Antiglycative activity of sulforaphane: a new avenue to counteract neurodegeneration?

摘要: Neurodegeneration is a key aspect of large number diseases that come under the umbrella “neurodegenerative diseases” with most notable being Parkinson's, Alzheimer's, and Huntington's (AD, PD, HD). They are all incurable debilitating conditions result in progressive degeneration and/or death neurons leading cause disability elderly. The incidence these on rise yet there paucity effective therapies to treat them. The etiopathogenesis multifactorial complex may involve different characteristics like mitochondrial dysfunction, excitotoxicity, abnormal protein aggregation, inflammation. In particular AD, common dementia worldwide, characterized by an accumulation extracellular amyloid-β (Aβ) peptide intracellular neurofibrillary tangles cerebral cortex hippocampus. Reactive oxygen species (ROS) has been suggested play pathogenic role onset progression AD contributing formation aggregation Aβ tau hyperphosphorylation (Moneim, 2015). addition synergically oxidative stress, also glycative overwhelming unfavourable glycation state glycated proteins, reported have causative (Angeloni et al., 2014). Non-enzymatic process post-translational modification which reducing sugars or toxic aldehydes react amino groups, heterogeneous class compounds called advanced end products (AGEs). AGEs strictly linked neurodegeneration because they accumulate brains patients (Krautwald 2011) co-localize plaques tangles. High levels measured both astroglia 2014). Methylglyoxal (MG), endogenous α-ketoaldehyde, powerful precursor AGE production. MG produced endogenously as intermediate metabolism carbohydrates, lipids acids normal pathological conditions. main pathways degradation glycolytic triose-phosphate intermediates, acetone metabolism, lipoperoxidation catabolism threonine glycine detoxified anti-glycation enzymes comprise glyoxalase I (GLO1) catalyzes production S-D-lactoylglutathione (SLG) from reduced glutathione (GSH), II hydrolysis SLG non-toxic D-lactate. When increased high glucose stress when GLO system activity deranged, proteins brain lead playing fundamental establishment neurodegenerative disorders such (Ramasamy 2005). Since no drugs available counteract progression, today research focus shifted nutraceutical alternative form prevention/treatment. isothiocyanate sulforaphane (isothiocyanato-4-(methylsulfinyl)-butane) (SF), abundant Cruciferous vegetables, received considerable attention its protective vitro vivo animal models (Tarozzi 2013). Moreover, SF bioavailability central nervous (CNS) widely demonstrated As studies carried out elucidate effect counteracting damage neurons, we investigated effects against MG-induced neuroblastoma SH-SY5Y cells focusing targets 2015). First tried clarify neutralizing stress. Our results indicated counteracts ROS two possible mechanisms action: increase GSH enhancement MG-detoxification through up-regulation systems. Since GLO1 decreases (Kuhla 2007), ability strengthen expression could represent new avenue deleterious therefore prevent AD. These observations underpinned findings Xue al. (2012) observed mediated transcription factor Nrf2 (nuclear factor-erythroid 2 p45 subunit-related 2) binds functional ARE (antioxidant-response element) 5’-untranslated region exon 1 mammalian gene. shown be neuroprotective many paradigms neuronal injury neurodegeneration. activate (Hong 2005), this pathway regarded essential for effects. We previously protects cortical 5-S-cysteinyl-dopamine-induced neurotoxicity stimulating antioxidant gene (Vauzour 2010). Another mechanism exerts modulation mitogen-activated kinase (MAPK) signaling involved apoptotic cell death. exposure leads activation signal-regulated 1/2 (ERK1/2), c-Jun N-terminal (JNK) p38 MAPK systems (Zhou cells, SF-pre-treatment significantly inhibited induced phosphorylation ERK1/2, JNK suggesting due inhibition pro-apoptotic kinases. highlight SF, activated (Zhu 2001), their importance modulators demonstrated. Brain-derived neurotrophic (BDNF), member neurotrophin family growth factors associated survival interactions tyrosine receptor B (TrkB) p75 cellular receptors. BDNF pathophysiology proposal serum biomarker risk (Gezen-Ak showed reduces toxicity Aβ1–42 Aβ25–35 (Arancibia 2008) boosts de-phosphorylation (Elliott 2005). exhibits peculiar BDNF/TrkB it unexpected whose nullified strong down-regulation TrkB (Di Loreto 2008). data SH-SY5H confirmed observation. pre-treatment, before addition, not only further levels, but reverting negative 2015). Glucose hypometabolism transport additional metabolic phenotype Alzheimer's brain. administration rats intolerance, GLUT4 GLUT2 expressions (Dhar 2011), uptake (Rizzo Interestingly, totally reverts reduction caused exposure, maintaining availability This particularly important neuron energy status, since related defects (de Arriba 2006). On other hand, glycolysis innocuous inevitably produces MG, defined “the dark side glycolysis” (Allaman able influx into highly one potent glycating agents cells. In conclusion, pleiotropic actions (summarized Figure 1) protection exposure. action, fact, ascribed simple anti-glycative process, but, considering “tandem” free radical fall concentration, can multitarget agent modulating functions pro-survival frame prevention/counteraction AD. Figure 1 Potential exerted injury. All Authors contributed equally writing critically revising paper. Part researches described was supported MIUR-FIRB (project RBAP11HSZS) Fondazione del Monte di Bologna e Ravenna (ITALY). authors certify affiliations involvement any organization entity financial non-financial interest subject matter discussed