Abstract
Purpose :
A small molecule activator of TrkB, HIOC, has been shown to protect against vision loss following ocular blast injury (Dhakal et al, J Neurotrauma 2021;38:2896). In this study, we assessed the protective effects of a fluoropyridine analog of HIOC.
Methods :
Using HIOC as a lead structure, an analog (HIFN) containing fluorine substituted pyridine was synthesized. Adult male C57BL/6J mice were subjected to blast overpressure injury at ~20psi. Within 30 minutes of blast, animals were administered intraperitoneally either vehicle, HIFN or HIOC (40mg/kg). The treatment was continued for another 6 days. Contrast sensitivity at a spatial frequency of 0.064c/d and visual acuity (spatial frequency threshold) were measured using the optomotor response. Scotopic electroretinogram (ERG) and pattern ERG (spatial frequency of 0.155 c/d, 2.1 contrast reversal/sec and mean luminance of 50cd/m2) were recorded. TrkB activation was assessed by western blot analysis of TrkB phosphorylation. Animals were administered with TrkB specific inhibitor, ANA-12 (0.5mg/kg), 2.5 h prior to treatment with compound.
Results :
HIOC and HIFN both reduced the visual acuity (p≤0.05 vs Blast-Veh) and contrast sensitivity deficits after blast (p≤0.05 vs Blast-Veh). The protection of contrast sensitivity afforded by HIFN was better than that by HIOC at 7-week post blast (p≤0.05). No effects of blast, HIFN, or HIOC were observed in the scotopic ERG a-wave or b-wave amplitudes. At 8-week post blast there was a significant decline in P1 and N2 wave amplitude of pERG in Blast-Veh group (p≤0.001). HIFN and HIOC treatment reduced the decline in P1 amplitude (p≤0.05 vs Blast-Veh). HIFN and HIOC showed a trend to increase the N2 amplitude compared to vehicle, but the effects were not statistically significant (p=0.06 vs Blast-Veh). HIFN activated TrkB at a concentration of 10 nM in NIH/3T3 cells expressing human TrkB. The TrkB inhibitor, ANA-12, blocked the protective effects exhibited by HIFN and HIOC in blast animals.
Conclusions :
HIFN protects against blast-induced vision loss and retinal ganglion cell damage, as assessed by pERG. HIFN appears to preserve contrast sensitivity better than HIOC, although this needs to be assessed at different drug doses. The protective effects of HIFN are due to activation of TrkB receptor.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.