Stage-dependent vulnerability of fetal mesencephalic neuroprogenitors towards dopaminergic neurotoxins

• Published in: Neurotoxicology (Park Forest South) Vol. 29; no. 4; pp. 714 - 721
• Main Authors: Sabolek, Michael, Mieskes, Ines, Lenk, Thomas, Lehmensiek, Vera, Hermann, Andreas, Schwarz, Johannes, Storch, Alexander
• Format: Journal Article
• Language: English
• Published: Orlando, FL Elsevier B.V 01.07.2008; Elsevier
• Subjects: 1-Methyl-4-phenylpyridinium (MPP +); 1-Methyl-4-phenylpyridinium - pharmacology; 6-Hydroxydopamine; Animals; Biological and medical sciences; Cell Count - methods; Cell Death - drug effects; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Colforsin - pharmacology; Cytokines - pharmacology; Dopamine - metabolism; Dopaminergic toxicity; Dose-Response Relationship, Drug; Embryo, Mammalian; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; H 2O 2; Hydrogen Peroxide - metabolism; Medical sciences; Mesencephalon - cytology; Mesencephalon - embryology; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Neural stem cells; Neurons - drug effects; Neurons - physiology; Neuroprogenitor cells; Oxidopamine - pharmacology; Rats; Rats, Wistar; Stem Cells - drug effects; Stem Cells - physiology; Time Factors; Toxicology; H 2O 2; Neuroprogenitor cells; Neural stem cells; Dopaminergic toxicity; 1-Methyl-4-phenylpyridinium (MPP +); 6-Hydroxydopamine; Toxin; Clinical stage; 1-Methyl-4-phenylpyridinium (MPP+);6-Hydroxydopamine;H2O2;Neuroprogenitor cells;Neural stem cells;Dopaminergic toxicity; Toxicity; Neurotoxin; Fetus; Vulnerability; Stem
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2008.04.007

Although extensive knowledge exists on selective vulnerability of dopaminergic neurons against parkinsonism-inducing neurotoxins, there is a complete lack of such data on immature neuroprogenitors. Here we investigated the toxicity of 1-methyl-4-phenylpyridinium (MPP +), 6-hydroxydopamine (6-OHDA) and the free radical generator H 2O 2 on various developmental stages of predopaminergic mesencephalic neuroprogenitors (mNPCs) to evaluate stage-dependency of selective dopaminergic neurotoxicity. Striatal NPCs (sNPCs) without dopaminergic differentiation potential served as controls. Exposure of both undifferentiated NPCs to MPP + resulted in concentration-dependent cell death at concentrations of >10 μM after 72 h without differences between both cell types, while 6-OHDA led to relevant cell death at 1000 μM after 24 h with significant higher sensitivity of mNPCs compared to sNPCs. H 2O 2 did not induce relevant cell death in all cell types. In NPC cultures differentiated for 14 days, MPP + showed enhanced toxicity compared to the undifferentiated counterparts, but no significant differences between both NPC type and differentiation conditions. 6-OHDA showed similar toxicity pattern in differentiated compared to undifferentiated NPCs. By evaluating the toxicity of MPP + on MAP2ab + neurons derived from both mNPCs and sNPCs as well as tyrosine hydroxylase (TH) + dopaminergic cells from mNPCs, we found concentration-dependent cell death of all cell types with no increased vulnerability of TH + cells. Primary TH + neurons showed significantly higher vulnerability to MPP +. Together, we demonstrated stage-dependent vulnerability of NPCs towards dopaminergic neurotoxins, but no selective vulnerability of NPC-derived TH + dopaminergic cells towards MPP +. This cell system seems not suitable as a screening tool for selective dopaminergic toxicity.