title: Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models.
abstract: Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. We had previously shown that doxycycline administered for 3 months at 40 mg/Kg/ml in the drinking water, was capable of removing TTR amyloid deposits present in stomachs of old TTR-V30M transgenic mice; the removal was accompanied by a decrease in extracellular matrix remodeling proteins that accompany fibrillar deposition, but not of non-fibrillar TTR deposition and/or markers associated with pre-fibrillar deposits. On the other hand, Tauroursodeoxycholic acid (TUDCA), a biliary acid, administrated to the same mouse model was shown to be effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages. In the present work we evaluated different doxycycline administration schemes, including different periods of treatment, different dosages and different FAP TTR V30M animal models. Evaluation included CR staining, immunohistochemistry for TTR, metalloproteinase 9 (MMP-9) and serum amyloid P component (SAP). We determined that a minimum period of 15 days of treatment with a 8 mg/Kg/day dosage resulted in fibril removal. The possibility of intermittent treatments was also assessed and a maximum period of 15 days of suspension was determined to maintain tissues amyloid-free. Combined cycled doxycycline and TUDCA administration to mice with amyloid deposition, using two different concentrations of both drugs, was more effective than either individual doxycycline or TUDCA, in significantly lowering TTR deposition and associated tissue markers. The observed synergistic effect of doxycycline/TUDCA in the range of human tolerable quantities, in the transgenic TTR mice models prompts their application in FAP, particularly in the early stages of disease.
authors.affiliation: Molecular Neurobiology Unit, IBMC- Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cardoso
authors.forename: Diana
authors.initials: D
authors.lastname: Martins
authors.forename: Tania
authors.initials: T
authors.lastname: Ribeiro
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy*; D000818:Animals; D058578:Biglycan; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002809:Chondroitin Sulfates / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D011228:Prealbumin / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D013270:Stomach / Q000201:enzymology / Q000473:pathology; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D016326:Extracellular Matrix Proteins; D006360:Heat-Shock Proteins; D011228:Prealbumin; D011509:Proteoglycans; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D002809:Chondroitin Sulfates; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline