The objective of this research project is to determine if adrenal chromaffin tissue can be successfully transplanted in primates to improve fixed neurologic dysfunction. The MPTP-induced Parkinson- like syndrome is an excellent model to test transplantation in nonhuman primates. Preliminary studies have demonstrated potential for correcting the Parkinson-like movement abnormalities using adrenal medullary tissue in the rhesus monkey (Macaca mulatta). The behavioral performance of chromaffin-grafted monkeys will be compared to non-operated and surgical controls that will receive the same operation but without placement of a graft. The goal is first to determine if grafting of chromaffin tissue to the head of the caudate by a transcortical intraventricular approach can produce statistically significant improvement in parkinson-like behavior. Once this is evaluated, then multiple aspects of the grafting technique will be explored (i.e., purity of the tissue separation, quantity of the graft, etc.) Behavioral assessment of motor function will be performed by clinical examination, computerized image analysis of spontaneous home cage activity and drug-induced rotation, and performance of learned forelimb tasks. Each animal will be tested prior to administration of MPTP, after stabilization of the Parkinson-like state, and following treatment, thus allowing each animal to serve as its own control. Anatomical assessment will allow comparison of treatment with control groups by quantification of loss of dopaminergic cells in the substantia nigra by immunocytologic staining for tyrosine hydroxylase. Graft cell survival will be evaluated by chromaffin and modified Giemsa staining as well as by tyrosine hydroxylase, dopamine-B- hydroxylase, and chromagranin A immunocytochemical reaction. Biochemical assessment will be performed by serial measurements of dopamine metabolites in the CSF and by measurement of levels of dopamine, dopamine metabolites, and tyrosine hydroxylase activity in the striatum post-mortem. If the neurologic deficits can be successfully improved in animals with this Parkinson-like syndrome, the implications are extremely important not only for the potential treatment of parkinsonism but also for any disease having a neurochemical deficiency responsible for a fixed neurologic deficit.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024340-02
Application #
3408840
Study Section
Neurology A Study Section (NEUA)
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Other Domestic Higher Education
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Howel, L L; Byrd, L D; McDonough, A M et al. (2000) Behavioral evaluation of hemiparkinsonian MPTP monkeys following dopamine pharmacological manipulation and adrenal co-graft transplantation. Cell Transplant 9:609-22
Starr, P A; Wichmann, T; van Horne, C et al. (1999) Intranigral transplantation of fetal substantia nigra allograft in the hemiparkinsonian rhesus monkey. Cell Transplant 8:37-45
Bakay, R A; Boyer, K L; Freed, C R et al. (1998) Immunological responses to injury and grafting in the central nervous system of nonhuman primates. Cell Transplant 7:109-20
Betarbet, R; Zigova, T; Bakay, R A et al. (1996) Dopaminergic and GABAergic interneurons of the olfactory bulb are derived from the neonatal subventricular zone. Int J Dev Neurosci 14:921-30
Betarbet, R; Zigova, T; Bakay, R A et al. (1996) Migration patterns of neonatal subventricular zone progenitor cells transplanted into the neonatal striatum. Cell Transplant 5:165-78
Ansari, A A; Mayne, A; Freed, C R et al. (1995) Lack of a detectable systemic humoral/cellular allogeneic response in human and nonhuman primate recipients of embryonic mesencephalic allografts for the therapy of Parkinson's disease. Transplant Proc 27:1401-5
Watts, R L; Mandir, A S; Bakay, R A (1995) Intrastriatal cografts of autologous adrenal medulla and sural nerve in MPTP-induced parkinsonian macaques: behavioral and anatomical assessment. Cell Transplant 4:27-38
Bakay, R A (1993) Neurotransplantation: a clinical update. Acta Neurochir Suppl (Wien) 58:8-16
Ellis, J E; Byrd, L D; Bakay, R A (1992) A method for quantitating motor deficits in a nonhuman primate following MPTP-induced hemiparkinsonism and co-grafting. Exp Neurol 115:376-87
Besharse, J C; Iuvone, P M (1992) Is dopamine a light-adaptive or a dark-adaptive modulator in retina? Neurochem Int 20:193-9