Nigral Graft Programmes
Functional repair of experimental parkinsonism with nigral grafts
- to understand the principles of survival and function of dopamine cell transplantation in experimental animals;
- to develop strategies from experimental protocols in the research laboratory to clinical application;
- to identify alternative sources of donor tissue to replace or avoid
the present dependent on human foetal tissues in clinical transplantation.
At present, no more than 5-10% of dopamine cells survive in nigral transplants, whether undertaken in rats and mice, monkeys or man. The loss of cells occurs predominantly in the first hours and days after transplantation. We seek to refine methods of cell preparation, to identify strategies for delivering neurotrophic molecules, and the administration of various neuroprotective regimes, with the ultimate goal of achieving >50% survival.
This will be sufficient to use one donor to one host in present clinical transplantation trials using primary embryonic tissues, and will translate to improved survival in future trials using alternative sources of cells and tissues also.
At present we do not understand fully the mechanisms by which grafts exert a functional effect on the host animals. Is it by providing an alternative source of secreted dopamine? Is it by replacing neurons that restore proper connections in the host brain? The research programme seeks to understand the mechanisms of recovery when it occurs, and the reasons for failure when it does not so that future trials can be designed to address the particular patterns and profiles of symptoms relevant to the patients.
At present we have a variety of simple motor test for evaluating graft function in rats and mice. In parallel we are developing refined tests of cognition and motor control that can yield more valid indices of functional impairment and recovery relevant to problems actually suffered by patients.
Selected recent publications
- Torres EM, Dunnett SB (2006) Amphetamine induced rotations in the assessment of lesions and grafts in the unilateral rat model of Parkinson's disease. Eur Neuropsychopharmacol in press.
- Dowd E, Monville C, Torres EM, Dunnett SB (2005) The corridor task: a simple test of lateralised response selection and neglect sensitive to unilateral dopamine deafferentation and graft-derived replacement in the striatum. Brain Res Bull 68: 24-30.
- Dowd E, Dunnett SB (2005) Comparison of 6-hydroxydopamine-induced medial forebrain bundle and nigrostriatal terminal lesions using a lateralised nose-poking task in rats. Behav Brain Res 159: 153-161.
- Dowd E, Dunnett SB (2005) Comparison of 6-hydroxydopamine-induced medial forebrain bundle and nigrostriatal terminal lesions in rats using a lateralised nose-poking task with low stimulus-response compatibility. Behav Brain Res 165: 181-186.
- Dowd E, Dunnett SB (2004) Deficits in a lateralised associative learning task in dopamine-depleted rats, with selective recovery by dopamine-rich transplants. Eur J Neurosci 20: 1953-1959.
- Björklund A, Dunnett SB, Brundin P, Stoessl AJ, Freed CR, Breeze RE, Levivier M, Peschanski M, Studer L, Barker R (2003) Neural transplantation for the treatment of Parkinson's disease. Lancet Neurol 2: 437-445.
- Zietlow R, Sinclair SR, Schwiening CJ, Dunnett SB, Fawcett JW (2002) The release of excitatory amino acids, dopamine and potassium following transplantation of embryonic mesencephalic dopaminergic grafts to the rat striatum, and their effect on dopaminergic neuronal survival in vitro. Cell Transplant 11: 637-652.
- Brundin P, Dunnett SB, Björklund A, Nikkhah G (2001) Transplanted dopaminergic neurons: More or less? Nat Med 7: 512.
- Dunnett SB, Björklund A, Lindvall O (2001) Cell therapy in Parkinson's disease - stop or go? Nat Rev Neurosci 2: 365-369.
- Hurelbrink CB, Armstrong RJE, Luheshi LM, Dunnett SB, Rosser AE, Barker RA (2001) Death of dopaminergic neurons in vitro and in nigral grafts: re-evaluating the role of caspase activation. Exp Neurol 171: 46-58.
- Dunnett SB, Björklund A (2000) Functional Neural Transplantation II. Novel Cell Therapies for CNS Disorders. Amsterdam: Elsevier Science.
- Winkler C, Kirik D, Björklund A, Dunnett SB (2000) Transplantation in the rat model of Parkinson's disease: ectopic versus homotopic graft placement. Prog Brain Res 127: 233-265.
- Sinclair SR, Fawcett JW & Dunnett (1999). Dopamine cells in nigral grafts differentiate prior to implantation. Eur J Neurosci 11: 4341-4348.
- Dunnett SB & Björklund A (1999). Prospects for new restorative and neuroprotective treatments in Parkinson's disease. Nature 399 (suppl.): 32-39.
- Sinclair SR, Zietlow R, Fawcett JW & Dunnett (1999). Delayed implantation of nigral grafts improves survival of dopamine neurones and rate of functional recovery. NeuroReport 10: 1263-1267