title: Lamotrigine Attenuates Proteasome Inhibition-Induced Apoptosis by Suppressing the Activation of the Mitochondrial Pathway and the Caspase-8- and Bid-Dependent Pathways.
abstract: Proteasome impairment has been shown to be involved in neuronal degeneration. Antiepileptic lamotrigine has been demonstrated to have a neuroprotective effect. However, the effect of lamotrigine on the proteasome inhibition-induced neuronal cell death has not been studied. Therefore, we assessed the effect of lamotrigine on the proteasome inhibition-induced neuronal cell apoptosis in relation to cell death process using differentiated PC12 cells and SH-SY5Y cells. The proteasome inhibitors MG132 and MG115 induced a decrease in the levels of Bid and Bcl-2 proteins, an increase in the levels of Bax and p53, loss of the mitochondrial transmembrane potential, cytochrome c release and activation of caspases (-8, -9 and -3). The addition of lamotrigine reduced the proteasome inhibitor-induced changes in the apoptosis-related protein levels, production of reactive oxygen species, depletion and oxidation of glutathione (GSH), and cell death in both cell lines. Lamotrigine and N-acetylcysteine alone did not affect the levels of 26S proteasome and activity of 20S proteasome. MG132 did not alter the levels of 26S proteasome but decreased activity of 20S proteasome. Lamotrigine and N-acetylcysteine attenuated MG132-induced decrease in the activity of 20S proteasome. The results show that lamotrigine appears to suppress the proteasome inhibitor-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The suppressive effect of lamotrigine appears to be associated with its inhibitory effect on the production of reactive oxygen species, the depletion and oxidation of GSH and the activity reduction of 20S proteasome.
authors.affiliation: Department of Pharmacology, College of Medicine, BK21(plus) Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea.
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, College of Medicine, BK21(plus) Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea.
authors.forename: Arum
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, SoonChunHyang University Hospital, Bucheon, Kyung-Gi-Do, 420-767, South Korea.
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, BK21(plus) Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea.
authors.forename: Yong Kyoo
authors.initials: YK
authors.lastname: Shin
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Chung-Ang University Hospital, Seoul, 156-755, South Korea.
authors.forename: Dong Suep
authors.initials: DS
authors.lastname: Sohn
authors.affiliation: Department of Pharmacology, College of Medicine, BK21(plus) Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea. leecs@cau.ac.kr.
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D000077213:Lamotrigine; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D014227:Triazines; D045304:Cytochromes c; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex; D000077213:Lamotrigine
keywords: Antiepileptic lamotrigine; Apoptosis-related proteins; Cell protection; Differentiated PC12 cells; Proteasome inhibition