Activation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's disease.
BACKGROUND
Parkinson's disease (PD) is caused by degeneration of dopamine (DA) neurons in the ventral midbrain (vMB) and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR) provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons in vitro. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable in vitro-platform using mouse embryonic stem cells (mESCs).


RESULTS
We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268) and the RXR-Nurr1 ligand XCT0139508 (XCT) in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA) and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H2O2) or the excitotoxic agent kainic acid (KA). The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions.


CONCLUSIONS
RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible in vitro-platform for studying PD inducing toxins and potential trophic agents.
Friling
Stina
S
The Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, S-171 77 Stockholm. stina.friling@vgregion.se
Bergsland
Maria
M
Kjellander
Susanna
S
D000818:Animals; D001711:Biotransformation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D053595:Embryonic Stem Cells; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D010300:Parkinson Disease; D051381:Rats; D047488:Retinoid X Receptors / Q000502:physiology*
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D047488:Retinoid X Receptors; D004298:Dopamine