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Hsiu-Mei Huang, Ying-Chao Chang; Activating the Wnt/β-catenin Pathway Did Not Protect Immature Retina from Hypoxic-Ischemic Injury. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):206.
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Visual loss associated with hypoxic-ischemic (HI) brain damage is currently the most common cause of visual impairment in children in developed countries. Retinal injury contributes significantly to the visual impairments with HI brain injury in rat pups. A neuroprotective role for Wnt signaling has been demonstrated in several animal models of neurodegenerative disorders. Induction of Dickkopf-1 (Dkk-1), the negative modulator of the Wnt/β-catenin pathway, is required for the ischemic neuronal death in the brain. However, the association of Wnt signaling with HI injury in immature retina has not been established.
On post natal day 7 (P7), HI was induced by unilateral common carotid artery ligation followed 1 hour later by 8% oxygen hypoxia for 2 hrs. The pups were intravitreous infused (i.v.i) with PBS, Dkk-1 antisense (AS) or sense (S) oligonucleotides at various concentrations in the right eye for pretreatment (24 hrs and 1 hr before HI) or posttreatment (1 hr and 4 hrs after HI). For chronic treatments, separate groups of animals received repeated intraperitoneal (i.p.) injection of Dkk-1-AS, Dkk-1-S oligonucleotides, lithium chloride or vehicles after HI. The retinal injury was assessed by electroretinography (P21 and P30) and immunohistochemical staining (P8 or P30).
There were progressive increases of DKK-1 immunoreactivity in the ipsilateral inner retina from 3 hrs post-HI to P8. But pretreatment with i.v.i. of DKK-1-AS oligonucleotides did not protect immature retina against HI injury at both pathological and functional levels. Posttreatment with i.v.i. or i.p. of DKK-1- AS oligonucleotides also did not attenuate HI retinopathy. Chronic systemic lithium treatment did not decrease Műller cell activation or neuronal damage in HI retinal injury.
Our data demonstrated that the inhibition of DKK-1 or chronic lithium treatment did not protect the immature retina from HI injury at both pathological and functional levels. It is tempting to speculate that the increase in activity of canonical Wnt/β-catenin signaling is essential, but not sufficient to protect the immature retina from HI injury.
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