Human embryonic stem cell-derived dopaminergic grafts alleviate L-DOPA induced dyskinesia
| Autor: | Osama F. Elabi, Rachel Pass, Irene Sormonta, Sara Nolbrant, Nicola Drummond, Agnete Kirkeby, Tilo Kunath, Malin Parmar, Emma L. Lane |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
abnormal involuntary movements
Dyskinesia Drug-Induced Dopamine Amphetamines Human Embryonic Stem Cells Parkinson Disease 6-OHDA lesioned rat human embryonic stem cells Rats Antiparkinson Agents Levodopa Rats Sprague-Dawley Disease Models Animal Cellular and Molecular Neuroscience L-dopa-induced dyskinesia Parkinson’s disease Animals Humans Neurology (clinical) Oxidopamine transplantation |
| Zdroj: | Elabi, O F, Pass, R, Sormonta, I, Nolbrant, S, Drummond, N, Kirkeby, A, Kunath, T, Parmar, M & Lane, E L 2022, ' Human Embryonic Stem Cell-Derived Dopaminergic Grafts Alleviate L-DOPA Induced Dyskinesia ', Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1881-1896 . https://doi.org/10.3233/JPD-212920 Elabi, O F, Pass, R, Sormonta, I, Nolbrant, S, Drummond, N, Kirkeby, A, Kunath, T, Parmar, M & Lane, E L 2022, ' Human embryonic stem cell-derived dopaminergic grafts alleviate L-DOPA induced dyskinesia ', Journal of Parkinson's disease, pp. 1-16 . https://doi.org/10.3233/JPD-212920 |
| ISSN: | 1877-7171 |
| Popis: | Background: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson’s disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft. Objective: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons. Methods: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for 18 weeks following surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories. Results: Grafts from both protocols elicited reduction in amphetamine-induced rotations. Reduced L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) or dopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons. Conclusion: Critically, we found that L-DOPA was not detrimental to graft function, potentially enhancing graft maturation and promoting an A9 phenotype. Early improvement of L-DOPA-induced dyskinesia suggests that grafts may support the handling of exogenously supplied dopamine earlier than improvements in amphetamine-induced behaviours indicate. Given that one of the protocols will be employed in the production of cells for the European STEM-PD clinical trial, this is vital information for the management of patients and achieving optimal outcomes following transplantation of hESC-derived grafts for PD. |
| Databáze: | OpenAIRE |
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