Limits...
AAV-mediated and pharmacological induction of Hsp70 expression stimulates survival of retinal ganglion cells following axonal injury.

Kwong JM, Gu L, Nassiri N, Bekerman V, Kumar-Singh R, Rhee KD, Yang XJ, Hauswirth WW, Caprioli J, Piri N - Gene Ther. (2014)

Bottom Line: We show here that a single intravitreal injection of 17-AAG (0.2 ug ul(-1)) results in an increased survival of ONC-injured RGCs by approximately 49% compared with the vehicle-treated animals.Expression of Hsp70 in retinas of 17-AAG-treated animals was upregulated approximately by twofold compared with control animals.Our data support the idea that the upregulation of Hsp70 has a beneficial effect on the survival of injured RGCs, and the induction of this protein could be viewed as a potential neuroprotective strategy for optic neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Jules Stein Eye Institute, UCLA, Los Angeles, CA, USA.

ABSTRACT
We evaluated the effect of AAV2- and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin)-mediated upregulation of Hsp70 expression on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). AAV2-Hsp70 expression in the retina was primarily observed in the ganglion cell layer. Approximately 75% of all transfected cells were RGCs. RGC survival in AAV2-Hsp70-injected animals was increased by an average of 110% 2 weeks after the axonal injury compared with the control. The increase in cell numbers was not even across the retinas with a maximum effect of approximately 306% observed in the inferior quadrant. 17-AAG-mediated induction of Hsp70 expression has been associated with cell protection in various models of neurodegenerative diseases. We show here that a single intravitreal injection of 17-AAG (0.2 ug ul(-1)) results in an increased survival of ONC-injured RGCs by approximately 49% compared with the vehicle-treated animals. Expression of Hsp70 in retinas of 17-AAG-treated animals was upregulated approximately by twofold compared with control animals. Our data support the idea that the upregulation of Hsp70 has a beneficial effect on the survival of injured RGCs, and the induction of this protein could be viewed as a potential neuroprotective strategy for optic neuropathies.

Show MeSH

Related in: MedlinePlus

RGC density in vehicle- and 17-AAG-treated animals. A. Representative images of flat mounted rat retinas used for quantification of RGCs. RGCs immunolabeled with Rbpms antibodies were counted in three sampling fields (0.32 X 0.24 mm each) within the superior, temporal, inferior and nasal retinal quadrants at 1, 2, 3 and 4 mm from the optic disc. B. Two weeks after ONC, RGC density in vehicle-treated rats was decreased approximately 80% compared to the uninjured vehicle-treated animals. The number of surviving RGCs in retinas of 17-AAG/ONC animals was approximately 49% higher than in Vehicle/ONC retinas (*P=0.007).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4320032&req=5

Figure 4: RGC density in vehicle- and 17-AAG-treated animals. A. Representative images of flat mounted rat retinas used for quantification of RGCs. RGCs immunolabeled with Rbpms antibodies were counted in three sampling fields (0.32 X 0.24 mm each) within the superior, temporal, inferior and nasal retinal quadrants at 1, 2, 3 and 4 mm from the optic disc. B. Two weeks after ONC, RGC density in vehicle-treated rats was decreased approximately 80% compared to the uninjured vehicle-treated animals. The number of surviving RGCs in retinas of 17-AAG/ONC animals was approximately 49% higher than in Vehicle/ONC retinas (*P=0.007).

Mentions: Cell protective effect of 17-AAG-induced Hsp70 expression on RGC survival was analyzed similar to AAV2-Hsp70 study. RGC density in Vehicle/ONC group was decreased to approximately 355±63 cells/mm2, which is about 19% of total number of cells in vehicle-treated animals with no damage to RGC axons (1860±175 cells/mm2; Figs. 4A and B). In 17-AAG injected rats with no ONC injury, RGC density was 2050±157 cells/mm2, slightly higher (4.8%) than in vehicle-treated uninjured animals although not statistically significant. The number of remaining RGCs in retinas of 17-AAG/ONC animals was approximately 527±30 cells/mm2. Compared to the Vehicle/ONC group, the administration of 17-AAG preserved approximately 49% more cells (n=8; P=0.007). RGC numbers in 17-AAG-treated animals were higher in all three retinal quadrants (inferior, superior and temporal) used in this study for RGC counting, with the most notable increase in cell density observed in the temporal region (~120%; P=0.01). With respect to the retinal location, RGC densities at 1, 2, 3 and 4 mm from the center of optic nerve head were higher by 61% (P=0.01), 57% (P=0.01), 26% (P=0.13) and 52% (P=0.01), respectively in the 17-AAG/ONC group compared to the Vehicle/ONC group.


