TY - JOUR
T1 - Neuroprotective Effects of Psalmotoxin-1, an Acid-Sensing Ion Channel (ASIC) Inhibitor, in Ischemia Reperfusion in Mouse Eyes
AU - Dibas, Adnan
AU - Millar, Cameron
AU - Al-Farra, Abraham
AU - Yorio, Thomas
N1 - Funding Information:
This publication was supported in part by grants from Brightfocus Foundation and intramural grant from UNTHSC to A.D. We thank Dr. He who assisted in the proof-reading of the manuscript. The authors have no financial interests.
Funding Information:
This work was supported by the BrightFocus Foundation and intramural grant from UNTHSC to A.D.
Publisher Copyright:
© 2018, © 2018 Taylor & Francis Group, LLC.
PY - 2018/7/3
Y1 - 2018/7/3
N2 - Purpose: The purpose of the current study is to assess changes in the expression of Acid-Sensing Ion Channel (ASIC)1a and ASIC2 in retinal ganglion cells (RGCs) after retinal ischemia and reperfusion (I/R) injury and to test if inhibition of ASIC1a provides RGC neuroprotection. Methods: Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. RGC function was measured by Pattern electroretinography (PERG). In addition, retinal ASIC1a and ASIC2 were observed by immunohistochemistry and western blot. Changes in calpain, fodrin, heat shock protein 70 (HSP70), Brn3a, super oxide dismutase-1 (SOD1), catalase, and glutathione perioxidase-4 (GPX4) protein levels were assessed by western blot. RGC numbers were measured by immunohistochemistry on whole retinal flat mounts using anti-RNA binding protein with multiple splicing (RBPMS) antibodies. Intravitreal injection of psalmotoxin-1, a selective ASIC1a blocker, was used to assess the neuroprotective effect of ASIC1a inhibition. Results: Levels of ASIC1a and ASIC2 after I/R increased in RGCs. Upregulation of ASIC1a but not ASIC2 was attenuated by intravitreal injection of psalmotoxin-1. I/R induced activation of calpain and degradation of fodrin, HSP70, and reduction in Brn3a. In contrast, while psalmotoxin-1 attenuated calpain activation and increased Brn3a levels, it failed to block HSP70 degradation. Unlike SOD1 protein which was reduced, catalase protein levels increased after I/R. Psalmotoxin-1, although not affecting SOD1 and GPX4, increased catalase levels significantly. Psalmotoxin-1 also increased RBPMS-labeled RGCs following I/R as judged by immunohistochemistry of retinal flat mounts. Finally, psalmotoxin-1 enhanced the amplitude of PERG following I/R, suggesting partial rescue of RGC function. Conclusion: Psalmotoxin-1 appears to exert a neuroprotective effect under ischemic insults and targeting inhibition of ASICs may represent a new therapeutic approach in ischemic retinal diseases.
AB - Purpose: The purpose of the current study is to assess changes in the expression of Acid-Sensing Ion Channel (ASIC)1a and ASIC2 in retinal ganglion cells (RGCs) after retinal ischemia and reperfusion (I/R) injury and to test if inhibition of ASIC1a provides RGC neuroprotection. Methods: Transient ischemia was induced in one eye of C57BL/6 mice by raising intraocular pressure to 120 mmHg for 60 min followed by retinal reperfusion by restoring normal pressure. RGC function was measured by Pattern electroretinography (PERG). In addition, retinal ASIC1a and ASIC2 were observed by immunohistochemistry and western blot. Changes in calpain, fodrin, heat shock protein 70 (HSP70), Brn3a, super oxide dismutase-1 (SOD1), catalase, and glutathione perioxidase-4 (GPX4) protein levels were assessed by western blot. RGC numbers were measured by immunohistochemistry on whole retinal flat mounts using anti-RNA binding protein with multiple splicing (RBPMS) antibodies. Intravitreal injection of psalmotoxin-1, a selective ASIC1a blocker, was used to assess the neuroprotective effect of ASIC1a inhibition. Results: Levels of ASIC1a and ASIC2 after I/R increased in RGCs. Upregulation of ASIC1a but not ASIC2 was attenuated by intravitreal injection of psalmotoxin-1. I/R induced activation of calpain and degradation of fodrin, HSP70, and reduction in Brn3a. In contrast, while psalmotoxin-1 attenuated calpain activation and increased Brn3a levels, it failed to block HSP70 degradation. Unlike SOD1 protein which was reduced, catalase protein levels increased after I/R. Psalmotoxin-1, although not affecting SOD1 and GPX4, increased catalase levels significantly. Psalmotoxin-1 also increased RBPMS-labeled RGCs following I/R as judged by immunohistochemistry of retinal flat mounts. Finally, psalmotoxin-1 enhanced the amplitude of PERG following I/R, suggesting partial rescue of RGC function. Conclusion: Psalmotoxin-1 appears to exert a neuroprotective effect under ischemic insults and targeting inhibition of ASICs may represent a new therapeutic approach in ischemic retinal diseases.
KW - Acid-Sensing Ion Channels (ASICs)
KW - Glaucoma
KW - ischemia
KW - neuroprotection
KW - retinal ganglion cells
UR - http://www.scopus.com/inward/record.url?scp=85044532118&partnerID=8YFLogxK
U2 - 10.1080/02713683.2018.1454478
DO - 10.1080/02713683.2018.1454478
M3 - Article
C2 - 29595330
AN - SCOPUS:85044532118
SN - 0271-3683
VL - 43
SP - 921
EP - 933
JO - Current Eye Research
JF - Current Eye Research
IS - 7
ER -