Quercetin Completely Ameliorates Hypoxia-Reoxygenation-Induced Pathophysiology Severity in NY1DD Transgenic Sickle Mice: Intrinsic Mild Steady State Pathophysiology of the Disease in NY1DD Is Also Reversed.

Sangeetha Thangaswamy,Kamalakar Ambadipudi,Craig A Branch,Seetharama A Acharya

doi:10.3390/biom11101473

Sangeetha Thangaswamy, Kamalakar Ambadipudi + Show 2 more

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https://doi.org/10.3390/biom11101473

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Abstract

The vaso-occlusive crisis (VOC) is a major complication of sickle cell disease (SCD); thus, strategies to ameliorate vaso-occlusive episodes are greatly needed. We evaluated the therapeutic benefits of quercetin in a SCD transgenic sickle mouse model. This disease model exhibited very mild disease pathophysiology in the steady state. The severity of the disease in the NY1DD mouse was amplified by subjecting mice to 18 h of hypoxia followed by 3 h of reoxygenation. Quercetin (200 mg/kg body weight) administered to hypoxia challenged NY1DD mice in a single intraperitoneal (i.p.) dose at the onset of reoxygenation completely ameliorated all hypoxia reoxygenation (H/R)-induced pathophysiology. Additionally, it ameliorated the mild intrinsic steady state pathophysiology. These results are comparable with those seen with semisynthetic supra plasma expanders. In control mice, C57BL/6J, hypoxia reoxygenation-induced vaso-occlusion was at significantly lower levels than in NY1DD mice, reflecting the role of sickle hemoglobin (HbS) in inducing vaso-occlusion; however, the therapeutic benefits from quercetin were significantly muted. We suggest that these findings represent a unique genotype of the NY1DD mice, i.e., the presence of high oxygen affinity red blood cells (RBCs) with chimeric HbS, composed of mouse α-chain and human βS-chain, as well as human α-chain and mouse β-chain (besides HbS). The anti-anemia therapeutic benefits from high oxygen affinity RBCs in these mice exert disease severity modifications that synergize with the therapeutic benefits of quercetin. Combining the therapeutic benefits of high oxygen affinity RBCs generated in situ by chemical or genetic manipulation with the therapeutic benefits of antiadhesive therapies is a novel approach to treat sickle cell patients with severe pathophysiology.

Highlights

The vaso-occlusive crisis (VOC) is a common complication in patients with sickle cell disease (SCD)
All concentrations used in this study induced a quercetin therapeutic benefit, but the effect exerted by 200 mg/kg quercetin provided the most significant improvement in vaso-occlusive and hemodynamic parameters in postcapillary venules, and was chosen as the dose for the present study
NY1DD mice, is a unique observation, and we suggest that this high efficacy might be due to the antioxidant therapeutic activity of quercetin synergized with intrinsic anti-anemia therapeutic activity towards high oxygen affinity red blood cells (RBCs) present in the NY1DD mice model

Summary

Introduction

The vaso-occlusive crisis (VOC) is a common (yet challenging) complication in patients with sickle cell disease (SCD). It generally requires admitting the patients to the hospital. VOC episodes are induced by multifactorial processes that involve abnormal blood rheology, ischemic inflammation, increased oxidative stress, vascular adhesion, coagulation, and vascular tone modulation [1]. The basal level of vaso-occlusion is a normal feature of SCD, and the crisis is generally induced in patients by stressful events. Recent studies have shown that oxidative phenomena play significant roles in the severity of the pathophysiology of SCD [2,3,4]. Oxidative stress may even contribute to the sickling process through the formation of dense cells, the development of vaso-occlusive leukocytes, and shortened red blood cell (RBC) survival. The oxidant damage in sickle red blood cells

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