AAV-mediated and pharmacological induction of Hsp70 expression stimulates survival of retinal ganglion cells following axonal injury.

Kwong JM, Gu L, Nassiri N, Bekerman V, Kumar-Singh R, Rhee KD, Yang XJ, Hauswirth WW, Caprioli J, Piri N - Gene Ther. (2014)

RGC density in vehicle- and 17-AAG-treated animals. A. Representative images of flat mounted rat retinas used for quantification of RGCs. RGCs immunolabeled with Rbpms antibodies were counted in three sampling fields (0.32 X 0.24 mm each) within the superior, temporal, inferior and nasal retinal quadrants at 1, 2, 3 and 4 mm from the optic disc. B. Two weeks after ONC, RGC density in vehicle-treated rats was decreased approximately 80% compared to the uninjured vehicle-treated animals. The number of surviving RGCs in retinas of 17-AAG/ONC animals was approximately 49% higher than in Vehicle/ONC retinas (*P=0.007).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4320032&req=5

Figure 4: RGC density in vehicle- and 17-AAG-treated animals. A. Representative images of flat mounted rat retinas used for quantification of RGCs. RGCs immunolabeled with Rbpms antibodies were counted in three sampling fields (0.32 X 0.24 mm each) within the superior, temporal, inferior and nasal retinal quadrants at 1, 2, 3 and 4 mm from the optic disc. B. Two weeks after ONC, RGC density in vehicle-treated rats was decreased approximately 80% compared to the uninjured vehicle-treated animals. The number of surviving RGCs in retinas of 17-AAG/ONC animals was approximately 49% higher than in Vehicle/ONC retinas (*P=0.007).
Mentions: Cell protective effect of 17-AAG-induced Hsp70 expression on RGC survival was analyzed similar to AAV2-Hsp70 study. RGC density in Vehicle/ONC group was decreased to approximately 355±63 cells/mm2, which is about 19% of total number of cells in vehicle-treated animals with no damage to RGC axons (1860±175 cells/mm2; Figs. 4A and B). In 17-AAG injected rats with no ONC injury, RGC density was 2050±157 cells/mm2, slightly higher (4.8%) than in vehicle-treated uninjured animals although not statistically significant. The number of remaining RGCs in retinas of 17-AAG/ONC animals was approximately 527±30 cells/mm2. Compared to the Vehicle/ONC group, the administration of 17-AAG preserved approximately 49% more cells (n=8; P=0.007). RGC numbers in 17-AAG-treated animals were higher in all three retinal quadrants (inferior, superior and temporal) used in this study for RGC counting, with the most notable increase in cell density observed in the temporal region (~120%; P=0.01). With respect to the retinal location, RGC densities at 1, 2, 3 and 4 mm from the center of optic nerve head were higher by 61% (P=0.01), 57% (P=0.01), 26% (P=0.13) and 52% (P=0.01), respectively in the 17-AAG/ONC group compared to the Vehicle/ONC group.

Bottom Line: We show here that a single intravitreal injection of 17-AAG (0.2 ug ul(-1)) results in an increased survival of ONC-injured RGCs by approximately 49% compared with the vehicle-treated animals.Expression of Hsp70 in retinas of 17-AAG-treated animals was upregulated approximately by twofold compared with control animals.Our data support the idea that the upregulation of Hsp70 has a beneficial effect on the survival of injured RGCs, and the induction of this protein could be viewed as a potential neuroprotective strategy for optic neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Jules Stein Eye Institute, UCLA, Los Angeles, CA, USA.

ABSTRACT
We evaluated the effect of AAV2- and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin)-mediated upregulation of Hsp70 expression on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). AAV2-Hsp70 expression in the retina was primarily observed in the ganglion cell layer. Approximately 75% of all transfected cells were RGCs. RGC survival in AAV2-Hsp70-injected animals was increased by an average of 110% 2 weeks after the axonal injury compared with the control. The increase in cell numbers was not even across the retinas with a maximum effect of approximately 306% observed in the inferior quadrant. 17-AAG-mediated induction of Hsp70 expression has been associated with cell protection in various models of neurodegenerative diseases. We show here that a single intravitreal injection of 17-AAG (0.2 ug ul(-1)) results in an increased survival of ONC-injured RGCs by approximately 49% compared with the vehicle-treated animals. Expression of Hsp70 in retinas of 17-AAG-treated animals was upregulated approximately by twofold compared with control animals. Our data support the idea that the upregulation of Hsp70 has a beneficial effect on the survival of injured RGCs, and the induction of this protein could be viewed as a potential neuroprotective strategy for optic neuropathies.

Show MeSH
Related in: MedlinePlus