Intracellular disulfide reduction by phosphine-borane complexes: Mechanism of action for neuroprotection.
Phosphine-borane complexes are novel cell-permeable drugs that protect neurons from axonal injury in vitro and in vivo. These drugs activate the extracellular signal-regulated kinases 1/2 (ERK1/2) cell survival pathway and are therefore neuroprotective, but do not scavenge superoxide. In order to understand the interaction between superoxide signaling of neuronal death and the action of phosphine-borane complexes, their biochemical activity in cell-free and in vitro assays was studied by electron paramagnetic resonance (EPR) spectrometry and using an intracellular dithiol reporter that becomes fluorescent when its disulfide bond is cleaved. These studies demonstrated that bis(3-propionic acid methyl ester) phenylphosphine-borane complex (PB1) and (3-propionic acid methyl ester) diphenylphosphine-borane complex (PB2) are potent intracellular disulfide reducing agents which are cell permeable. EPR and pharmacological studies demonstrated reducing activity but not scavenging of superoxide. Given that phosphine-borane complexes reduce cell injury from mitochondrial superoxide generation but do not scavenge superoxide, this implies a mechanism where an intracellular superoxide burst induces downstream formation of protein disulfides. The redox-dependent cleavage of the disulfides is therefore a novel mechanism of neuroprotection.
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, United States.
Nicholas J
NJ
Niemuth
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, United States.
Alex F
AF
Thompson
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, United States.
Megan E
ME
Crowe
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, United States.
Christopher J
CJ
Lieven
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, United States; Departments of Ophthalmology and Neurology, McGill University, Canada.
Leonard A
LA
Levin
D000818:Animals; D001880:Boranes / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D004220:Disulfides / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D000066829:Neuroprotection / Q000502:physiology*; D010084:Oxidation-Reduction; D010720:Phosphines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013552:Swine
D001880:Boranes; D004220:Disulfides; D010720:Phosphines; C515674:bis(3-propionic acid methyl ester)diphenylphosphine borane complex; C515673:bis(3-propionic acid methyl ester)phenylphosphine borane complex
Disulfide reduction; Neuroprotection; Phosphine-borane complexes