title: Ibuprofen and lipoic acid codrug 1 control Alzheimer's disease progression by down-regulating protein kinase C ε-mediated metalloproteinase 2 and 9 levels in β-amyloid infused Alzheimer's disease rat model.
abstract: Alzheimer's disease (AD) commonly begins with loss of recent memory and is associated to pathological and histological hallmarks such as β amyloid plaques, neural tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus. The amyloid cascade hypothesis implies the activity of β, γ secretases which mediate the cleavage of APP (Amyloid Precursor Protein), the formation of amyloidogenic Aβ fragment (1-42), which compacts into amyloid plaques, while the cleavage by α secretase of APP, within the Aβ segment (non-amyloidogenic processing) forms sAPP and prevents the formation of Aβ. Among the proteases which have Aβ-degrading activity, Metalloproteinase (MMP) 2, disclosing β secretase-like activity, is included, while MMP9 seems to contribute to neuronal death. In addition, since intracellular signaling protein kinase C (PKC) can control either directly α secretase or indirectly through regulation of ERK1/2, preventing the formation of β amyloid, created by β and γ secretase, and prolonging the life span of Alzheimer's disease mutant mice, here we show the effects exerted by new codrug 1 on PKC ε-mediated MMP2 and MMP9 levels regulation in Aβ (1-40) infused rat cerebral cortex. Interestingly codrug 1, lowering metalloproteinases expression via PKC ε down-modulation, seems to control Alzheimer's disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioral deterioration.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Chieti-Pescara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zara
authors.forename: M
authors.initials: M
authors.lastname: Rapino
authors.forename: P
authors.initials: P
authors.lastname: Sozio
authors.forename: A
authors.initials: A
authors.lastname: Di Stefano
authors.forename: C
authors.initials: C
authors.lastname: Nasuti
authors.forename: A
authors.initials: A
authors.lastname: Cataldi
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016229:Amyloid beta-Peptides; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010446:Peptide Fragments; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D008063:Thioctic Acid; D051744:Protein Kinase C-epsilon; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007052:Ibuprofen