Olomoucine inhibits cathepsin L nuclear translocation, activates autophagy and attenuates toxicity of 6-hydroxydopamine.
The finding of nuclear translocation of cathepsin L and its ability to process the CDP/Cux transcription factor uncovers an important role of cathepsin L in control of cell cycle progression. As the expression of certain cell cycle regulators is associated with nigral neuronal death, the present study was sought to investigate if nuclear translocation of cathepsin L and expression of certain cyclins were induced in DA neurons by 6-hydroxydopamine (6-OHDA). The neuroprotective effects of the cell cycle inhibitor olomoucine against 6-OHDA-induced death of nigral neurons were examined. Using immunocytochemistry and real-time PCR we demonstrated that cyclin D1, cyclin B1 and proliferating cell nuclear antigen (PCNA) were aberrantly expressed in some dopaminergic neurons after 6-OHDA infusion. The nuclear translocation of cathepsin L and up-regulation of LC3, a protein involved in autophagy, were observed in nigral DA neurons. Olomoucine, a cyclin dependent kinase (CDK) inhibitor, reduced contralateral rotations and the loss of TH-positive neurons in substantia nigra induced by lesion with 6-OHDA. Pretreatment of rats or primary DA neurons with olomoucine resulted in a partial blockade of nuclear translocation of cathepsin L. Olomoucine also increased the expression of punctate LC3 immunoreactivity, indicating activation of autophagy. These findings suggest that olomoucine may exert neuroprotective effects through inhibiting cathepsin L nuclear translocation and activating autophagy.
Department of Pharmacology, Soochow University School of Medicine, Suzhou, China.
Xi-Feng
XF
Fei
Zheng-Hong
ZH
Qin
Bei
B
Xiang
Ling-Yun
LY
Li
Feng
F
Han
Kohji
K
Fukunaga
Zhong-Qin
ZQ
Liang
D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D007701:Kinetin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D056668:Cathepsin L; D002403:Cathepsins; D019926:Cyclin B; D019938:Cyclin D1; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors; D007701:Kinetin; D008869:Microtubule-Associated Proteins; D016627:Oxidopamine; D018809:Proliferating Cell Nuclear Antigen; D014446:Tyrosine 3-Monooxygenase; C526109:Anxa3 protein, rat; C090046:olomoucine; C534280:Ctsl protein, rat