Abstract
To analyze the neuroprotective effects of 7,8-Dihydroxyflavone (DHF) in vivo and ex vivo, adult albino Sprague-Dawley rats were given a left intraorbital optic nerve transection (IONT) and were divided in two groups: One was treated daily with intraperitoneal (ip) DHF (5 mg/kg) (n = 24) and the other (n = 18) received ip vehicle (1% DMSO in 0.9% NaCl) from one day before IONT until processing. At 5, 7, 10, 12, 14, and 21 days (d) after IONT, full field electroretinograms (ERG) were recorded from both experimental and one additional naïve-control group (n = 6). Treated rats were analyzed 7 (n = 14), 14 (n = 14) or 21 d (n = 14) after IONT, and the retinas immune stained against Brn3a, Osteopontin (OPN) and the T-box transcription factor T-brain 2 (Tbr2) to identify surviving retinal ganglion cells (RGCs) (Brn3a+), α-like (OPN+), α-OFF like (OPN+Brn3a+) or M4-like/α-ON sustained RGCs (OPN+Tbr+). Naïve and right treated retinas showed normal ERG recordings. Left vehicle-treated retinas showed decreased amplitudes of the scotopic threshold response (pSTR) (as early as 5 d), the rod b-wave, the mixed response and the cone response (as early as 10 d), which did not recover with time. In these retinas, by day 7 the total numbers of Brn3a+RGCs, OPN+RGCs and OPN+Tbr2+RGCs decreased to less than one half and OPN+Brn3a+RGCs decreased to approximately 0.5%, and Brn3a+RGCs showed a progressive loss with time, while OPN+RGCs and OPN+Tbr2+RGCs did not diminish after seven days. Compared to vehicle-treated, the left DHF-treated retinas showed significantly greater amplitudes of the pSTR, normal b-wave values and significantly greater numbers of OPN+RGCs and OPN+Tbr2+RGCs for up to 14 d and of Brn3a+RGCs for up to 21 days. DHF affords significant rescue of Brn3a+RGCs, OPN+RGCs and OPN+Tbr2+RGCs, but not OPN+Brn3a+RGCs, and preserves functional ERG responses after IONT.
Highlights
The rodent visual system has been used to explore the degenerative and regenerative potential of adult mammalian central nervous system neurons [1,2,3,4,5,6,7,8,9]
We show that following intraorbital optic nerve transection (IONT), there is: (i) significant, progressive and permanent diminutions of the scotopic threshold response, which are prevented in the DHF-treated group; (ii) significant diminutions of the b-wave of the rod response, the mixed and photopic response, which were prevented with DHF-treatment; (iii) rapid and massive loss in vehicle-treated retinas of Brn3a+, OPN+, OPN+ Brn3a+ (α-OFF like) and OPN+ T-brain 2 (Tbr2)+
Our in vivo studies indicate that optic nerve injury results in reductions of the b-wave, as well as drastic and permanent reductions of the early component of the ERG, the positive scotopic threshold response, and we show that most of these functional alterations are prevented with systemic DHF treatment
Summary
The rodent visual system has been used to explore the degenerative and regenerative potential of adult mammalian central nervous system neurons [1,2,3,4,5,6,7,8,9]. 7,8-Dihydroxiflavone, a potent TrkB agonist that acts as a BDNF mimetic (for review see [36]) and crosses the blood brain barrier [37], has been shown to prevent axotomy-induced RGC loss in adult rats in vivo [38] through TrkB signaling and subsequent activation of two main intracellular downstream pathways: mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT [39], that block both the intrinsic and extrinsic pathways of apoptosis [40]. At present we ignore whether the large proportion of RGCs rescued with DHF from axotomy-induced cell death maintain their functional properties
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