title: Anthraquinone-2-sulfonic acid (AQ2S) is a novel neurotherapeutic agent.
abstract: Anthraquinone derivatives such as emodin have recently been shown to protect in models of beta amyloid β (Aβ) and tau aggregation-induced cell death. The mechanisms of action possibly involve preconditioning effects, anti-aggregation properties, and/or enhancing the phosphatidylinositol-3-kinase (PI3K)/AKT survival mechanism. We studied several natural (emodin, rhein, and aloin) and synthetic (AQ2S) anthraquinones, to screen for post-treatment therapeutic benefit in two models of neuronal death, namely hydrogen peroxide (H(2)O(2)) and staurosporine (STS)-induced injury. Treatment with emodin, rhein, or aloin failed to reduce H(2)O(2) injury. Moreover, consistent with emodin behaving like a mild toxin, it exacerbated oxidative injury at the highest concentration used (50 μM) in our post-treatment paradigm, and potently inhibited AKT. In contrast, AQ2S was neuroprotective. It reduced H(2)O(2) injury at 50 and 75 μM. In addition, AQ2S potently inhibited staurosporine (STS)-induced injury. The mechanisms of action involve caspase inhibition and AKT activation. However, blockade of AKT signaling with LY294002 failed to abolish AQ2S-mediated protection on the STS assay. This is the first study to report that AQ2S is a new neuroprotective compound and a novel caspase inhibitor.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, Safar Center for Resuscitation Research, Pittsburgh, PA 15260, USA. jacksontc@upmc.edu
authors.forename: T C
authors.initials: TC
authors.lastname: Jackson
authors.forename: J D
authors.initials: JD
authors.lastname: Verrier
authors.forename: P M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004642:Emodin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000633:toxicity
chemical_list: D000880:Anthraquinones; D002867:Chromones; D009025:Morpholines; D018696:Neuroprotective Agents; C023554:anthraquinone sulfonate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D019311:Staurosporine; D004642:Emodin; C006457:alloin; C020491:rhein