Replacement of striatal dopamine (DA) remains the main goal of therapeutics for Parkinson's disease (PD). Many therapeutic alternatives to levodopa therapy are being tested. Among these is transplantation of immature DA neurons either derived from fetal donors or stem cells. This approach continues to be conceptually attractive, especially for late stage PD in which therapies that rely upon plasticity of remaining neurons are unlikely to be effective. The main problem associated with use of cell implants is the extremely poor survival of grafted DA neurons and/or the instability of DA phenotype after grafting. Over the past several years we have identified several molecules that augment survival and function of cultured and grafted fetal DA neurons. Many of these molecules ameliorate the negative impact of distinct threats to DA neuron viability. It is the goal of this proposal to systematically evaluate combinations of these factors to formulate a therapy to optimize survival and function of grafted DA neurons. Such an optimal approach will allow reduction in the number of cells required for therapeutic efficacy, improve standardization of graft composition and potentially enrich grafts in the DA neuron type relevant for striatal DA replacement. Cell grafts derived from fetal or stem cell sources contain a mixture of the major DA neuron types of the midbrain: A9 type and A10 type. It recently has been demonstrated that only A9 type neurons reinnervate the striatum after grafting. Thus, our analysis of augmentation effects will focus upon determining whether particular combination therapies specifically enrich the DA neuron population in the relevant A9 cell type. Our previous studies have identified the following molecules to be individually effective in promoting survival and function of cultured and grafted DA neurons: SO2A conditioned medium (neurotrophic support), vascular endothelial growth factor (VEGF)(neurotrophic, stimulates vascular supply), melatonin (anti-oxidant), creatine (cellular energy), erythropoeitin (anti-apoptotic), and minocycline (anti-inflammatory). We will use a series of experiments utilizing cell culture followed by grafting in DA-depleted rats to formulate a multi-factorial approach to promoting survival and stable DA phenotype in grafted fetal DA neurons and DA neurons derived from human embryonic stem cells. With optimization, cell replacement therapy could become a practical therapeutic option for late stage PD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-N (02))
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Sutherland, Margaret L
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University of Cincinnati
Schools of Medicine
United States
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Madhavan, Lalitha; Daley, Brian F; Davidson, Beverly L et al. (2015) Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration. PLoS One 10:e0137136
Madhavan, Lalitha; Daley, Brian F; Sortwell, Caryl E et al. (2012) Endogenous neural precursors influence grafted neural stem cells and contribute to neuroprotection in the parkinsonian rat. Eur J Neurosci 35:883-95
Kordower, Jeffrey H; Dodiya, Hemraj B; Kordower, Adam M et al. (2011) Transfer of host-derived ? synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 43:552-7
Madhavan, Lalitha; Collier, Timothy J (2010) A synergistic approach for neural repair: cell transplantation and induction of endogenous precursor cell activity. Neuropharmacology 58:835-44
Madhavan, Lalitha; Daley, Brian F; Paumier, Katrina L et al. (2009) Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson's disease. J Comp Neurol 515:102-15