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H. Saragovi, P. Dergham, S. ZhiHua, K. Burgess, K. E. Neet, H. Mehta, S. Woo, Y. Zhuo, Y. Bai; Neuroprotection in Optic Nerve Axotomy: In vivo Efficacy of Receptor-Selective Neurotrophin Analogues and Peptidomimetics. Invest. Ophthalmol. Vis. Sci. 2009;50(13):113.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the pharmacological concept of neuroprotection in optic nerve (ON) axotomy, an acute form of neurodegeneration, by targeting specific neurotrophin receptors TrkA or p75 with selective functional ligands. We tested the effectiveness of (a) wild type Nerve Growth Factor (NGF) versus receptor-selective NGF mutants, and (b) drug-like small molecule neurotrophin mimetics which target selectively TrkA, or p75.
Optic nerve axotomy was performed on Wistar rats, unilaterally. The eyes were injected intraocularly, post-axotomy, with test agents or controls. The primary endpoint was the survival of retinal ganglion cells (RGCs) 14 days post-axotomy. The number of retrogradely-labeled RGCs (flurogold) in each eye were determined in flat mounted retinas at day 14 post-axotomy. In each rat the experimental eye was compared versus the contralateral control eye, and all experimental groups were compared to each other.
In retinas from eyes whose ON were axotomized few RGCs remained viable: 10% RGCs remained viable in untreated eyes, and 12% when treated with PBS vehicle. Treatment with wild type NGF (that binds to TrkA and p75) did not alter the pattern of RGC death. However, an NGF mutant that only activates TrkA receptors (but not the p75 receptors) was significantly neuroprotective and 24% of the RGCs remained viable. In contrast, an NGF mutant selective for p75 did not alter the pattern of RGC death and only 10% remained viable. We also used an antibody NGF30 that blocks NGF-p75 interactions. NGF30 modifies the action of endogenous NGF and affords significant 27% RGCs survival.Significant neuroprotection was also obtained with peptidomimetic ligands. TrkA agonists termed D3 and 3Ak afford 37% and 36% RGC survival respectively. Lastly, p75 antagonists termed C-24 and C-28-35 afford 22% and 20% RGC survival respectively.
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