title: Therapeutic Retrobulbar Inhibition of STAT3 Protects Ischemic Retina Ganglion Cells.
abstract: Astrocytes play an important role in the pathogenesis of glaucoma. Abnormal activation and/or proliferation of astrocytes, termed astrogliosis, have been observed during optic nerve degeneration. Our previous study identified signal transducer and activator of transcription 3 (STAT3) signaling as an important regulator of astrogliosis in the optic nerve in a rat transient ischemia/reperfusion model. In this study, we used pharmacological inhibition of STAT3 activation in the same model to assess whether it could attenuate reactive astrogliosis and to observe its influence on optic nerve damage and retinal ganglion cell (RGC) damage. Our findings show that retrobulbar inhibition of STAT3 in optic nerve head astrocytes leads to (a) increased nerve fiber bundle survival in the optic nerve, (b) increased nerve fiber bundle and RGC survival in the retina, (c) decreased astrocyte reactivation in the optic nerve (d) decreased remodeling of astrocytes in the optic nerve, and (e) no influence of astrocyte reactivation inside the retina. Taken together, the Janus kinase/STAT3 pathway contributes to astrocyte reactivation in the optic nerve, which plays a pivotal role in neurodegeneration after transient ischemia/reperfusion in vivo. Inhibition of this pathway provides a potential therapeutic strategy for the treatment of glaucomatous neuropathy, and could extend to other neurodegenerative diseases.
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China.
authors.forename: Mansin
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100191, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China.|Department of Ophthalmology, Shenyang Institute of Ophthalmology, The 4th People's Hospital of Shenyang, Liaoning, 110031, China.
authors.forename: Shaodan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China.|Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: School of Psychology, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Chaoran
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Neural & Behavioral Sciences, Pennsylvania State University, Hershey, PA, 17033, USA.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Barnstable
authors.affiliation: Department of Neural & Behavioral Sciences, Pennsylvania State University, Hershey, PA, 17033, USA.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Peking University Eye Center, Peking University Third Hospital, Beijing, 100191, China. huangping512@gmail.com.|Department of Ophthalmology, Peking University Third Hospital, 49 North Huayuan Road, Beijing, 100191, China. huangping512@gmail.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004341:Drug Evaluation; D005901:Glaucoma / Q000150:complications; D005911:Gliosis / Q000209:etiology / Q000517:prevention & control; D056965:Injections, Intraocular; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009798:Ocular Hypertension / Q000139:chemically induced / Q000150:complications; D009898:Optic Disk / Q000473:pathology*; D018917:Optic Neuropathy, Ischemic / Q000188:drug therapy* / Q000209:etiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507927:Jak2 protein, rat; D053614:Janus Kinase 2
keywords: Astrocyte; Astrogliosis; Glaucoma; JAK/STAT3 pathway; Neuroprotection; Optic nerve head