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Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension.
Mol Vis. 2011 Apr 06; 17:864-75.MV

Abstract

PURPOSE

To correlate retinal ganglion cell (RGC) loss and optic nerve (ON) damage with the duration of acute glaucoma attacks in a rat experimental model and to determine whether the c-Jun N-terminal kinase (JNK) inhibitor SP600125 protects against such attacks.

METHODS

To model an acute glaucoma attack, rat intraocular pressure (IOP) was elevated by a controllable compression method using pulleys and specific weights. Intraocular pressure was measured with a TonoLab® rebound tonometer. Time-dependent ocular hypertension-induced damage was evaluated by ON morphology, retina morphology (both retina layer thickness in cross-sections and RGC counts in Dextran tetramethylrhodamine crystals [DTMR] labeled flatmounts), and scotopic flash electroretinography (ERG). A c-Jun N-terminal kinase (JNK) inhibitor, SP600125 (0, 1.5, 5, or 15 mg/kg), was administered by intraperitoneal injection immediately before and after induction of ocular hypertension, then once daily for seven days. Retinal cross-sections were measured to determine the thickness of various retinal layers and the cell density in the ganglion cell layer (GCL). Retinal flatmounts immunolabeled with anti-rat Brn-3a primary antibody were used to quantify RGC numbers.

RESULTS

Elevated rat IOP induced by corneal limbus compression correlated with the different weights. Elevation to 45 mmHg for up to 7 h did not significantly affect the thicknesses of the outer nuclear layer, outer plexiform layer, or inner nuclear layer. Amplitudes of A- and B-waves were not affected. However, elevation to 45 mmHg for up to 7 h decreased the inner retinal thickness and caused ON damage. Most importantly, IOP elevation induced a time-dependent RGC loss. Cell density in the GCL decreased to 70%, 62%, and 49% of that of the control after 5 h, 6 h, and 7 h, respectively, of pressure increases. In retinal flatmount studies, labeled RGCs were reduced 56±4% (mean±SEM) versus the control (p<0.001) after 7 h of ocular hypertension. SP600125 dose-dependently protected against ocular hypertension-induced RGC loss. The difference in RGC density between the vehicle and SP600125-treated (15 mg/kg) groups was statistically significant (p<0.001).

CONCLUSIONS

The correlation of inner retinal morphological changes with the duration of the application of 45 mmHg IOP was demonstrated. Treatment with SP600125 significantly protected RGC survival against this insult. Inhibitors of JNK may be an interesting pharmacological class for treating glaucoma.

Authors+Show Affiliations

Department of Physiology, Shandong University School of Medicine, Shandong, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21527996

Citation

Sun, Hui, et al. "Protective Effect of a JNK Inhibitor Against Retinal Ganglion Cell Loss Induced By Acute Moderate Ocular Hypertension." Molecular Vision, vol. 17, 2011, pp. 864-75.
Sun H, Wang Y, Pang IH, et al. Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension. Mol Vis. 2011;17:864-75.
Sun, H., Wang, Y., Pang, I. H., Shen, J., Tang, X., Li, Y., Liu, C., & Li, B. (2011). Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension. Molecular Vision, 17, 864-75.
Sun H, et al. Protective Effect of a JNK Inhibitor Against Retinal Ganglion Cell Loss Induced By Acute Moderate Ocular Hypertension. Mol Vis. 2011 Apr 6;17:864-75. PubMed PMID: 21527996.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension. AU - Sun,Hui, AU - Wang,Ying, AU - Pang,Iok-Hou, AU - Shen,Jiaquan, AU - Tang,Xia, AU - Li,Ying, AU - Liu,Chuanyong, AU - Li,Bing, Y1 - 2011/04/06/ PY - 2010/11/07/received PY - 2011/04/01/accepted PY - 2011/4/30/entrez PY - 2011/4/30/pubmed PY - 2011/9/9/medline SP - 864 EP - 75 JF - Molecular vision JO - Mol Vis VL - 17 N2 - PURPOSE: To correlate retinal ganglion cell (RGC) loss and optic nerve (ON) damage with the duration of acute glaucoma attacks in a rat experimental model and to determine whether the c-Jun N-terminal kinase (JNK) inhibitor SP600125 protects against such attacks. METHODS: To model an acute glaucoma attack, rat intraocular pressure (IOP) was elevated by a controllable compression method using pulleys and specific weights. Intraocular pressure was measured with a TonoLab® rebound tonometer. Time-dependent ocular hypertension-induced damage was evaluated by ON morphology, retina morphology (both retina layer thickness in cross-sections and RGC counts in Dextran tetramethylrhodamine crystals [DTMR] labeled flatmounts), and scotopic flash electroretinography (ERG). A c-Jun N-terminal kinase (JNK) inhibitor, SP600125 (0, 1.5, 5, or 15 mg/kg), was administered by intraperitoneal injection immediately before and after induction of ocular hypertension, then once daily for seven days. Retinal cross-sections were measured to determine the thickness of various retinal layers and the cell density in the ganglion cell layer (GCL). Retinal flatmounts immunolabeled with anti-rat Brn-3a primary antibody were used to quantify RGC numbers. RESULTS: Elevated rat IOP induced by corneal limbus compression correlated with the different weights. Elevation to 45 mmHg for up to 7 h did not significantly affect the thicknesses of the outer nuclear layer, outer plexiform layer, or inner nuclear layer. Amplitudes of A- and B-waves were not affected. However, elevation to 45 mmHg for up to 7 h decreased the inner retinal thickness and caused ON damage. Most importantly, IOP elevation induced a time-dependent RGC loss. Cell density in the GCL decreased to 70%, 62%, and 49% of that of the control after 5 h, 6 h, and 7 h, respectively, of pressure increases. In retinal flatmount studies, labeled RGCs were reduced 56±4% (mean±SEM) versus the control (p<0.001) after 7 h of ocular hypertension. SP600125 dose-dependently protected against ocular hypertension-induced RGC loss. The difference in RGC density between the vehicle and SP600125-treated (15 mg/kg) groups was statistically significant (p<0.001). CONCLUSIONS: The correlation of inner retinal morphological changes with the duration of the application of 45 mmHg IOP was demonstrated. Treatment with SP600125 significantly protected RGC survival against this insult. Inhibitors of JNK may be an interesting pharmacological class for treating glaucoma. SN - 1090-0535 UR - https://www.unboundmedicine.com/medline/citation/21527996/Protective_effect_of_a_JNK_inhibitor_against_retinal_ganglion_cell_loss_induced_by_acute_moderate_ocular_hypertension_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21527996/ DB - PRIME DP - Unbound Medicine ER -