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Toshiyuki Oshitari, Guzel Bikbova, Shuichi Yamamoto; Neuroprotective and regenerative effect of taurine-conjugated urosodeoxycholic acid in rat retinas exposed to high glucose. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5833.
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© ARVO (1962-2015); The Authors (2016-present)
To examine the neuroprotective and regenerative effects of taurine-conjugated ursodeoxycholic acid (TUDCA), an anti-endoplasmic reticulum stress agent, in rat retinas exposed to high glucose.
All of the procedures were performed in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Retinas isolated from 6 adult male SD rats were cultured in normal-glucose (NG) or high-glucose (HG) media. TUDCA or neurotrophin-4 (NT-4) was added to the HG medium. After 7 days, the number of regenerating neurites was counted. The explants were cryosectioned and stained by TUNEL and immunostained for p-c-Jun and p-JNK. Statistical analyses were performed with Mann-Whitney U tests.
In the HG group, the percentage of TUNEL-positive cells in the ganglion cell layer (GCL) was 32.7±11.7% and in the NG group it was 18.8±7.3% (P=0.0002). In the HG group supplemented with TUDCA (HG+TUDCA), the percentage of TUNEL-positive cells was 19.8±7.0% and that supplemented by NT-4 (HG+NT-4) was 19.9±6.4% (P=0.0396, P=0.0367, respectively). In the HG group, the percentage of p-c-Jun- and p-JNK-positive cells in the GCL was 27.9±12.5% and 18.6±5.2%, and both were significantly higher than those in the NG group at 12.1±5.8% (P=0.003) and 13.2±10.4% (P=0.005). In the both groups, the percentage of p-c-Jun-positive (8.7±6.4% and 7.2±5.6%) and p-JNK-positive cells (7.5±2.2% and 7.6±3.6%) were significantly lower than in the HG group (27.9±12.5% and 18.6±5.2%; P=0.0006, P=0.0003, P<0.0001, P<0.0001, respectively). In the HG group, the number of regenerating neurites was significantly fewer than in the NG groups (70.4±45.1/mm2 vs. 140.6±63.1/mm2; P<0.0001). In the HG+TUDCA and HG+NT-4 groups, the number of neurites was significantly higher than in the HG group (130.5±59.2/mm2 vs. 70.2±45.1/mm2, 254.7±74.0/mm2 vs. 70.2±45.1/mm2; P=0.0002, P<0.0001, respectively). In the HG+NT-4 group, the number of neurites was significantly higher than that in the HG+TUDCA group (P=0.00004).
The neuroprotective effects of TUDCA and NT-4 are similar and are correlated with the suppression of p-c-Jun and p-JNK expression. The stronger regenerative effect of NT-4 than TUDCA shows that not only the suppression of endoplasmic reticulum stress but also other molecular mechanisms may be involved in the regenerative effect of NT-4.
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