Involvement of endoplasmic reticulum stress on neuronal cell death in the lateral geniculate nucleus in the monkey glaucoma model.
We investigated whether endoplasmic reticulum (ER) stress was involved in the pathophysiological mechanisms underlying neuronal death of the lateral geniculate nucleus (LGN) after intraocular pressure (IOP) elevation. Five cynomolgus monkeys, four with a glaucomatous left eye after laser photocoagulation treatment and one normal monkey, were studied. At 4, 11, 15 and 24 weeks after the laser photocoagulation treatment, the numbers of LGN neurons and atrophy were immunohistochemically evaluated using anti-parvalbumin-antibody, which was used to specifically label relay neurons connecting to the visual cortex. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, polyubiquitin, and production of ER stress-related proteins, such as the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and C/EBP-homologous protein (CHOP), were also measured using in situ hybridization and immunostaining. Loss of neurons and/or neuronal atrophy in layers 1, 4 and 6 of the LGN on the contralateral side were observed at 4-24 weeks after the laser photocoagulation treatment. Furthermore, the retinal input from the high IOP eye projected to layers 2 (magnocellular layer), 3 and 5 (parvocellular layer) on the ipsilateral side. Neuronal damage was also confirmed in these layers. In the LGN region, TUNEL-positive cells, polyubiquitin, p-eIF2α and CHOP were also detected at 11-24 weeks after the laser photocoagulation treatment. These findings indicate that ER stress may play a pivotal role in neuronal death of the LGN after IOP elevation.
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan.
Yasushi
Y
Ito
Masamitsu
M
Shimazawa
Yuta
Y
Inokuchi
Hajime
H
Yamanaka
Kazuhiro
K
Tsuruma
Kazuyuki
K
Imamura
Hirotaka
H
Onoe
Yasuyoshi
Y
Watanabe
Makoto
M
Aihara
Makoto
M
Araie
Hideaki
H
Hara
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005829:Geniculate Bodies / Q000166:cytology / Q000473:pathology / Q000502:physiology; D005901:Glaucoma / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007429:Intraocular Pressure / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009900:Optic Nerve / Q000166:cytology / Q000473:pathology / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000473:pathology / Q000502:physiology; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000378:metabolism
D051742:Transcription Factor CHOP