Anat Cell Biol.  2022 Jun;55(2):217-228. 10.5115/acb.22.006.

Therapeutic effect of the mesenchymal stem cells on vigabatrin-induced retinopathy in adult male albino rat

• Domouky AM
• Samy WM
• Rashad WA

• KMID: 2531208
• DOI: http://doi.org/10.5115/acb.22.006

Abstract

Vigabatrin (VGB) is an effective antiepileptic drug used mainly to treat infantile spasms and refractory complex partial seizures. However, using VGB was restricted as it was known to cause retinal toxicity that appears as a severe peripheral visual field defect. Accordingly, this study was conducted to examine the histopathological and biochemical effects of VGB on the retina in adult male albino rats and assess the possible therapeutic role of mesenchymal stem cells (MSCs) against this potential toxicity. The rats were divided into three groups (control group, VGB group, and VGB/MSCs group), one week after 65 days of VGB treatment ±MSCs. The right eyeballs were prepared for histological and immunohistochemical examination, whereas the left eyeballs were prepared for real-time polymerase chain reaction analysis. Our results demonstrated that MSCs ameliorated retinal pathological changes and downregulated the expression of glial fibrillary acidic protein, vascular endothelial growth factor, and synaptophysin after VGB administration suggesting MSCs function and vascular modulating effect. Moreover, MSCs regulate retinal tissue gene expression of BAX, Bcl-2, BDNF, NGF, synapsin, interleukin (IL)-6, IL-1β, and occludin suggesting MSCs antiapoptotic and immunomodulating effect. In conclusion, MSCs administration could be a suitable therapeutic line to ameliorate VGB-induced retinopathy.

Keyword

Retina; Brain-derived neurotrophic factor; Nerve growth factor; Synapsins, Synaptophysin

Figure

• 

  Fig. 1 (A) MSCs at day 14 are characterized by their adhesiveness and fusiform shape (black arrows). (B) Flowcytometry charts (M1, negative; M2, positive) show that MSCs express CD105 and don’t express CD34. (C) Representative fluorescence micrographs of retina from VGB/MSCs group following MSCs injection showing the homing of MSCs by PKH26 dye (yellow arrows). FITC, fluorescein isothiocyanate; FSC, forward scatter; MSC, mesenchymal stem cells; PE, phycoerythrin; SSC, side scatter; VGB, vigabatrin.

• 

  Fig. 2 A photomicrograph of a parasagittal section of a rat’s retina (A, C, G, K, I: H&E, ×400; B, D, H, L: toluidine blue, ×400; E, F, J, M, N: H&E, ×1,000), (A, B) showing normal arrangement of the different layers of retina. H&E staining in control group (20 rats), (C) shows GCL formed of a single row of large round to oval cells (arrow) with continued NFL above (arrowhead), IPL and OPL are formed of dense synaptic zone (black and orange stars). INL and ONL are formed of densely dark stained rounded cells arranged mainly in regular rows in control group (orange arrows), R&C is regularly vertical arrangement (®). With toluidine blue staining, (D) shows same histological finding with normal continued OLM (orange arrowheads), inner segment (orange circle) is obviously darker than OS with regular arrangement (orange triangle). In (E, F) GCL is formed of a single row of large ganglion cells exhibiting round to oval, pale, and vesicular nuclei (arrows) with intermingled with nerve fibers (star), INL includes retinal inter-neuronal cell bodies (bipolar cells [red circles], horizontal cells [red rectangles], amacrine cells [red triangles], and Müller glial cells [red pentagon]), ONL arranged normally in regular rows (triple arrows). H&E staining in VGB group (20 rats) (G, I); GCL containing fewer cells (curved arrow), IPL and OPL is formed of less dense synaptic zone (black and orange stars). INL and ONL are arranged in irregular groups (red circles) with marked irregularity at periphery (arrows), R&C is lightly stained (®). With toluidine blue staining, (H) shows discontinued OLM (orange arrowhead). (J) shows degeneration of GCL and NFL and appearance of vacuolation (v) and small dark glial cells (zigzag arrows). The less dense synaptic IPL and OPL well noticeable (black and orange stars). Loss of clear discrimination between types of cells of INL with spaces (s), pyknosis (zigzag arrow), and fragmentation (arrowhead); ONL showing irregular alignments in grouping (circles) with wide spaces (red arrowhead). In VGB/MSCs group (20 rats) (K, L) show same histological features as control, with ×1,000 mag. (M, N) show GC formed of complete single row of cells with some vacuolation (v) and some dark cell (zigzag arrow), INL includes retinal inter-neuronal cell bodies but disarranged with spaces in between (v), ONL (yellow circles) cells regenerate but still disarranged. Moreover, morphometrical analysis (O, P) in comparing to control group showing that VGB group has a highly significant decrease in total retinal thickness, thicknesses of the individual retinal layers, and in mean ganglion cell count, while in VGB/MSCs group there was no significant different with control group. MSC, mesenchymal stem cells; VGB, vigabatrin; PCL, photoreceptor (rod and cone) cell layer. *Significant vs control subgroup; **Significant vs VGB group.

• 

  Fig. 3 Glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and synaptophysin (SYN) immunohistochemical analysis; GFAP immune-stained sections in control group (20 rats) (A) and VGB/MSCs group (20 rats) (C) limited in the ganglion cell layer (GCL) and nerve fiber layer (NFL) (arrows) and in some Müller glial cell in inner nuclear layer (INL) (arrowheads), in VGB group (20 rats) (B), the immunoreactivity is increased and appeared as marked thickening of NFL (double arrows) with downward indentation (zigzag arrows). VEGF immune-stained sections in control group (D) and VGB/MSCs group (F) revealed negative expression, in VGB group (E) VEGF immunoreactivity showed positive expression in most of the retinal layers. Positive reaction for SYN in the outer plexiform layer (OPL) and the inner plexiform layer (IPL) (stars) was moderately stained in control group (G), strong stained in VGB/MSCs group (I), heavily stained in VGB group (H). (J) Charts demonstrate morphometric analysis of GFAP, SYN, and VEGF expression showing both significant increase in area% immunoreactivity of GFAP and VEGF as well as SYN intensity in VGB group when compared with control group, while, in VGB/MSCs group, MSCs lead to downregulation of GFAP, SYN, and VEGF expression. MSC, mesenchymal stem cells; VGB, vigabatrin. *Significant vs control subgroup; **Significant vs VGB group.

Reference

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