RP58 knockdown contributes to hypoxia-ischemia-induced pineal dysfunction and circadian rhythm disruption in neonatal rats.

Abstract

Hypoxia-ischemia (HI) of the brain not only impairs neurodevelopment but also causes pineal gland dysfunction, which leads to circadian rhythm disruption. However, the underlying mechanism of circadian rhythm disruption associated with HI-induced pineal dysfunction remains unknown. The zinc finger protein RP58 is involved in the development and differentiation of nerve cells. In this study, we established an HI model in neonatal rats to investigate the expression of RP58 and its role in pineal dysfunction and circadian rhythm disruption induced by HI. We demonstrated that RP58 was highly expressed in the pineal gland under normal conditions and significantly downregulated in the pineal gland and primary pinealocytes following HI. Knockdown of RP58 decreased the expression of enzymes in the melatonin synthesis pathway (TPH1, ASMT and AANAT) as well as clock genes (CLOCK and BMAL1), and it also reduced the production of melatonin, caused pineal cell injury, and disrupted circadian rhythms in vivo and in vitro. Similarly, HI reduced the expression of melatonin synthesis enzymes (TPH1, ASMT and AANAT) and clock genes (CLOCK and BMAL1) and caused pineal injury and circadian rhythm disruption, which were exacerbated by RP58 knockdown. The detrimental effects of RP58 knockdown on pineal dysfunction and circadian rhythm disruption was reversed by the addition of exogenous melatonin. Furthermore, exogenous melatonin reversed HI-induced pineal dysfunction and circadian rhythm disruption, as reflected by improvements in melatonin production, voluntary activity periods, and activity frequency as well as a diminished decrease in the expression of melatonin synthesis enzymes and clock genes. The present study suggests that RP58 is an endogenous source of protection against pineal dysfunction and circadian rhythm disruption after neonatal HI. This article is protected by copyright. All rights reserved.