ABSTRACT
Degenerative neurological diseases have multiple roots and interactive pathogeneses, and many are characterized by the loss of relatively vulnerable groups of neurons. A major pathological hallmark of Parkinson’s disease (PD) is the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc), which subsequently causes a dysregulation of striatal neurotransmission and development of motor symptoms of PD (bradykinesia, rigidity, tremor) (Fahn 2003). If possible, it would be reasonable to initiate neuroprotective strategies at preclinical stages of the disease to prevent further neuronal degeneration. However, in reality, most patients remain free of clinical motor symptoms until the PD pathology has already reached an advanced stage, with most (∼60%) of the relatively vulnerable dopamine neurons dysfunctional or dead and with a consequent depletion of roughly 70% of striatal dopamine (Cooper et al. 2009, Isacson and Kordower 2008) (Figure 69.1). For this reason, and since any retardation of degeneration is unlikely to be absolute, it is rational to develop cell replacement for the lost neurons (Figure 69.1). Such “live cell” replacement therapies are conceptually different from classical pharmacology. The current mainstay treatment for PD is based on a pharmacological approach using levodopa or dopaminergic agonists that elevate dopamine levels or stimulate dopamine receptors. Although this treatment can be effective for many years, its long-term and chronic use can
result in the development of “motor complications,” including wearing-off, “on-off” Ÿuctuations, and abnormal movements termed levodopa-induced dyskinesia (Fahn 2003). Levodopa crosses the blood-brain barrier where it is converted to dopamine by dopa-decarboxylase-containing cells; these include the remaining striatal dopaminergic terminals themselves and also non-dopaminergic cells, including cells in the blood-brain barrier wall and serotonin neurons (Figure 69.2). Conversion of levodopa to dopamine in non-dopaminergic cells following oral (noncontinuous) administration of levodopa results in a pulsatile, non-physiological release of dopamine, which may act on supersensitive dopamine receptors in the striatum and contribute to the development of dyskinesia (Cenci and Lindgren 2007). Cell-based therapy approaches in PD aim to replace nigrostriatal dopamine terminals lost by the disease process, with fetal or stem cell-derived dopamine neurons placed directly into the striatum and substantia nigra (Figure 69.2). The new dopamine neurons grow and integrate with host neurons (Doucet et al. 1989, Freund et al. 1985, Mahalik et al. 1985, Soderstrom et al. 2008) and release dopamine in a physiological manner (Isacson 2003, Piccini et al. 1999, 2000, Vinuela et al. 2008), with long-term remarkable and neurologically clear benets to PD patients. These clinical benets are associated with evidence of physiological changes (Ÿuorodopa positron emission tomography [PET] scans and functional magnetic resonance imaging) (Figure 69.3), with long-lasting (beyond 14 years) and clinically meaningful (approximately 50%–60% reduction in Unied Parkinson’s Disease Rating Scale [UPDRS] scores off dopaminergic drug therapy) benet
Transfer of Midbrain Dopamine Neurons for Cell Restorative Therapy in Parkinson’s Disease ............................................. 921 Methodological Differences in the Initial Clinical Applications of Cell-Based Neurorestorative Treatment Approaches for Parkinson’s Disease ........................................................................................................................ 922 Optimizing Graft Function and Reducing Adverse Effects by Obtaining a Specic Cellular Dopamine Replacement and Reconstitution of Synaptic Connectivity .................................................................................... 926 Subpopulations of Midbrain Dopamine Neurons Perform Different Functions and Reach Different Targets: Potential Relevance to Repair of Parkinson’s Disease Brains ................................................... 929 Generation of a Stem Cell-Derived Therapy for Parkinson’s Disease ..................................................................................... 930
Embryonic Stem Cells.......................................................................................................................................................... 931 Induced Pluripotent Stem Cells ............................................................................................................................................ 931
Future Considerations ............................................................................................................................................................... 932 Acknowledgments ..................................................................................................................................................................... 932 References ................................................................................................................................................................................. 932
(Mendez et al. 2005, Piccini et al. 1999, 2000). Transfer of a fetal dopamine neuron-containing suspension (about 5% dopamine cell content) into the putamen (Mendez et al. 2002, 2005, Piccini et al. 1999, 2000) has so far yielded the best results in PD patients.
