tetracycline and Amyloidosis

The use of tetracyclines has declined because of the appearance of resistant bacterial strains. However, the indications of nonantimicrobial activities of these drugs have considerably raised interest and triggered clinical trials for a number of different pathologies. About 10 years ago we first reported that tetracyclines inhibited the aggregation of prion protein fragments and Alzheimer's β peptides, destabilizing their aggregates and promoting their degradation by proteases. On the basis of these observations, the antiamyloidogenic effects of tetracyclines on a variety of amyloidogenic proteins were studied and confirmed by independent research groups. In this review we comment on the data available on their antiamyloidogenic activity in preclinical and clinical studies. We also put forward that the beneficial effects of these drugs are a result of a peculiar pleiotropic action, comprising their interaction with oligomers and disruption of fibrils, as well as their antioxidant, anti-inflammatory, antiapoptotic, and matrix metalloproteinase inhibitory activities.

Topics: Amyloid; Amyloidogenic Proteins; Amyloidosis; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Clinical Trials as Topic; Drug Administration Schedule; Humans; Matrix Metalloproteinase Inhibitors; Protein Conformation; Tetracyclines

The misfolding of amyloid proteins is closely correlated with the pathogenesis of protein conformation-related diseases, such as Alzheimer's disease (AD), prion disease, and type 2 diabetes mellitus (T2DM). The deposition of human islet amyloid polypeptide (hIAPP) and amyloid-β (Aβ) protein is entangled in AD and diabetes mellitus. The development of potential inhibitors is a feasible therapeutic strategy to treat these diseases by resisting peptide aggregation. Doxycycline is a typical clinical antibiotic that has been utilized in neurodegenerative studies. However, the roles of tetracyclines in hIAPP aggregation remain unclear. Herein, we studied the inhibitory effects of three tetracycline derivatives, namely, minocycline hydrochloride (1), methacycline hydrochloride (2), and doxycycline (3), on the fibril formation and cytotoxicity of hIAPP and compared with that of Aβ. The well-known 3 was selected and compared with 1 and 2. Tetracycline derivatives acted as effective inhibitors to reverse the self-assembly of hIAPP and Aβ, and disaggregate the aged peptides fibrils into mostly monomers. Tetracycline derivatives also reduced the cytotoxicity induced by amyloid peptide oligomerization. Further molecular mechanism studies revealed hydrophobic and hydrogen bond interactions as the primary binding pattern between tetracycline derivatives and peptides. A good bioactivity against amyloidosis was demonstrated by three tetracyclines. This work provided a basis for using tetracycline antibiotics as potential inhibitors against hIAPP aggregation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Protein Aggregation, Pathological; Tetracycline

Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the proteins of this germ line in AL patients. In this work, five small molecules were tested as inhibitors of the formation of amyloid fibrils from the 6aJL2-R24G protein. We have found by thioflavin T fluorescence and transmission electron microscopy that EGCG inhibits 6aJL2-R24G fibrillogenesis. Furthermore, using nuclear magnetic resonance spectroscopy, dynamic light scattering, and isothermal titration calorimetry, we have determined that the inhibition is due to binding to the protein in its native state, interacting mainly with aromatic residues.

Topics: Amino Acid Sequence; Amino Acid Substitution; Amyloid; Amyloidosis; Catechin; Humans; Immunoglobulin Light Chains; In Vitro Techniques; Melatonin; Microscopy, Electron, Transmission; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Multimerization; Quercetin; Recombinant Proteins; Rifampin; Tetracycline

Following the induction of three different forms of experimental hypertension, deposits of amyloid were found in the spleens of 5-20 per cent of the mice late in the course of the hypertension, Amyloidosis was found in nude (with genetical aplasia of the thymus) as well as in haired (normal) mice. The highest frequency of amyloidosis was observed in mice with hypertension due to partial infarction of one kidney and contralateral nephrectomy. The hypertensive vascular disease, involving lesion of the vessels and of the organs supplied by the affected vessels, is believed, to represent a stimulus for the reticulo endothelial system (RES) with development of amyloidosis as a secondary event.

Topics: Amyloidosis; Animals; Blood Pressure; Desoxycorticosterone; Female; Hypertension, Renal; Male; Mice; Mice, Inbred Strains; Mice, Nude; Nephrectomy; Sodium Chloride; Spleen; Splenic Diseases; Tetracycline

Topics: Adolescent; Adult; Age Factors; Aged; Amyloidosis; Child; Child, Preschool; Epidermolysis Bullosa; Erythema Multiforme; Erythromycin; Female; Gingivitis, Necrotizing Ulcerative; Hand, Foot and Mouth Disease; Herpangina; Herpes Zoster; Humans; Infant; Middle Aged; Mouth Diseases; Pemphigus; Stomatitis, Aphthous; Tetracycline

Topics: Amyloidosis; Anti-Bacterial Agents; Boston; Hydrocortisone; Kidney Diseases; Massachusetts; New England; Pathology; Penicillins; Pigmentation; Sodium Chloride; Streptomycin; Tetracycline