Viewpoint: Mechanisms of Action and Therapeutic Potential of Neurohormetic Phytochemicals

Abstract

ᮀ The nervous system is of fundamental importance in the adaptive (hormesis) responses of organisms to all types of stress, including environmental "toxins". Phytochemicals present in vegetables and fruits are believed to reduce the risk of several major diseases including cardiovascular disease, cancers and neurodegenerative disorders. Although antioxidant properties have been suggested as the basis of health benefits of phytochemicals, emerging findings suggest a quite different mechanism of action. Many phytochemicals normally function as toxins that protect the plants against insects and other damaging organisms. However, at the relatively low doses consumed by humans and other mammals these same "toxic" phytochemicals activate adaptive cellular stress response pathways that can protect the cells against a variety of adverse conditions. Recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors. Such hormetic pathways stimulate the production of antioxidant enzymes, protein chaperones and neurotrophic factors. In several cases neurohormetic phytochemicals have been shown to suppress the disease process in animal models relevant to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and can also improve outcome following a stroke. We are currently screening a panel of biopesticides in order to establish hormetic doses, neuroprotective efficacy, mechanisms of action and therapeutic potential as dietary supplements.

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…Taken together these findings indicate the dose dependent dimorphic actions of Bardoxolone methyl analogs on CKD progression with favorable effect at a low drug dosage and toxic effects at a high dosage. The dimorphic response to the Bardoxolone analogs which are potent synthetic Nrf2 inducers is consistent with the well-known hormetic properties of the natural plantbased Nrf2 activators [37,38]. These phytochemicals found in fruits and vegetables are known to reduce the risk of cancers, neurodegenerative disorders, and cardiovascular disease.…”

Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner

“…SF has been used as a chemopreventive compound (19). The cytoprotective effect of SF is explained mainly by activation of the Nrf2-ARE pathway (20). In vivo studies have shown that SF protects the brain against hypoxicSulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner ischemic injury through induction of Nrf2-dependent phase 2 enzyme (21).…”

Cellular membrane affinity chromatography (CMAC) in drug discovery from complex natural matrices

“…Plants use the array of phytochemicals that serve multiple purposes, for example: protection from abiotic stress, like excessive UV radiation (polyphenols, terpenes and terpenoids), attraction of pollinators (volatile terpenes), warding off herbivores (noxious phytochemicals, e.g. alkaloids), protection from bacterial or fungal infections (polyphenols, terpenoids, etc) [1][2][3][4]. Herbivores evolved different forms of biochemical changes, that protect them from the deleterious effects of some of the phytochemicals, for example: CYP450 superfamily of enzymes, transporter proteins and stress-response cellular signalling pathways [1][2][3][4].…”

“…alkaloids), protection from bacterial or fungal infections (polyphenols, terpenoids, etc) [1][2][3][4]. Herbivores evolved different forms of biochemical changes, that protect them from the deleterious effects of some of the phytochemicals, for example: CYP450 superfamily of enzymes, transporter proteins and stress-response cellular signalling pathways [1][2][3][4]. Many of these mechanisms are highly conserved adaptive stress response systems that humans share with simple herbivores.…”