Heme Oxygenase as a Therapeutic Funnel in Nutritional Redox Homeostasis and Cellular Stress Response

Abstract

Reduction of cellular expression and activity of antioxidant proteins and the consequent increase of oxidative stress are fundamental causes for both the aging processes and neurodegenerative diseases. Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimer’s disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. There is now evidence to suggest that networks of responses exist in the brain to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. Recent studies have shown that the heat shock response contributes to establish a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine (LAC) is proposed as a therapeutic agent for several neurodegenerative disorders, and there is evidence that LAC may play a critical role as a modulator of cellular stress response in health and disease states. In the present review we discuss the role of the heme oxygenase pathway in cellular stress response. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and hence potentiate brain stress tolerance.