Effects of scoparone on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells.
The effects of scoparone on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. PC12 cells treated with scoparone at concentrations of 100-200 microM showed a 128-136% increase in dopamine levels over the course of 24 hr. Scoparone significantly increased the secretion of dopamine into the culture medium. Under the same conditions, the activities of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) were enhanced by treatment with 200 microM scoparone for 6-48 hr, but the activity of TH was regulated for a longer period than that of AADC. The intracellular levels of cyclic AMP and Ca(2+) were increased by treatment with 200 microM scoparone. The levels of TH mRNA and the phosphorylation of cyclic AMP-response element-binding protein (CREB) were also significantly increased by treatment with 200 microM scoparone. In addition, scoparone at a concentration of 200 microM stimulated the activities of cyclic AMP-dependent protein kinase (PKA), protein kinase C (PKC), and Ca(2+)/calmodulin kinase II (CaMK II). Finally, pretreatment with 200 microM scoparone reduced the cytotoxicity induced by L-DOPA (20-100 microM) at 24 hr. These results suggest that scoparone enhances dopamine biosynthesis by regulating TH activity and TH gene expression, which is mediated by the PKA, CREB, PKC, and CaMK II pathways, and protects cells from L-DOPA-induced cytotoxicity by inducing cyclic AMP-PKA systems in PC12 cells.
Yang
Yoo Jung
YJ
College of Pharmacy and Research Center for Bioresources and Health, Chungbuk National University, Cheongju, Republic of Korea.
Lee
Hak Ju
HJ
Huang
Hai Shan
HS
Lee
Byung Koo
BK
Choi
Hyun Sook
HS
Lim
Sung Cil
SC
Lee
Chong Kil
CK
Lee
Myung Koo
MK
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003374:Coumarins / Q000494:pharmacology* / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism; D003603:Cytotoxins / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000633:toxicity; D004298:Dopamine / Q000096:biosynthesis*; D015259:Dopamine Agents / Q000009:adverse effects / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D003374:Coumarins; D003603:Cytotoxins; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D014665:Vasodilator Agents; D007980:Levodopa; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D011494:Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C018145:scoparone; D004298:Dopamine