title: The link between mitochondrial complex I and brain-derived neurotrophic factor in SH-SY5Y cells--The potential of JNX1001 as a therapeutic agent.
abstract: Mitochondrial complex I, which is the first member of the electron transport chain responsible for producing ATP, can produce reactive oxygen species and oxidative stress when it becomes dysfunctional. Complex I dysfunction and oxidative stress are strongly implicated in bipolar disorder (BD), a debilitating psychiatric disease, as is decreased levels of brain derived neurotrophic factor (BDNF) found in patients with BD, which is related to complex I activity. JNX1001, a clinical trial ready brain penetrant sapogenin, increases BDNF levels in animal models. Hence, we aimed to examine if JNX1001 can prevent complex I dysfunction-induced alterations produced by rotenone treatment in human neuroblastoma cells (SH-SY5Y). Complex I dysfunction decreased cell viability and increased protein carbonylation and nitration, confirming previous findings. Complex I dysfunction also decreased intracellular and extracellular BDNF levels. JNX1001 pre-treatment prevented complex I dysfunction-induced protein carbonylation and nitration and improved cell viability at concentrations of 30 nM and 300 nM, but more robustly at 300 nM. JNX1001 was also able to prevent decreased intracellular and extracellular BDNF levels, where it produced a ten-fold increase in intracellular BDNF levels at a concentration of 300 nM. While further studies are required to examine the neuroprotective ability of JNX1001 against alterations produced by complex I defect in more complex systems, such as in animal models, the findings of this study demonstrate the potential of JNX1001 to be used as a therapeutic agent to protect against complex I dysfunction-induced alterations that may be highly relevant to BD.
authors.affiliation: Departments of Pharmacology and Psychiatry, University of Toronto, Toronto, ON, Canada M5S 1A8. Electronic address: kyunghee.kim@mail.utoronto.ca.
authors.forename: Helena K
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Federal University of Sao Paulo, Sao Paulo, SP 04021-001 Brazil. Electronic address: kikmm277@gmail.com.
authors.forename: Karina M
authors.initials: KM
authors.lastname: Mendonça
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada M5T 2S8. Electronic address: p.howson@atuka.com.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Howson
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada M5T 2S8. Electronic address: j.brotchie@atuka.com.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
authors.affiliation: Departments of Pharmacology and Psychiatry, University of Toronto, Toronto, ON, Canada M5S 1A8; Centre of Addiction and Mental Health, Toronto, ON, Canada M5T 1R8. Electronic address: ana.andreazza@utoronto.ca.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Andreazza
mesh_terms: D001714:Bipolar Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D050050:Protein Carbonylation / Q000187:drug effects; D012402:Rotenone / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D013150:Spirostans / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000609174:JNX1001; D018696:Neuroprotective Agents; D013150:Spirostans; D012402:Rotenone; C002744:3-nitrotyrosine; D014443:Tyrosine; C579455:BDNF protein, human; D042967:Electron Transport Complex I
keywords: BDNF; Carbonylation; JNX1001; Mitochondrial complex I; Nitration; Oxidative stress