Send Orders of Reprints at reprints@benthamscience.net 30 Central Nervous System Agents in Medicinal Chemistry, 2013, 13, 30-35 Neuroprotective Actions of Flavones and Flavonols: Mechanisms and Relationship to Flavonoid Structural Features Federico Dajas * , Abin-Carriquiry Juan Andrés, Arredondo Florencia, Echeverry Carolina and Rivera-Megret Felicia Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay Abstract: Epidemiological studies have shown positive preventive action of flavonoids on cardiovascular and neurodegenerative events. Among the six groups in which flavonoids are classified, the flavones and flavonols, based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) are the most commonly encountered within the families and genera of the higher plants. Numerous studies support a neuroprotective activity of flavones such as luteolin and flavonols such as kaempherol and quercetin in experimental focal ischemia and models of neurodegeneration. Antioxidation, modulation of signaling cascades and gene expression as well as anti-inflammation appear as the main protective mechanisms and mitochondria are a likely main target mediating the preventive actions against oxidative stress. Flavones and flavonols re-establish the redox regulation of proteins, transcription factors and signaling cascades that are otherwise inhibited by elevated oxidative stress. The final survival or death of the neuron depends on flavone and flavonol concentrations, time of exposure and, mainly, metabolic and oxidative neuronal circumstances. Neuroprotection appears to be linked to specific structural motifs, beyond those involved in antioxidation. By themselves or as templates for synthetic compounds, flavone and flavonol molecules show potential as multi-targeted therapeutic tools for protecting the brain. Nonetheless, more research needs to be done on the correlation of potential beneficial effects of flavones and flavonols and their mechanisms of action. Keywords: Flavones, flavonols, neuroprotection, oxidative stress, quercetin, signalling. 1. INTRODUCTION 1.1. Brain Pathology, Redox Homeostasis and Oxidative Stress It is known that brain pathology in the form of cerebrovascular and neurodegenerative disease is a leading cause of death all over the world, with an incidence of about 2/1000 and an 8% total death rate [1, 2]. Moreover, stroke and dementia are a source of high individual and family suffering mainly because of the lack of efficient therapeutic alternatives. The latter motivates research efforts to identify the mechanisms of neuronal death and to discover new compounds to prevent them. Neuronal death in these neuropathologies is a complex phenomenon involving failure of metabolic processes, protein impaired mitochondrial function, increased oxidative damage, defects in the proteasome system, protein aggregation, changes in iron metabolism, and events of excitotoxicity and inflammation [3]. The interaction between all these cellular processes would not be necessarily a cascade but a cycle of events, of which oxidative stress is a major component [4]. Under physiologic conditions, the balance between the generation and the elimination of reactive oxygen and nitrogen species (ROS, NOS) maintains a redox homeostasis *Address correspondence to this author at the Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, Avda Italia 3318, 11600, Montevideo, Uruguay; Tel:/Fax: 5982 4872603; E-mail: fdajas@gmail.com to ensure the correct function of redox-sensitive signaling proteins. However, when homeostasis is disturbed, oxidative stress may take place leading to damage of lipids, proteins and nucleic acids and disruption of redox signaling [5, 6]. Aberrant redox cell signaling may in turn cause cell death, contributing to disease onset [7-10]. With only 2% of the body weight, the brain represents almost 20% of the O 2 consumption of the organism [11]. Indeed, because of its high metabolic rate and relatively reduced capacity for cellular defense and regeneration compared with other organs, the brain is believed to be particularly susceptible to oxidative stress events. In this sense, the maintenance of cellular redox homeostasis appears as a cue to the control and the prevention of oxidative stress- related brain diseases [12, 13]. The above-described situation has led to the search of a variety of antioxidant approaches to attenuate acute ischemic and chronic neurodegenerative disease injuries [14, 15]. Nevertheless, promising results showing strong neuroprotective effects in different preclinical models, failed systematically in clinical trials [16]. In this context, it is likely that molecules acting on multiple targets and involved in all the events of the neurodegenerative processes would be required to be therapeutically effective [3]. 1.2. Flavonoids: Flavones and Flavonols Flavonoids represent the most common group of polyphenolic compounds in the human diet and are widely 1875-6166/13 $58.00+.00 © 2013 Bentham Science Publishers