白内障は水晶体が混濁し、失明や視力低下を引き起こす眼疾患である。この水晶体混濁を防ぐため、水晶体には還元型グルタチオン（GSH）やアスコルビン酸（AsA）が豊富に存在し水晶体を保護している。私はこれまでに、天然フラボノイドの一種であるヘスペレチンに着目し、ヘスペレチンの白内障進行抑制効果を報告してきた。本申請研究では、体内動態改善と生体内滞留時間延長による長時間作用を期待してステアリン酸および、オレイン酸エステルとした化合物を合成し、それらの白内障進行抑制効果を検討した。13日齡SD系ラットに各化合物 (10nmol/kg) を１日1回、ラット皮下に3日間連続投与した。化合物1回目投与の4時間後に亜セレン酸ナトリウム（20マイクロmol/kg体重）をラットに皮下投与した。亜セレン酸ナトリウム投与6日後、目視で水晶体混濁程度を観察した。水晶体観察後ラットを安楽死させ、水晶体を摘出して水晶体内GSH, AsA濃度測定およびシャペロン活性測定を行った。
その結果、亜セレン酸ナトリウム誘導白内障は、ヘスペレチン投与により、混濁の有意な改善が認められ、ヘスペレチン脂肪酸エステルではより強い混濁改善効果が認められた。白内障発症ラットの水晶体内GSH濃度およびアスコルビン酸濃度は亜セレン酸投与により減少したが、ヘスペレチンおよびその誘導体投与によりそれらの濃度減少は抑制された。さらに白内障発症により減少した水晶体内シャペロン活性は、ヘスペレチンおよびその誘導体投与により活性減少の抑制が認められた。
以上のことより、ヘスペレチン脂肪酸エステルとすることでより強い白内障進行抑制効果が認められた。
本研究成果は、Molecular Medicine Reports (2018)に掲載された。
Cataracts are the major cause of blindness in the world. As anti-cataract pharmaceutical therapies require long-term treatment, identifying anti-cataract compounds that are ubiquitous in the human diet, have no adverse effects, and are affordable, is of paramount importance. In this study, we focused on hesperetin and its derived compounds, hesperetin stearic acid ester (Hes-S) and hesperetin oleic acid ester (Hes-O), to investigate their therapeutic potential to treat cataracts in a selenite animal model. Thirteen-day-old Sprague Dawley rats were divided into 12 groups. Animals in groups 1 and 7 were subcutaneously injected with vehicle, those in groups 2 and 8 were hesperetin, those in groups 3 and 9 were stearic acid, those in groups 4 and 10 were oleic acid, those in groups 5 and 11 were Hes-S, and those in groups 6 and 12 were Hes-O (10 nmol/ kg body weight on days 0, 1, and 2). Animals in the groups 7 to 12 were treated with sodium selenite (20 micro mol/kg body weight given 4 h after the test compound treatment on day 0) to induce cataract. On day 6, rats had less severe central opacities and lower stage cataracts than rats in the selenite treatment-only control groups. The levels of glutathione (GSH) and ascorbic acid (AsA) in lenses with selenite-induced cataracts declined to one-third of that of controls, and the reduction in GSH and AsA levels was rescued after hesperetin, Hes-S, or Hes-O treatment, with concentrations remaining to 70–80% of that of controls. However, there were no changes in the blood levels of GSH and AsA following the treatments. Administration of either hesperetin or hesperetin-derived compounds prevented the reduction of chaperone activity in the lens, and rats treated with Hes-S or Hes-O treatment had significantly greater chaperone activity than hesperetin-treated rats. Collectively, these results suggest that both hesperetin and hesperetin-derived compounds are novel drug compounds that have the potential to prevent or delay the onset of cataracts.
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