title: Dysregulation of neurotrophic and inflammatory systems accompanied by decreased CREB signaling in ischemic rat retina.
abstract: Although permanent bilateral common carotid artery occlusion (2VO) has been demonstrated to induce retinal injury, there is still a lack of systematic research on the complex processing of retinal degeneration. In the present study, time-dependent (at three, 14, 60 days after 2VO surgery) changes of neurotrophic and inflammatory systems, as well as cAMP-responsive element binding protein (CREB) signaling, which has been previously reported to effectively regulate these two systems, were evaluated. First, a morphological study confirmed that 2VO surgery progressively induced severe inner retinal degeneration and down-regulation of synaptic proteins, PSD95 and synaptophysin. The mRNA or protein levels of neurotrophic factors (NGF, BDNF, NT-3 and GDNF) and their receptors (TrkA, TrkB and TrkC) showed marked and persistent down-regulation in the rat retina since three days after 2VO surgery, whereas the gene transcription levels of CNTF were increased and p75(NTR) mRNA levels remained unchanged. In contrast to inner retinal degeneration, retinal Müller cells displayed rapid and prolonged activation since three days after 2VO lesion, whereas the microglia cell number, and TNF-α and IL-1β levels showed a robust increase with a maximal effect at three days and returned to levels that were slightly over baseline at 14 and 60 days after 2VO lesion. Interestingly, the gene expression levels of iNOS significantly decreased in the rat retina at both three and 14 days after 2VO surgery. Finally, as we hypothesized, remarkable reduction of CREB and extracellular signal-regulated kinase (ERK) phosphorylation levels were observed in the rat retina at three days after 2VO surgery. Thus, for the first time, our study demonstrated that chronic ischemia induced long-term aberrant CREB signaling and time-dependent progressive dysregulation of neurotrophic and inflammatory systems in the retina, which may provide important clues for a better understanding of the pathogenesis of retinal ischemic damage.
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Xian Jun
authors: XJ
authors: Guo
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Xue Song
authors: XS
authors: Tian
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Zhi
authors: Z
authors: Ruan
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Yu Ting
authors: YT
authors: Chen
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Lei
authors: L
authors: Wu
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Qi
authors: Q
authors: Gong
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Wei
authors: W
authors: Wang
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: hzhang@mail.shcnc.ac.cn.
authors: Hai Yan
authors: HY
authors: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015153:Blotting, Western; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D003623:Dark Adaptation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D017628:Microglia / Q000166:cytology; D009414:Nerve Growth Factors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012025:Reflex, Pupillary / Q000502:physiology; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D014157:Transcription Factors; D019892:eIF-2 Kinase; C500984:CRTC1 protein, human
keywords: bilateral common carotid arteries occlusion; cAMP-responsive element binding protein; extracellular signal-regulated kinase; inflammation; neurotrophic system; retina