title: Systemic simvastatin rescues retinal ganglion cells from optic nerve injury possibly through suppression of astroglial NF-κB activation.
abstract: Neuroinflammation is involved in the death of retinal ganglion cells (RGCs) after optic nerve injury. The purpose of this study was to determine whether systemic simvastatin can suppress neuroinflammation in the optic nerve and rescue RGCs after the optic nerve is crushed. Simvastatin or its vehicle was given through an osmotic minipump beginning one week prior to the crushing. Immunohistochemistry and real-time PCR were used to determine the degree of neuroinflammation on day 3 after the crushing. The density of RGCs was determined in Tuj-1 stained retinal flat mounts on day 7. The effect of simvastain on the TNF-α-induced NF-κB activation was determined in cultured optic nerve astrocytes. On day 3, CD68-positive cells, most likely microglia/macrophages, were accumulated at the crushed site. Phosphorylated NF-κB was detected in some astrocytes at the border of the lesion where the immunoreactivity to MCP-1 was intensified. There was an increase in the mRNA levels of the CD68 (11.4-fold), MCP-1 (22.6-fold), ET-1 (2.3-fold), GFAP (1.6-fold), TNF-α (7.0-fold), and iNOS (14.8-fold) genes on day 3. Systemic simvastatin significantly reduced these changes. The mean ± SD number of RGCs was 1816.3±232.6/mm(2) (n = 6) in the sham controls which was significantly reduced to 831.4±202.5/mm(2) (n = 9) on day 7 after the optic nerve was crushed. This reduction was significantly suppressed to 1169.2±201.3/mm(2) (P = 0.01, Scheffe; n = 9) after systemic simvastatin. Simvastatin (1.0 µM) significantly reduced the TNF-α-induced NF-κB activation in cultured optic nerve astrocytes. We conclude that systemic simvastatin can reduce the death of RGCs induced by crushing the optic nerve possibly by suppressing astroglial NF-κB activation.
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Seita
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Oku
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Horie
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tonari
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Teruyo
authors.initials: T
authors.lastname: Kida
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Okubo
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Department of Pharmacology, Osaka Medical College, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D007150:Immunohistochemistry; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D019332:Endothelin-1; D016328:NF-kappa B; D019821:Simvastatin; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule