Effects of dopamine and L-DOPA on survival of PC12 cells.
The effects of dopamine and L-DOPA on survival were examined in differentiated PC12 cells. Addition of dopamine to the culture medium at 3-30 microM prevented cell death induced by depletion of serum and nerve growth factor (NGF). At 100 microM, dopamine induced cell death. The cell-protective effect of dopamine was not affected by nomifensine, an inhibitor of dopamine uptake, or pargyline, an inhibitor of monoamine oxidase, suggesting that dopamine is working outside the cell. The cell-protective effect of dopamine was blunted by SCH-23390, a D(1) antagonist, but not sulpiride, a D(2) antagonist, indicating that the cell protective effect of dopamine is mediated by D(1) receptors in PC12 cells. L-DOPA also protected PC12 cells from cell death induced by depletion of serum and NGF at low concentrations and showed toxicity at high concentration. The effect of L-DOPA was unchanged after inhibition of conversion of L-DOPA to dopamine by m-hydroxybenzylhydrazine (NSD-1015), an inhibitor of DOPA decarboxylase, suggesting that L-DOPA itself is working for cell protection. Intracellular Ca(2+) concentration and mitogen-activated protein (MAP) kinase activity were increased by both dopamine and L-DOPA. The effects of dopamine and L-DOPA on cell survival were blunted by nicardipine, a Ca(2+) channel blocker, and PD-98059, an inhibitor of MAP kinase kinase (MEK). These results taken together raised the possibility that dopamine and L-DOPA protect PC12 cells from cell death at low concentrations by activating MAP kinase activity via elevation of intracellular Ca(2+) concentration.
Koshimura
K
K
First Division, Department of Medicine, Shimane Medical University, Izumo, Japan. kunio@shimane-med.ac.jp
Tanaka
J
J
Murakami
Y
Y
Kato
Y
Y
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002121:Calcium Channel Blockers; D016895:Culture Media, Serum-Free; D018765:Dopamine Uptake Inhibitors; D005419:Flavonoids; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D017447:Receptors, Dopamine D1; D007980:Levodopa; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium; D004298:Dopamine