title: Dual blockade of the A1 and A2A adenosine receptor prevents amyloid beta toxicity in neuroblastoma cells exposed to aluminum chloride.
abstract: In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl3) enhanced the neurotoxicity of the amyloid beta(25-35) fragment (Abeta(25-35)) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A2A adenosine receptors (A2AR), although it also inhibits A1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta(25-35)+AlCl3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta(25-35)+AlCl3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A1R and A2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl3 treatment exacerbated Abeta(25-35) toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta(25-35) only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta(25-35)+AlCl3-induced damage, suggesting that A1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A1R inhibition in the setting of combined Abeta(25-35)+AlCl3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum.
authors: Department of Bio-Medical Sciences, Section of Anatomy and Histology, University of Catania, Italy.
authors: Salvatore
authors: S
authors: Giunta
authors: Department of Pediatrics and Public Health Sciences, University of Turin, Italy.
authors: Violetta
authors: V
authors: Andriolo
authors: Department of Bio-Medical Sciences, Section of Anatomy and Histology, University of Catania, Italy. Electronic address: alecasto@unict.it.
authors: Alessandro
authors: A
authors: Castorina
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000009:adverse effects*; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001252:Astringents / Q000009:adverse effects; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000009:adverse effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D009447:Neuroblastoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D017607:Aluminum Compounds; D016229:Amyloid beta-Peptides; D001252:Astringents; D002712:Chlorides; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D014970:Xanthines; D000077410:Aluminum Chloride; D002110:Caffeine; C051360:1,3-dipropyl-8-cyclopentylxanthine
keywords: Adenosine receptor; Aluminum; Alzheimer's disease; Caffein; Neurotoxicity