title: Global SUMOylation facilitates the multimodal neuroprotection afforded by quercetin against the deleterious effects of oxygen/glucose deprivation and the restoration of oxygen/glucose.
abstract: The putative neuroprotective properties of various flavonoids have long been reported. Among this class of chemicals, quercetin, a major flavone/flavonol naturally occurring in plants, deserves focused attention because of the myriad of beneficial effects observed in various in vitro and in vivo models of central nervous system damage/degeneration. However, the mechanisms governing the beneficial outcomes mediated by quercetin remain to be elucidated. In an effort to define the underlying molecular mechanisms, our study employed human/rat neuroblastoma cell lines (SHSY5Y and B35, respectively) and E18-derived rat primary cortical neurons upon which the effects of various flavonoids were examined. Of note, increases in the levels of global SUMOylation, a post-translational modification with the Small Ubiquitin-like MOdifier (SUMO) were pronounced. Quercetin treatment increased SUMOylation levels in both SHSY5Y cells and rat cortical neurons in a dose and time-dependent manner, possibly via the direct inactivation of certain SENPs (SUMO-specific isopeptidases). Of particular interest, cells treated with quercetin displayed increased tolerance to oxygen/glucose deprivation exposure, an in vitro model of ischemia. SHSY5Y cells treated with quercetin also increased the expression of Nrf2 (via a decrease in the levels of Keap1), heme oxygenase-1 (HO-1), and nitric oxide synthase 1 (NOS1), which provide further protection from oxidative stress. In addition, the increased SUMOylation of HIF-1α was noted and deemed to be significant. We hypothesize that SUMOylated HIF-1α plays a fundamental role in the protection afforded and may underlie some of quercetin's ability to protect cells from oxygen/glucose deprivation-induced cell death, via an up-regulation of HO-1 and NOS1, which ultimately leads to the induction of pro-life NOS1/protein kinase G signaling. Quercetin acts to increase survival in the face of ischemia via an increase of SENP3 expression, the possible inactivation of SENPs 1/2, and via a decrease in KEAP1 levels (thereby increasing Nrf2 stability). These changes may then lead to increase in HIF-1α SUMOylation and HO-1 activation, followed by an up-regulation of NOS1/PKG signaling. Pathways altered via quercetin treatment within our experimental system are represented by blue arrowheads. Solid black arrows represent relationships that have been explored while a dotted arrow represents a relationship that has yet to be confirmed.
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, Maryland, USA.
authors.forename: Yang-Ja
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, Maryland, USA.
authors.forename: Joshua D
authors.identifier: 0000-0002-7814-3867
authors.initials: JD
authors.lastname: Bernstock
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, Maryland, USA.
authors.forename: Nandakumar
authors.initials: N
authors.lastname: Nagaraja
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, Maryland, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ko
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH), Bethesda, Maryland, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hallenbeck
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011794:Quercetin / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D025841:Small Ubiquitin-Related Modifier Proteins; D011794:Quercetin; D007770:L-Lactate Dehydrogenase; D005947:Glucose
keywords: SUMO-specific isopeptidase (SENPs); SUMOylation; flavonoids; hypoxia-inducible factor-1 alpha (HIF-1α); oxygen/glucose deprivation (OGD); quercetin