Abstract
Oxidative damage and redox metal homeostasis loss are two contributing factors in brain aging and widely distributed neurodegenerative diseases. Oxidative species in company with excessive amounts of intracellular free iron result in Fenton-type reaction with subsequent production of highly reactive hydroxyl radicals which initiate peroxidation of biomolecules and further formation of non-degradable toxic pigments called lipofuscin that amasses in long-lived postmitotic cells such as neurons. Dietary flavonoid baicalein can counteract the detrimental consequences through exertion of a multiplicity of protective actions within the brain including direct ROS scavenging activity and iron chelation. In this study, we evaluated the neuroprotective effects of baicalein in menadione (superoxide radical generator)-treated SK-N-MC neuroblastoma cell line. Our results showed that treatment of cells with menadione led to lipofuscin formation due to elevated intracellular iron contents and accumulation of oxidative products such as MDA and PCO. Also, menadione caused apoptotic cell death in SK-N-MC cells. However, pretreatment with baicalein (40 μM) reversed the harmful effects by chelating free iron and preventing biomolecules peroxidations. Moreover, baicalein prevented cell death through modulation of key molecules in apoptotic pathways including suppression of Bax and caspase-9 activities and induction of bcl2 expression. Key structural features such as presence of hydroxyl groups and iron-binding motifs in baicalein make it the appropriate candidate in antioxidant-based therapy in age-related neurodegenerative diseases.
Highlights
The key precept of the oxidative stress theory of aging is that senescence-related loss of function is due to the progressive and irreparable accrual of molecular oxidative damage which is brought about by powerful pro-oxidant species including reactive oxygen species (ROS) [1,2]
Our results showed that treatment of cells with menadione led to lipofuscin formation due to elevated intracellular iron contents and accumulation of oxidative products such as MDA and Protein carbonyls (PCOs)
Menadione is a quinone known to induce an oxidative stress generated primarily by superoxide radicals leading to cell death [31]
Summary
The key precept of the oxidative stress theory of aging is that senescence-related loss of function is due to the progressive and irreparable accrual of molecular oxidative damage which is brought about by powerful pro-oxidant species including reactive oxygen species (ROS) [1,2]. ROS include a broad range of partially reduced metabolites of oxygen (e.g. superoxide, hydrogen peroxide and hydroxyl radical) having higher reactivity than molecular oxygen [3]. Free radical or oxidative stress theory of aging was first proclaimed by Denham Harman demonstrating the role of oxidative species in aging process acceleration and cell death [5,6] This theory can explain many of the senescent changes including accumulation of brown-yellow, electron-dense, autofluorescent bodies in cells called lipofuscin pigments or age pigments [5,7,8]. Some researchers believe that lipofuscin formation does not have any serious effects on normal func-
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