Hsiu-Mei Huang1, Chao-Ching Huang2,3, Meng-Han Tsai4, Yi-Chieh Poon1, Ying-Chao Chang5. 1. Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City, Taiwan. 2. Department of Pediatrics, National Cheng Kung University Hospital, No.1, Tainan City, Taiwan. 3. Department of Pediatrics, Taipei Medical University, College of Medicine, Taipei City, Taiwan. 4. Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City, Taiwan. 5. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City, Taiwan.
Abstract
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. Chinese Abstract.
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. Chinese Abstract.
Authors: Vivek Gupta; Nitin Chitranshi; Veer Gupta; Yuyi You; Rashi Rajput; Joao A Paulo; Mehdi Mirzaei; Maarten van den Buuse; Stuart L Graham Journal: Neuroscience Date: 2022-02-23 Impact factor: 3.708