title: Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.
abstract: We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer's disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca(2+) levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca(2+) level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca(2+) in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. saathoffjm@vcu.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Saathoff
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. kliu4@vcu.edu.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. chojnackij@vcu.edu.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Chojnacki
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. lhe3@vcu.edu.
authors.forename: Liu
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Medicine, Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA. qchen8@vcu.edu.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Medicine, Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA. ejlesnefsky@vcu.edu.|Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. ejlesnefsky@vcu.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. szhang2@vcu.edu.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D012307:Risk Factors
chemical_list: C000608788:17MN compound; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D002784:Cholesterol; D003474:Curcumin; D002118:Calcium
keywords: Alzheimer’s disease; bivalent compound; calcium; mitochondria; multifunctional; neuroprotection