Parkinson's disease (PD) affects more than a million persons in the U.S. and is the 2nd most common progressive, neurodegenerative disease. Early on, the movement deficits (tremor, rigidity, slowed movement, altered gait), usually respond to oral levodopa (L-DOPA) and other medications. However, with disease progression, L-DOPA's effectiveness gradually diminishes and dyskinesia and motor fluctuations emerge. Most symptoms of PD are due to a reduction of dopamine (DA)-secreting cells in the substantia nigra. In PD, L-DOPA restores function by replacing lost DA. Endogenous L-DOPA and DA concentrations are largely regulated by astrocytes, which maintain extracellular homeostasis. Although astrocytes have several transporter systems for monoamine uptake, including DA, we have shown that astrocytes take up excess of DA via low-affinity, high-capacity Uptake2 transporters. We also demonstrated that astrocytes wrapping around blood vessels take up L-DOPA and contain monoamine oxidase (MAO) type B which oxidizes DA taken up by the cell. We hypothesize that astrocytes take up and oxidize the vast majority of DA converted from L-DOPA, especially when DA neurons are severely degenerated due to PD. Reducing the ability of astrocytes to take up DA through use of specific transporter blockers may permit the use of lower doses of L-DOPA, thereby diminishing DA pulsatility and motor fluctuations. This hypothesis will be tested here in 3 Aims.
Aim 1. Identify the specific transporter molecules involved in dopamine reuptake by astrocytes using brain slice and cell culture models.
Aim 2. Identify which specific transporter blockers can slow DA reuptake using an astrocyte brain slice model.
Aim 3. Identify which Uptake2 blockers are effective in reducing therapeutic L-DOPA concentrations in a whole animal model of PD. The results will greatly enhance the understanding of the role of astrocytes in PD etiology and pave the way to the development of preventive measures for L-DOPA-induced dyskinesia.

Public Health Relevance

L-DOPA is the drug used to relieve Parkinson's symptoms, because it is converted to dopamine which is necessary for motor functions. Our preliminary data indicate that astrocytes remove 'excess' dopamine, thus possibly reducing positive L-DOPA effects. We propose to study how to block temporally the ability of astrocyte to take up dopamine and, therefore, help to decrease L-DOPA dose and side effects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Pilot Research Project (SC2)
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Special Emphasis Panel (ZGM1)
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Krasnova, Irina N
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Universidad Central Del Caribe
Schools of Medicine
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Valentín-Guillama, Gabriel; López, Sheila; Kucheryavykh, Yuriy V et al. (2018) HIV-1 Envelope Protein gp120 Promotes Proliferation and the Activation of Glycolysis in Glioma Cell. Cancers (Basel) 10:
Zayas-Santiago, Astrid; Ríos, David S; Zueva, Lidia V et al. (2018) Localization of ?A-Crystallin in Rat Retinal Müller Glial Cells and Photoreceptors. Microsc Microanal 24:545-552
Inyushin, Mikhail Y; Sanabria, Priscila; Rojas, Legier et al. (2017) A? Peptide Originated from Platelets Promises New Strategy in Anti-Alzheimer's Drug Development. Biomed Res Int 2017:3948360
Makarov, Vladimir; Zueva, Lidia; Golubeva, Tatiana et al. (2017) Quantum mechanism of light transmission by the intermediate filaments in some specialized optically transparent cells. Neurophotonics 4:011005
Khmelinskii, Igor; Golubeva, Tatiana; Korneeva, Elena et al. (2017) Spectral selectivity model for light transmission by the intermediate filaments in Müller cells. J Photochem Photobiol B 173:282-290
Kucheryavykh, Lilia Y; Dávila-Rodríguez, Josué; Rivera-Aponte, David E et al. (2017) Platelets are responsible for the accumulation of ?-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis. Brain Res Bull 128:98-105
Inyushin, M; Kucheryavih, Yu; Kucheryavih, L et al. (2016) Superparamagnetic Properties of Hemozoin. Sci Rep 6:26212
Morales-Cruz, Moraima; Cruz-Montañez, Alejandra; Figueroa, Cindy M et al. (2016) Combining Stimulus-Triggered Release and Active Targeting Strategies Improves Cytotoxicity of Cytochrome c Nanoparticles in Tumor Cells. Mol Pharm 13:2844-54