TY - JOUR
T1 - Systemic 7,8-dihydroxyflavone treatment protects immature retinas against hypoxic-ischemic injury via müller glia regeneration and MAPK/ERK activation
AU - Huang, Hsiu Mei
AU - Huang, Chao Ching
AU - Tsai, Meng Han
AU - Poon, Yi Chieh
AU - Chang, Ying Chao
N1 - Publisher Copyright:
© 2018 The Authors.
PY - 2018/6
Y1 - 2018/6
N2 - PURPOSE. Perinatal hypoxic-ischemic (HI) injury causes significant damages in the immature retina. The brain-derived neurotrophic factor is well known for its neuroprotective role but has limited clinical applications. A selective agonist of tyrosine kinase receptor B, 7,8-dihydroxyflavone (DHF), is a powerful therapeutic tool, when administered systemically. However, it remains unclear whether DHF treatment can protect the immature retinas against HI injury. METHODS. Postnatal (P) day 7 rat pups were intraperitoneally injected with DHF or vehicle 2 hours before and 18 hours after being subjected to HI injury. The outcomes were assessed at various timepoints after injury by electroretinography and histologic examinations. Neurogenesis was assessed by double-labeling of retinal sections with 5-bromo-2'-deoxyuridine and different neuronal markers. RESULTS. At P8, 24-hours postinjury, brain-derived neurotrophic factor mRNA levels in the retina decreased significantly. DHF treatment partially protected immature retinas at both histologic and functional levels between P14 and P30 but did not prevent apoptosis, inflammation, or damage of the blood-retinal barrier (BRB) at P8. On the other hand, DHF treatment promoted the survival of proliferating inner retinal cells, including Müller glia, and enhanced their transdifferentiation to bipolar cells at P17. Moreover, DHF treatment rescued the levels of extracellular signal-regulated kinase (ERK) phosphorylation, which were significantly decreased after injury. The neuroprotective effects of DHF were markedly eliminated by inhibition of ERK phosphorylation. CONCLUSIONS. Early systemic DHF treatment has neuroprotective effects against HI injury in immature retinas, possibly via promoting neurogenesis through the tyrosine kinase receptor B/ERK signaling pathway.
AB - PURPOSE. Perinatal hypoxic-ischemic (HI) injury causes significant damages in the immature retina. The brain-derived neurotrophic factor is well known for its neuroprotective role but has limited clinical applications. A selective agonist of tyrosine kinase receptor B, 7,8-dihydroxyflavone (DHF), is a powerful therapeutic tool, when administered systemically. However, it remains unclear whether DHF treatment can protect the immature retinas against HI injury. METHODS. Postnatal (P) day 7 rat pups were intraperitoneally injected with DHF or vehicle 2 hours before and 18 hours after being subjected to HI injury. The outcomes were assessed at various timepoints after injury by electroretinography and histologic examinations. Neurogenesis was assessed by double-labeling of retinal sections with 5-bromo-2'-deoxyuridine and different neuronal markers. RESULTS. At P8, 24-hours postinjury, brain-derived neurotrophic factor mRNA levels in the retina decreased significantly. DHF treatment partially protected immature retinas at both histologic and functional levels between P14 and P30 but did not prevent apoptosis, inflammation, or damage of the blood-retinal barrier (BRB) at P8. On the other hand, DHF treatment promoted the survival of proliferating inner retinal cells, including Müller glia, and enhanced their transdifferentiation to bipolar cells at P17. Moreover, DHF treatment rescued the levels of extracellular signal-regulated kinase (ERK) phosphorylation, which were significantly decreased after injury. The neuroprotective effects of DHF were markedly eliminated by inhibition of ERK phosphorylation. CONCLUSIONS. Early systemic DHF treatment has neuroprotective effects against HI injury in immature retinas, possibly via promoting neurogenesis through the tyrosine kinase receptor B/ERK signaling pathway.
KW - DHF
KW - ERK inhibitor
KW - Hypoxic-ischemic
KW - Immature retinal injury
KW - TrkB agonist
UR - http://www.scopus.com/inward/record.url?scp=85060808943&partnerID=8YFLogxK
U2 - 10.1167/iovs.18-23792
DO - 10.1167/iovs.18-23792
M3 - 文章
C2 - 30025123
AN - SCOPUS:85060808943
SN - 0146-0404
VL - 59
SP - 3124
EP - 3135
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 7
ER -