title: ACS84, a novel hydrogen sulfide-releasing compound, protects against amyloid β-induced cell cytotoxicity.
abstract: Hydrogen sulfide (H(2)S) is a novel neurotransmitter. We studied here the effect of ACS 84, a new H(2)S releasing compound, on the cytotoxicity induced by amyloid beta (Aβ) in microglia. Treatment with Aβ(1-40) (25μmol/L) for 24h significantly inhibited MTT reduction and increased lactate dehydrogenase release in BV-2 microglia cells. Pretreatment with ACS 84 (10μM) for 30min attenuated the above cytotoxicity caused by Aβ(1-40), suggesting that ACS 84 may protect microglia against Aβ(1-40)-induced cell injury. ACS 84 also significantly attenuated nitric oxide release and TNF-α production in BV-2 cells treated with Aβ peptides (Aβ(1-40) or Aβ(1-42)), but had no significant effect on the up-regulated protein expression of cyclooxygenase 2. These data suggest that ACS 84 may produce anti-inflammatory effect via inhibition of the release of inflammatory cytokines but not via suppression of the prostanoids production. Furthermore, pretreatment with ACS 84 also attenuated mitochondrial membrane potential loss (Δψ(m)) caused by Aβ(1-40) in both microglia and neurons. To examine the underlying signaling mechanism, we detected the phosphorylation of p38-, JNK- and ERK-MAPKs. It was found that Aβ(1-40) stimulated phosphorylation of all above three types of MAKPs. However, ACS 84 only attenuated the activation of p38 and JNK, but had no significant effect on that of ERK. Taken together, our data suggest that ACS 84 may protect Aβ-induced cell injury via anti-inflammation and preservation of mitochondrial function in a p38 and JNK dependent mechanism. Our work suggests that ACS 84 may have potential for the treatment of neurodegenerative diseases.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
authors.forename: Yan-Ying
authors.initials: YY
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Bian
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006862:Hydrogen Sulfide / Q000819:agonists / Q000378:metabolism*; D007980:Levodopa / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C583845:ACS 84; D016229:Amyloid beta-Peptides; D004220:Disulfides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D007980:Levodopa; D006862:Hydrogen Sulfide