Systemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats

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Vidal Villegas, Beatriz and Pierdomenico, Johnny Di and Gallego Ortega, Alejandro and Galindo Romero, Caridad and Martínez de la Casa, Jose Maria and García Feijoo, Julián and Villegas Pérez, María Paz and Vidal Sanz, Manuel (2021) Systemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats. Experimental Eye Research, 210 (108694). ISSN 0014-4835

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Official URL: https://doi.org/10.1016/j.exer.2021.108694




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.


Item Type:Article
Additional Information:

Received 1 April 2021 / Received in revised form 26 May 2021 / Accepted 1 July 2021 / Available online 8 July 2021.

Uncontrolled Keywords:Optic nerve section; Axotomy; Intraorbital optic nerve transection; Intrinsically photosensitive retinal ganglion; Cells; BDNF neuroprotection; 7,8-Dihydroxiflavone; Melanopsin; Retinal ganglion cells; Apoptosis; Adult albino rats; Brn3a; Neuroprotection; BDNF-Mimetic
Subjects:Medical sciences > Medicine > Neurosciences
Medical sciences > Medicine > Ophtalmology
ID Code:67753
Deposited On:14 Dec 2021 13:29
Last Modified:14 Dec 2021 13:29

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