ABSTRACT
It is becoming increasingly clear that neurological disorders are multifactorial, involving disruptions in multiple cellular systems. Thus, while each disease has its own initiating mechanisms and pathologies, certain common pathways appear to be involved in most, if not all, neurological disorders described to date. These include alterations in redox homeostasis, gene transcription, protein modication and processing, neurotrophic factor signaling, mitochondrial function, and the immune response. Therefore, it is unlikely that hitting a single target will result in signicant benets to patients with a neurological disorder.1,2 However, current drug research efforts are almost exclusively focused on single protein targets and the identication of small molecules that can modulate these targets with high afnity.3 Thus, for the treatment of neurological disorders, it may be
14.1 Introduction .......................................................................................................................... 189 14.2 Fisetin Can Maintain Intracellular Glutathione Levels and Promote
the Survival of Nerve Cells in Response to Multiple Toxic Insults ...................................... 190 14.3 Fisetin Can Activate Neurotrophic Factor Signaling Pathways ........................................... 193 14.4 Fisetin Can Enhance Cognitive Function ............................................................................. 194 14.5 Fisetin Can Regulate Protein Homeostasis (Proteostasis) .................................................... 195 14.6 Anti-Inammatory Effects of Fisetin ................................................................................... 197 14.7 Other Activities of Fisetin That Could Be Relevant to Its Ability
to Maintain Neuronal Function ............................................................................................ 198 14.7.1 Iron Chelation/Inhibition of Lipid Peroxidation ....................................................... 198 14.7.2 Inhibition of PARP Activity ..................................................................................... 199 14.7.3 Inhibition of Lipoxygenase Activity ......................................................................... 199 14.7.4 Inhibition of Cyclin-Dependent Kinases .................................................................. 199 14.7.5 Inhibition of NADPH Oxidase Activity ...................................................................200 14.7.6 Activation of Sirtuins ................................................................................................200
14.8 Metabolism of Fisetin ........................................................................................................... 201 14.9 Summary .............................................................................................................................. 201 Acknowledgments ..........................................................................................................................202 References ......................................................................................................................................202
necessary to use combinations of drugs directed against different targets. However, this approach is subject to a number of potential problems, including pharmacokinetic and bioavailability challenges, which in central nervous system (CNS) disorders are exacerbated by the difculty of getting multiple compounds across the blood-brain barrier and the potential for drug-drug interactions. An alternative approach is to identify small molecules that have multiple biological activities that are relevant to neurological disorders.
