Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

Abstract

Despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose–response relationships, their mechanistic foundations, and their relationship to the concept of biological plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling. Antioxid. Redox Signal. 13, 1763–1811. Introduction Hormesis Membrane Radical Dynamics Lipid Peroxidation and Sphingomyelin Metabolism Plasma Membrane Redox System Membrane-Related Hormesis Mechanisms Mitochondria: A Hub of Cellular Redox Processes Hormesis, Mitochondria, and Neuroprotection Proteotoxicity, Cellular Stress Response, and the Vitagene Network Sirtuins and the Integration of Adaptive Stress Responses in Neurons The Kelch-Like ECH-Associated Protein 1/Nrf2/Antioxidant Response Element Pathway Hormetic Phytochemicals and the Neuroprotective Effects of Pharmacological Activators of the Keap1/Nrf2/ARE Pathway Tert-butylhydroquinone Sulforaphane Dimethyl fumarate Diallyl trisulfide Celastrol Curcumin Ferulic acid Heme Oxygenases Adaptive ER Stress Responses: Calcium and Protein Chaperones Hsps and Neuroprotection Neuroprotective effects of extracellular Hsps Neuro Gas Biology and the Roles of CO, NO, and Hydrogen Sulfide in Brain Physiopathology Carbon monoxide NO and NO synthases Hydrogen sulfide H₂S and suspended animation Functional interrelation of NO, CO, and H₂S gases and their relevance to hormesis Future Directions