NEUROPROTECTIVE IMPACT OF PROTHYMOSIN ALPHA-DERIVED HEXAPEPTIDE AGAINST RETINAL ISCHEMIA-REPERFUSION

Prothymosin alpha (ProT alpha) has robustness roles against brain and retinal ischemia or serum-starvation stress. In the ProT alpha sequence, the active core 30-amino acid peptide/P-30 (a.a.49-78) is necessary for the original neuroprotective actions against ischemia. Moreover, the 9-amino acid peptide sequence/P-9 (a.a.52-60) in P-30 still shows neuroprotective activity against brain and retinal ischemia, though P-9 is less potent than P-30. As the previous structure-activity relationship study for ProT alpha may not be enough, the possibility still exists that any sequence smaller than P-9 retains potent neuroprotective activity. When different P-9- and P-30-related peptides were intravitreally injected 24 h after retinal ischemia in mice, the 6-amino acid peptide/P-6 (NEVDEE, a.a.51-56) showed potent protective effects against ischemia-induced retinal functional deficits, which are equipotent to the level of P-30 peptide in electroretinography (ERG) and histological damage in Hematoxylin and Eosin (HE) staining. Further studies using ERG and HE staining suggested that intravitreal or intravenous (i.v.) injection with modified P-6 peptide/P(6)Q (NEVDQE) potently inhibited retinal ischemia-induced functional and histological damage. In an immunohistochemical analysis, the ischemia-induced loss of retinal ganglion, bipolar, amacrine and photoreceptor cells were inhibited by a systemic administration with P(6)Q peptide 24 h after the ischemic stress. In addition, systemic post-treatment with P(6)Q peptide significantly inhibited retinal ischemia-induced microglia and astrocyte activation in terms of increased ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) intensity, respectively, as well as their morphological changes, increased number and migration. Thus, this study demonstrates the therapeutic significance of modified P-6 peptide P(6)Q (NEVDQE) derived from 6-amino acid peptide (P-6) in ProT alpha against ischemic damage. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.