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Farid M Khan, Ahmed S Ibrahim, amber still, Alan Saul, Nasrul Hoda, Mohamed Al-Sayed Al-Shabrawey, ; Supplementing Dietary DHA Attenuates Traumatic Optic Neuropathy by Manipulating 12/15-Lipoxygenase Activity . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):6028.
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Combat ocular/head trauma is a leading cause of traumatic optic neuropathy (TON), causing profound vision loss among veterans and civilians with long-term socioeconomic impact. In TON, neurovascular dysfunction is closely related to the local production of inflammatory mediators. Arachidonic acid (AA)-derived hydroxyeicosatertraenoic acids (HETEs) due to 12/15-Lipoxygenase-(LOX) activity have been shown to activate inflammatory signaling pathways. In contrast, docosahexaenoic acid (DHA)-derived metabolites have been shown to possess anti-inflammatory and neurovascular protective properties. Therefore, we aimed to characterize the role of 12/15-LOX in the pathogenesis of retinal dysfunction and test if modulation of 12/15-LOX activity in TON via direct inhibition or dietary supplement with DHA preserves retinal function.
20 Male C57BL/6J mice were grouped to receive either DHA/EPA supplement or water via oral gavage. Over 6 weeks, the mice were given dose of 0.39 g DHA/kg/day and 0.63 g EPA/kg/day. Mice then underwent optic nerve injury from a programmable impactor to induce TON, and were examined via electroretinogram (ERG) to quantify retinal function. TON was performed in either Wild type (WT) or 12/15-LOX(-/-) using an automated programmable impactor, PINPOINT (PCI3000 impactor) in one (Right) eye of each anesthetized mouse meanwhile Sham (S) surgery of TON was performed on the other (Left) eye. The PCI3000 parameters were: impact tip diameter 1 mm, a compression distance of 0.5 mm, and velocity 2.5 m/s.
Initial studies in wild-type mice revealed an increase in retinal 12-HETE level in eyes subjected to TON. To further assess the role of 12/15-LOX in TON, we studied the effects of 12/15-LOX deletion on TON-induced retinal dysfunction. Our results demonstrated a significant improvement in retinal function of TON eyes, assessed by both positive and negative STR of ERG (the most sensitive parameter representing inner retinal function) in 12/15-LOX-deficient mice. Furthermore, enrichment of retina with dietary supplement of DHA before TON shows an improved ganglion cell response as indicated by the STR amplitude tracings compared to Vehicle supplemented group.
Our results suggest that optimum 12/15-LOX activity and its diversion by DHA dietary supplement are beneficial in TON to improve endogenous neuroprotective mechanisms.
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