Publication: Systemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats
Authors
Vidal-Villegas, Beatriz ; Di Pierdomenico, Johnny ; Gallego Ortega, Alejandro ; Galindo Romero, Caridad ; Martínez-de-la-Casa, José M. ; García-Feijoo, Julián ; Villegas Pérez, Maria Paz ; Vidal Sanz, Manuel
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Facultad de Óptica y Optometría
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Publisher
Elsevier
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DOI
https://doi.org/10.1016/j.exer.2021.108694
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info:eu-repo/semantics/article
Description
Abstract
Purpose: To analyze responses of different RGC populations to left intraorbital optic nerve transection (IONT) and intraperitoneal (i.p.) treatment with 7,8-Dihydroxyflavone (DHF), a potent selective TrkB agonist. Methods: Adult albino Sprague-Dawley rats received, following IONT, daily i.p. injections of vehicle (1%DMSO in 0.9%NaCl) or DHF. Group-1 (n = 58) assessed at 7days (d) the optimal DHF amount (1–25 mg/kg). Group-2, using freshly dissected naïve or treated retinas (n = 28), investigated if DHF treatment was associated with TrkB activation using Western-blotting at 1, 3 or 7d. Group-3 (n = 98) explored persistence of protection and was analyzed at survival intervals from 7 to 60d after IONT. Groups 2–3 received daily i.p. vehicle or DHF (5 mg/kg). Retinal wholemounts were immunolabelled for Brn3a and melanopsin to identify Brn3a+RGCs and m+RGCs, respectively. Results: Optimal neuroprotection was achieved with 5 mg/kg DHF and resulted in TrkB phosphorylation. The percentage of surviving Brn3a+RGCs in vehicle treated rats was 60, 28, 18, 13, 12 or 8% of the original value at 7, 10, 14, 21, 30 or 60d, respectively, while in DHF treated retinas was 94, 70, 64, 17, 10 or 9% at the same time intervals. The percentages of m+RGCs diminished by 7d–13%, and recovered by 14d–38% in vehicle-treated and to 48% in DHF-treated retinas, without further variations. Conclusions: DHF neuroprotects Brn3a + RGCs and m + RGCs; its protective effects for Brn3a+RGCs are maximal at 7 days but still significant at 21d, whereas for m+RGCs neuroprotection was significant at 14d and permanent.
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Citation
Beatriz Vidal-Villegas, Johnny Di Pierdomenico, Juan Antonio Miralles de Imperial-Ollero, Arturo Ortin Martinez, Francisco Manuel Nadal-Nicolás, Jose Manuel Bernal-Garro, Nicolas Cuenca, María Paz Villegas-Pérez, Manuel Vidal-Sanz. Melanopsin+RGCs are fully resistant to NMDA-induced excitotoxicity. International Journal of Molecular Sciences (2019) 20(12).
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