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. 2024 Mar 13;12(3):637.
doi: 10.3390/biomedicines12030637.

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia-Reperfusion in the Eyes of Sprague Dawley Rats

Barbara Takács  1 , Anna Szilágyi  1 , Dániel Priksz  1 , Mariann Bombicz  1 , Adrienn Mónika Szabó  1 , Beáta Pelles-Taskó  1 , Ágnes Rusznyák  2 , Ádám Haimhoffer  3 , Rudolf Gesztelyi  1 , Zoltán Szilvássy  1 , Béla Juhász  1 , Balázs Varga  1
Affiliations

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia-Reperfusion in the Eyes of Sprague Dawley Rats

Barbara Takács et al. Biomedicines. .

Abstract

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-β-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia-reperfusion. It was also observed to counteract retinal thinning after ischemia-reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia-reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops.

Keywords: BGP-15; electroretinography (ERG); eyedrops; ischemia–reperfusion; ligation; retina; sulfobutylether-β-cyclodextrin (SBECD).

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Experimental protocol.
Figure 2
Figure 2
Representative scotopic electroretinographical waveforms elicited by flashlight intensity series (from the bottom (black line) to the top (blue line): 10, 100, 300, 1000, 3000, 10,000, 25,000 mcd*s*m−2). (A): control no-IR; (B): BGP no-IR; (C): control IR; (D): BGP IR.
Figure 3
Figure 3
Representative scotopic oscillatory potentials elicited by flashlight intensity series (from the bottom (black line) to the top (blue line): 10, 100, 300, 1000, 3000, 10,000, 25,000 mcd*s*m−2). (A): control no-IR; (B): BGP no-IR; (C): control IR; (D): BGP IR.
Figure 4
Figure 4
Results of scotopic ERG measurements plotted against increasing flashlight intensities (mcd*s*m−2). (A): Scotopic a-wave mean amplitudes (µV); (B): scotopic a-wave mean implicit times (ms); (C): scotopic b-wave mean amplitudes (µV); (D): scotopic b-wave mean implicit times (ms). Dots represent BGP-treated group NO-IR eyes, squares BGP-treated IR eyes, upward-pointing triangles represent control group NO-IR eyes and downward-pointing triangles represent control group IR eyes. All values are presented as group means. Statistically significant comparisons are marked with * in case of BGP NO-IR vs. control NO-IR comparisons, and # in case of BGP IR vs. control IR comparisons. The number of markers represents the statistical significance of the comparison * or # p < 0.05; ** or ## p < 0.01; *** or ### p < 0.001; **** or #### p < 0.0001.
Figure 5
Figure 5
Statistically most important comparisons in scotopic ERG measurements; flashlight intensity: 3000 mcd*s*m−2. (A): Mean a-wave amplitudes of the different groups (µV); (B): mean a-wave implicit times (ms); (C): mean b-wave amplitudes (µV); (D): mean b-wave implicit times (ms). All results are plotted as group mean ± SEM. ns = no significant difference. Statistically significant comparisons are marked with * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001.
Figure 6
Figure 6
Results and comparisons of dark-adapted oscillatory potential amplitudes and implicit times in different groups, flashlight intensity: 3000 mcd*s*m−2. (A): Mean oscillatory potential amplitudes for different groups (µV); (B): mean oscillatory potential implicit times (ms). All results are plotted as group mean ± SEM. ns = no significant difference. Statistically significant comparisons are marked with * p < 0.05; *** p < 0.001; **** p < 0.0001.
Figure 7
Figure 7
Representative photopic electroretinographical waveforms (A–D) and photopic oscillatory potentials (E–H) elicited by light-adapted flashlight intensities (black line for 3000 and blue line for 10,000 mcd*s*m−2). (A,E): Control NO-IR; (B,F): BGP NO-IR; (C,G): control IR; (D,H): BGP IR.
Figure 8
Figure 8
(A,B): Results of photopic ERG measurements plotted against light-adapted flashlight intensities. (A): Photopic b-wave mean amplitudes (µV); (B): photopic b-wave mean implicit times (ms). Dots represent BGP-treated group NO-IR eyes, squares represent BGP-treated IR eyes, upward-pointing triangles represent control group NO-IR eyes and downward-pointing triangles represent control group IR eyes. All values are presented as group means. Statistically significant comparisons are marked with * in case of BGP NO-IR vs. control NO-IR comparisons, and # in case of BGP IR vs. control IR comparisons. The number of markers represents the statistical significance of the comparison * or # p < 0.05; ## p < 0.01. (C,D): Statistically most important comparisons in photopic ERG measurements; flashlight intensity: 3000 mcd*s*m−2. (C): mean b-wave amplitudes for the different groups (µV); (D): mean b-wave implicit times (ms). All results are plotted as group mean ± SEM. ns = no significant difference. Statistically significant comparisons are marked with * p < 0.05; *** p < 0.001; **** p < 0.0001.
Figure 9
Figure 9
Histology results. (A): Representative histological sections of the different groups (from left to right): control NO-IR, BGP NO-IR, control IR and BGP IR. RPE: retinal pigment epithelium; PL: photoreceptor layer; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: Inner Plexiform Layer; and GCL: ganglion cell layer. (B): Graphs showing statistical analysis results of histology sections of the different groups. Data are shown as group mean ± SEM. ns = no significant difference, ** = p < 0.01, *** = p < 0.001, **** = p< 0.0001.
Figure 10
Figure 10
Thickness of the different retinal layers on histological sections. (A): photoreceptor layer (PL); (B): outer nuclear layer (ONL); (C): outer plexiform layer (OPL); (D): inner nuclear layer (INL); (E): inner plexiform layer (IPL); (F): ganglion cell layer (GCL). Data are shown as group mean ± SEM. ns = no significant difference, * = p < 0.05, ** = p < 0.01, **** = p< 0.0001.
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Grants and funding

The work was supported by GINOP-2.3.4-15-2016-00002 project. The research was financed by the Thematic Excellence Programme of the Ministry for Innovation and Technology and was also supported by the National Research, Development and Innovation Fund of Hungary within the frameworks of the preclinical thematic programme of the University of Debrecen (TKP2020-NKA-04) and within the frameworks of the Therapeutic Purpose Development thematic programme of the University of Debrecen (TKP2020-IKA-04). The research was implemented with the support provided by the National Research, Development and Innovation Fund of Hungary (TKP2021-EGA-18).

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