BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy
Kathleen Heng, Brent K. Young, BaoXiang Li, Ashley D. Nies, Xin Xia, Runxia R. Wen, Roopa Dalal, Gregory T. Bramblett, Andrew W. Holt, Jeffery M. Cleland, Jason N. Harris, Albert Y. Wu, Jeffrey L. Goldberg
Kathleen Heng, Brent K. Young, BaoXiang Li, Ashley D. Nies, Xin Xia, Runxia R. Wen, Roopa Dalal, Gregory T. Bramblett, Andrew W. Holt, Jeffery M. Cleland, Jason N. Harris, Albert Y. Wu, Jeffrey L. Goldberg
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Research Article Ophthalmology

BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy

Abstract

Traumatic optic neuropathy (TON) is a devastating condition that can occur after blunt or penetrating trauma to the head, leading to visual impairment or blindness. Despite these debilitating effects, no clinically available therapeutic targets neuroprotection or promotes axon regeneration in this or any optic neuropathy. Limited data in large-animal models are a major obstacle to advancing treatments toward clinical therapeutics. To address this issue, we refined a surgical model of TON in Yucatan minipigs. First, we validated the model by demonstrating visual impairment by flash visual-evoked potential and retinal ganglion cell degeneration and death. Next, we developed and optimized a delivery method and nontoxic dosing of intravitreal brain-derived neurotrophic factor (BDNF) and cAMP. Finally, we showed that intravitreal injection of BDNF and cAMP rescued visual function and protected against retinal ganglion cell death and optic nerve axon degeneration. Together these data in a preclinical large-animal model advance our understanding of and ability to model TON and further identify and develop candidate clinical therapeutics.

Authors

Kathleen Heng, Brent K. Young, BaoXiang Li, Ashley D. Nies, Xin Xia, Runxia R. Wen, Roopa Dalal, Gregory T. Bramblett, Andrew W. Holt, Jeffery M. Cleland, Jason N. Harris, Albert Y. Wu, Jeffrey L. Goldberg

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Figure 7

Treatment selection and experimental design.

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Treatment selection and experimental design. (A) Fundus photography of o...
(A) Fundus photography of optic nerve head and retinal vasculature after pupil dilation and varying doses of BDNF and cAMP at baseline and 1 week after injection in uncrushed eyes. (B) Experimental design. One week prior to optic nerve crush, baseline assessment of fVEP, intraocular pressure, and fundus photography were performed. At day 0, unilateral optic nerve crush was performed, and bilateral intravitreal injection of treatment (n = 5) or vehicle (n = 5) was administered at the end of the procedure. Weekly thereafter, an assessment was performed. At week 3, CTB was injected for axon labeling. At week 4, the retinas and optic nerves were harvested and processed. (C) Intraocular pressure was measured at baseline and weekly thereafter. No trends were observed (n = 5, P = 0.2154, 2-way repeated measures ANOVA).