TY - JOUR
T1 - A pyruvate dehydrogenase kinase inhibitor prevents retinal cell death and improves energy metabolism in rat retinas after ischemia/reperfusion injury
AU - Sato, Kota
AU - Mochida, Seiya
AU - Tomimoto, Daisuke
AU - Konuma, Takahiro
AU - Kiyota, Naoki
AU - Tsuda, Satoru
AU - Shiga, Yukihiro
AU - Omodaka, Kazuko
AU - Nakazawa, Toru
N1 - Funding Information:
The authors thank Tim Hilts for reviewing and editing the language of the manuscript, Junko Sato, Kanako Sakai, Mayumi Suda and Eriko Kamii for their technical assistance, and the Biomedical Research Unit of Tohoku University Hospital for technical support. Research funding was provided by Japan Tobacco Inc.
Publisher Copyright:
© 2020 The Authors
PY - 2020/4
Y1 - 2020/4
N2 - We aimed to assess the neuroprotective effect of a pyruvate dehydrogenase kinase (PDK) inhibitor, Nov3r after ischemia/reperfusion (IR) injury in rats. IR injury was induced by applying 150 mmHg of intraocular pressure for 50 min. Nov3r was orally administered (100 mg/kg) 3 h before and 24 h after IR injury. TUNEL-positive cells increased and immunoreactive RBPMS-positive cells decreased in the rat retinas after IR injury. Administration of Nov3r significantly ameliorated the increase in TUNEL-positive cells and prevented the RBPMS-positive cell decrease. Similarly, the number of IR-induced Iba1-positive microglial cells was significantly reduced with Nov3r treatment. Among metabolic parameters, IR damage induced the elevation of lactate and pyruvate, and the reduction of ATP. Oral administration of Nov3r ameliorated these changes. Our data suggest that the Nov3r had a retinal neuroprotective effect in IR injury in rats. This finding suggests that the regulation of pyruvate dehydrogenase (PDH) activity has potential therapeutic value by enabling metabolic reprograming in diseases associated with ischemic retinal damage, such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy and glaucoma.
AB - We aimed to assess the neuroprotective effect of a pyruvate dehydrogenase kinase (PDK) inhibitor, Nov3r after ischemia/reperfusion (IR) injury in rats. IR injury was induced by applying 150 mmHg of intraocular pressure for 50 min. Nov3r was orally administered (100 mg/kg) 3 h before and 24 h after IR injury. TUNEL-positive cells increased and immunoreactive RBPMS-positive cells decreased in the rat retinas after IR injury. Administration of Nov3r significantly ameliorated the increase in TUNEL-positive cells and prevented the RBPMS-positive cell decrease. Similarly, the number of IR-induced Iba1-positive microglial cells was significantly reduced with Nov3r treatment. Among metabolic parameters, IR damage induced the elevation of lactate and pyruvate, and the reduction of ATP. Oral administration of Nov3r ameliorated these changes. Our data suggest that the Nov3r had a retinal neuroprotective effect in IR injury in rats. This finding suggests that the regulation of pyruvate dehydrogenase (PDH) activity has potential therapeutic value by enabling metabolic reprograming in diseases associated with ischemic retinal damage, such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy and glaucoma.
KW - ATP
KW - Ischemia/reperfusion
KW - Lactate
KW - Microglial recruitment
KW - Pyruvate
KW - Pyruvate dehydrogenase
KW - Pyruvate dehydrogenase kinase
KW - Retina
KW - Retinal ganglion cells
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U2 - 10.1016/j.exer.2020.107997
DO - 10.1016/j.exer.2020.107997
M3 - Article
C2 - 32165157
AN - SCOPUS:85081371083
VL - 193
JO - Experimental Eye Research
JF - Experimental Eye Research
SN - 0014-4835
M1 - 107997
ER -