Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents.

Autor: Stankowska DL; a North Texas Eye Research Institute , University of North Texas Health Science Center , Fort Worth., Mueller BH 2nd; a North Texas Eye Research Institute , University of North Texas Health Science Center , Fort Worth., Oku H; b Department of Ophthalmology , Osaka Medical College , Takatsuki Osaka , Japan., Ikeda T; b Department of Ophthalmology , Osaka Medical College , Takatsuki Osaka , Japan., Dibas A; a North Texas Eye Research Institute , University of North Texas Health Science Center , Fort Worth.
Jazyk: angličtina
Zdroj: Current eye research [Curr Eye Res] 2018 Jan; Vol. 43 (1), pp. 84-95. Date of Electronic Publication: 2017 Nov 07.
DOI: 10.1080/02713683.2017.1383442
Abstrakt: Purpose: The purpose of the current study was to assess the potential involvement of acid-sensing ion channel 1 (ASIC1) in retinal ganglion cell (RGC) death and investigate the neuroprotective effects of inhibitors of ASICs in promoting RGC survival following optic nerve crush (ONC).
Results: ASIC1 protein was significantly increased in optic nerve extracts at day 7 following ONC in rats. Activated calpain-1 increased at 2 and 7 days following ONC as evidenced by increased degradation of α-fodrin, known substrate of calpain. Glial fibrillary acidic protein levels increased significantly at 2 and 7 days post-injury. By contrast, glutamine synthetase increased at 2 days while decreased at 7 days. The inhibition of ASICs with amiloride and psalmotoxin-1 significantly increased RGC survival in rats following ONC (p < 0.05, one-way ANOVA). The mean number of surviving RGCs in rats (n = 6) treated with amiloride (100 µM) following ONC was 1477 ± 98 cells/mm 2 compared with ONC (1126 ± 101 cells/mm 2 ), where psalmotoxin-1 (1 μM) treated rats (n = 6) and subjected to ONC had 1441 ± 63 RGCs/mm 2 compared with ONC (1065 ± 76 RGCs/mm 2 ). Average number of RGCs in control rats (n = 12) was 2092 ± 46 cells/mm 2 . Blocking of ASICs also significantly increased RGC survival from ischemic-like insult from 473 ± 80 to 842 ± 49 RGCs/mm 2 (for psalmotoxin-1) and from 628 ± 53 RGCs/mm 2 to 890 ± 55 RGCs/mm 2 (for amiloride) with p ≤ 0.05, using one-way ANOVA. Acidification (a known activator of ASIC1) increased intracellular Ca 2+ ([Ca 2+ ] i ) in rat primary RGCs, which was statistically blocked by pretreatment with 100 nM psalmotoxin-1.
Conclusions: ASIC1 up-regulation-induced influx of extracellular calcium may be responsible for activation of calcium-sensitive calpain-1 in the retina. Calpain-1 induced degradation of α-fodrin and leads to morphological changes and eventually neuronal death. Therefore, blockers of ASIC1 can be used as potential therapeutics in the treatment of optic nerve degeneration.
Abbreviations: 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF); acid-sensing ion channels (ASICs); analysis of variance (ANOVA); bicinchoninic acid (BCA); brain-derived neurotrophic factor (BDNF); central nervous system (CNS); ciliary neurotrophic factor (CNTF); dimethyl sulfoxide (DMSO); endoplasmic reticulum (ER); ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA); ethylenediaminetetraacetic acid (EDTA); Food and Drug Administration (FDA); glial fibrillary acidic protein (GFAP); glutamine synthetase (GS); intraocular pressure (IOP); kilodalton (kDa); Krebs-Ringer Buffer (KRB); optic nerve crush (ONC); phosphate-buffered saline (PBS); plasma membrane (PM); polymerase chain reaction (PCR); retinal ganglion cell (RGC); RNA Binding Protein With Multiple Splicing (RBPMS); room temperature (RT); standard error of the mean (SEM).
Databáze: MEDLINE
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