title: Sodium channels contribute to degeneration of dorsal root ganglion neurites induced by mitochondrial dysfunction in an in vitro model of axonal injury.
abstract: Axonal degeneration occurs in multiple neurodegenerative disorders of the central and peripheral nervous system. Although the underlying molecular pathways leading to axonal degeneration are incompletely understood, accumulating evidence suggests contributions of impaired mitochondrial function, disrupted axonal transport, and/or dysfunctional intracellular Ca(2+)-homeostasis in the injurious cascade associated with axonal degeneration. Utilizing an in vitro model of axonal degeneration, we studied a subset of mouse peripheral sensory neurons in which neurites were exposed selectively to conditions associated with the pathogenesis of axonal neuropathies in vivo. Rotenone-induced mitochondrial dysfunction resulted in neurite degeneration accompanied by reduced ATP levels and increased ROS levels in neurites. Blockade of voltage-gated sodium channels with TTX and reverse (Ca(2+)-importing) mode of the sodium-calcium exchanger (NCX) with KB-R7943 partially protected rotenone-treated neurites from degeneration, suggesting a contribution of sodium channels and reverse NCX activity to the degeneration of neurites resulting from impaired mitochondrial function. Pharmacological inhibition of the Na(+)/K(+)-ATPase with ouabain induced neurite degeneration, which was attenuated by TTX and KB-R7943, supporting a contribution of sodium channels in axonal degenerative pathways accompanying impaired Na(+)/K(+)-ATPase activity. Conversely, oxidant stress (H2O2)-induced neurite degeneration was not attenuated by TTX. Our results demonstrate that both energetic and oxidative stress targeted selectively to neurites induces neurite degeneration and that blockade of sodium channels and of reverse NCX activity blockade partially protects neurites from injury due to energetic stress, but not from oxidative stress induced by H2O2.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510; and Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut 06516.
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Persson
authors.forename: Insil
authors.initials: I
authors.lastname: Kim
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Mark
authors.initials: M
authors.lastname: Estacion
authors.forename: Joel A
authors.initials: JA
authors.lastname: Black
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D019771:Axotomy; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000502:physiology; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000503:physiopathology*; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D016877:Oxidants / Q000633:toxicity; D012402:Rotenone / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000502:physiology; D013779:Tetrodotoxin / Q000633:toxicity; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D016877:Oxidants; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D014475:Uncoupling Agents; D012402:Rotenone; D013779:Tetrodotoxin; D006861:Hydrogen Peroxide; D000254:Sodium-Potassium-Exchanging ATPase; D013890:Thiourea