000502:physiology* / Q000637:transplantation; D009457:Neuroglia / Q000187:drug effects; D016627:Oxidopamine; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013238:Stereotaxic Techniques; D013239:Stereotyped Behavior / Q000187:drug effects; D013563:Sympathectomy, Chemical
D007980:Levodopa; D016627:Oxidopamine; D002230:Carbidopa; D001058:Apomorphine; D003913:Dextroamphetamine