Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage.
Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.
Bachmann
Rosilla F
RF
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
Yun
Y
Yuan
Peixiong
P
Zhou
Rulun
R
Li
Xiaoxia
X
Alesci
Salvatore
S
Du
Jing
J
Manji
Husseini K
HK
D000447:Aldehydes; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001921:Brain / Q000648:ultrastructure; D045744:Cell Line, Tumor; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D009447:Neuroblastoma / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009930:Organic Chemicals; D010101:Oxygen Consumption / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D000447:Aldehydes; D018692:Antimanic Agents; D000697:Central Nervous System Stimulants; C507919:MitoTracker Red 580; D009930:Organic Chemicals; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; C111472:mitotracker green FM; D008694:Methamphetamine; D014635:Valproic Acid; D045304:Cytochromes c; D008094:Lithium; D014446:Tyrosine 3-Monooxygenase; D003576:Electron Transport Complex IV