title: Chemical basis for the disparate neuroprotective effects of the anthocyanins, callistephin and kuromanin, against nitrosative stress.
abstract: Oxidative and nitrosative stress are major factors in neuronal cell death underlying neurodegenerative disease. Thus, supplementation of antioxidant defenses may be an effective therapeutic strategy for diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this regard, treatment with nutraceutical antioxidants has garnered increasing attention; however, the differential neuroprotective effects of structurally similar nutraceuticals, which may affect their suitability as therapeutic agents, has not been directly examined. In this study we compare the ability of two anthocyanins, callistephin (pelargonidin-3-O-glucoside) and kuromanin (cyanidin-3-O-glucoside) to protect cerebellar granule neurons from damage induced by either oxidative or nitrosative stress. These anthocyanins differ by the presence of a single hydroxyl group on the B-ring of kuromanin, forming a catechol moiety. While both compounds protected neurons from oxidative stress induced by glutamate excitotoxicity, a stark contrast was observed under conditions of nitrosative stress. Only kuromanin displayed the capacity to defend neurons from nitric oxide (NO)-induced apoptosis. This protective effect was blocked by addition of Cu, Zn-superoxide dismutase, indicating that the neuroprotective mechanism is superoxide dependent. Based on these observations, we suggest a unique mechanism by which slight structural variances, specifically the absence or presence of a catechol moiety, lend kuromanin the unique ability to generate superoxide, which acts as a scavenger of NO. These findings indicate that kuromanin and compounds that share similar chemical characteristics may be more effective therapeutic agents for treating neurodegenerative diseases than callistephin and related (non-catechol) compounds.
authors.affiliation: Department of Biological Sciences, University of Denver, Denver CO 80208, United States.
authors.forename: Aimee N
authors.initials: AN
authors.lastname: Winter
authors.affiliation: Department of Biological Sciences, University of Denver, Denver CO 80208, United States.
authors.forename: Erika K
authors.initials: EK
authors.lastname: Ross
authors.affiliation: Department of Biological Sciences, University of Denver, Denver CO 80208, United States.
authors.forename: Sonia
authors.initials: S
authors.lastname: Khatter
authors.affiliation: Department of Chemistry and Biochemistry, University of Denver, Denver CO 80208, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Miller
authors.affiliation: Department of Biological Sciences, University of Denver, Denver CO 80208, United States; Eleanor Roosevelt Institute, University of Denver, Denver CO 80208, United States; Knoebel Institute for Healthy Aging, University of Denver, Denver CO 80208, United States. Electronic address: Daniel.Linseman@du.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Linseman
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D031985:Fragaria / Q000737:chemistry; D005960:Glucosides / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D000073039:Nitrosative Stress; D010936:Plant Extracts / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D065856:Rubus / Q000737:chemistry; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
chemical_list: D000872:Anthocyanins; D005960:Glucosides; D018696:Neuroprotective Agents; D010936:Plant Extracts; C000596494:cyanidin 3-O-glucopyranoside; D013481:Superoxides; D009569:Nitric Oxide; D018698:Glutamic Acid; C078485:pelargonidin-3-glucoside
keywords: Anthocyanins; Excitotoxicity; Neurodegeneration; Neuroprotection; Nitric Oxide; Nitrosative stress