Abstract

Reactive oxygen species (ROS) is major risk factor in neuronal diseases including ischemia. Although biliverdin reductase A (BLVRA) plays a pivotal role in cell survival via its antioxidant function, its role in hippocampal neuronal (HT-22) cells and animal ischemic injury is not clearly understood yet. In this study, the effects of transducible fusion protein Tat-BLVRA on H2O2-induced HT-22 cell death and in an animal ischemia model were investigated. Transduced Tat-BLVRA markedly inhibited cell death, DNA fragmentation, and generation of ROS. Transduced Tat-BLVRA inhibited the apoptosis and mitogen activated protein kinase (MAPK) signaling pathway and it passed through the blood-brain barrier (BBB) and significantly prevented hippocampal cell death in an ischemic model. These results suggest that Tat-BLVRA provides a possibility as a therapeutic molecule for ischemia.

Highlights

  • Biliverdin reductase is known as an evolutionarily conserved soluble protein which is found in various species, the biological function of biliverdin reductase is to convert biliverdin to bilirubin in the heme metabolism pathway [1]

  • Biliverdin reductase and bilirubin are involved in the regulation of mitogen activated protein kinase (MAPK), phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt), and protein kinase C delta (PKCδ) signaling pathways and various gene expressions related to cell survival, suggesting that biliverdin reductase may be a potential therapeutic agent for various diseases [9,10,11,12,13,14,15]

  • Hippocampal neuronal (HT-22) cells were treated with Tat-biliverdin reductase A (BLVRA) or control BLVRA (0.5–5 μM) for 2 h or with Tat-BLVRA or control BLVRA (5 μM) for various times (10–120 min)

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Summary

Introduction

Biliverdin reductase is known as an evolutionarily conserved soluble protein which is found in various species, the biological function of biliverdin reductase is to convert biliverdin to bilirubin in the heme metabolism pathway [1]. Other studies have demonstrated that biliverdin reductase and enzyme product bilirubin have antioxidant functions by reducing the reactive oxygen species (ROS) [4,5]. Biliverdin reductase and bilirubin are involved in various diseases, including brain damage and protection against oxidative stress-induced neuronal injury [6,7,8,9]. Oxidative stress-induced impairment of BLVRA increased accumulation of amyloid beta (Aβ) and tumor necrosis factor-alpha (TNF-α), that greatly contribute to the onset of brain insulin resistance along the progression of Alzheimer’s disease pathology [11]. Oxidative stress induces cellular ROS generation, excessive elevation of neuronal cell death by modification of cellular macromolecules, including DNA and proteins [16,17,18]. We examined the effect of Tat-BLVRA against oxidative stress-induced hippocampal neuronal cell death and in an insult animal model of ischemia

Purification and Transduction of Tat-BLVRA into HT-22 Cells
Protective Effect of Tat-BLVRA against H2O2-Induced Cytotoxicity
Cell Culture and Viability Measurements
Transduction of Tat-BLVRA into HT-22 Cells
Western Blot Analysis
Measurement of Activation of Akt and MAPK as well as Apoptosis Signals
Experimental Animals
Statistical Analysis
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