title: A cell-permeable phosphine-borane complex delays retinal ganglion cell death after axonal injury through activation of the pro-survival extracellular signal-regulated kinases 1/2 pathway.
abstract: The reactive oxygen species (ROS) superoxide has been recognized as a critical signal triggering retinal ganglion cell (RGC) death after axonal injury. Although the downstream targets of superoxide are unknown, chemical reduction of oxidized sulfhydryls has been shown to be neuroprotective for injured RGCs. On the basis of this, we developed novel phosphine-borane complex compounds that are cell permeable and highly stable. Here, we report that our lead compound, bis (3-propionic acid methyl ester) phenylphosphine borane complex 1 (PB1) promotes RGC survival in rat models of optic nerve axotomy and in experimental glaucoma. PB1-mediated RGC neuroprotection did not correlate with inhibition of stress-activated protein kinase signaling, including apoptosis stimulating kinase 1 (ASK1), c-jun NH2-terminal kinase (JNK) or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and downstream activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway. Pharmacological inhibition of ERK1/2 entirely blocked RGC neuroprotection induced by PB1. We conclude that PB1 protects damaged RGCs through activation of pro-survival signals. These data support a potential cross-talk between redox homeostasis and neurotrophin-related pathways leading to RGC survival after axonal injury.
authors.affiliation: Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central (GRSNC), University of Montreal, Montreal, Quebec, Canada.
authors.forename: Mohammadali
authors.initials: M
authors.lastname: Almasieh
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lieven
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Levin
authors.forename: Adriana
authors.initials: A
authors.lastname: Di Polo
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D019771:Axotomy; D015153:Blotting, Western; D001880:Boranes / Q000493:pharmacokinetics / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D016923:Cell Death; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009798:Ocular Hypertension / Q000473:pathology; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000473:pathology; D010720:Phosphines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019163:Reducing Agents / Q000138:chemical synthesis / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000737:chemistry
chemical_list: D001880:Boranes; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010720:Phosphines; D019163:Reducing Agents; C515673:bis(3-propionic acid methyl ester)phenylphosphine borane complex; D013481:Superoxides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3