Pharmacological Enhancement of Neuronal Survival

Abstract

This article is a comprehensive assessment of the quantitative features of the dose response for neuroprotective agents and their underlying mechanistic foundations. The data were derived from published studies using numerous primary neuronal cell cultures and neuronal cell lines. These biological models assessed normal developmental and aging processes, preconditioning adaptive responses, and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The nature of the dose response was generally U-shaped with quantitative features similar to the hormetic dose-response model and independent of biological model, endpoint measured, and chemical class. The agents displaying the U-shaped dose response for neuronal survival include numerous endogenous agonists, plant-derived agents, synthetic drugs, and widely used chemicals including potent neurotoxins. That neuroprotective agents display similar dose-response relationships regardless of experimental system, potency, and endpoint is an important observation with widespread biomedical and clinical implications.

Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity

“…Over the past decade, biology, medicine, pharmacology and toxicological sciences have focused great interest in understanding the mechanisms leading to the cell and organism hormetic adaptive responses to moderate stress (Calabrese, 2008b(Calabrese, , 2008cCalabrese et al, 2009a). The hormetic biphasic dose-response phenomenon is characterized by a stimulation in the low dose zone, followed by an inhibitory response at higher doses .…”

Dose-Response Features of Neuroprotective Agents: An Integrative Summary

“…Finally, Appendix 1 (1) summarizes the principal features of representative studies concerning the general area of neuroscience and hormesis, including but not limited to neuronal survival, neurite outgrowth, and astrocytes, and (2) provides a set of graphs of these dose responses along with quotes from each paper providing the authors' assessment of the dose-response findings as well as an interpretational segment provided by the original authors or myself. As noted already, far more extensive and integrative critiques of the effects of pharmacological agents on neuronal survival, neurite outgrowth, and astrocyte adaptation are provided in the subsequent three articles (Calabrese, 2008a(Calabrese, , 2008b(Calabrese, , 2008c. Chu, 2001), have been shown to enhance markers of neuronal survival at low doses while being inhibitory or toxic at higher doses.…”

Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways

“…Interestingly, some anti-AD drugs exhibit hormetic responses in improving memory [9]. In fact, neuroprotective agents seem to generally express their neuroprotective properties in a manner consistent with the hormetic response [7], [10]. In addition, various phytochemicals in moderate amounts exert neuroprotective effects by enhancing neural cell viability and activating signaling pathways involving cell survival, anti-apoptosis and anti-oxidation defense [11], [12].…”

“…A diverse range of chemicals (phytochemicals, endogenous agonists, synthetic drugs and neurotoxins) have been reported to display a hormetic responses in neuronal models [7], [8]. Interestingly, some anti-AD drugs exhibit hormetic responses in improving memory [9].…”