title: Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury.
abstract: The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI). In vivo retinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and the N-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI.
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Namekata
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Harada
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Katome
authors.affiliation: Department of Neuro-ophthalmology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mitamura
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Department of Neuro-ophthalmology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan. Electronic address: harada-tk@igakuken.or.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Harada
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000627:therapeutic use; D002452:Cell Count; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use; D020221:Optic Nerve Injuries / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012038:Regeneration / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D002352:Carrier Proteins; C410623:Dock3 protein, mouse; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Axon regeneration; Dock3; Neuroprotection; Optic nerve injury; p38