tetracycline and Parkinson-Disease

The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.

Topics: Alzheimer Disease; Animals; Anti-Bacterial Agents; Doxycycline; Drug Repositioning; Humans; Minocycline; Parkinson Disease; Tetracycline

The pathogenesis of rosacea is unclear, but increased matrix metalloproteinase target tissue activity appears to play an important role. Parkinson disease and other neurodegenerative disorders also display increased matrix metalloproteinase activity that contribute to neuronal loss.. To investigate the risk of incident (new-onset) Parkinson disease in patients with rosacea.. A nationwide cohort study of the Danish population was conducted using individual-level linkage of administrative registers. All Danish citizens 18 years or older from January 1, 1997, to December 31, 2011 (N = 5 472 745), were included. Data analysis was conducted from June 26 to July 27, 2015.. The main outcome was a diagnosis of Parkinson disease. Incidence rates (IRs) per 10 000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, medication, and comorbidity were estimated by Poisson regression models.. A total of 5 404 692 individuals were included in the reference population; of these, 22 387 individuals (9812 [43.8%] women; mean [SD] age at diagnosis, 75.9 [10.2] years) received a diagnosis of Parkinson disease during the study period and 68 053 individuals (45 712 [67.2%] women; mean age, 42.2 [16.5] years) were registered as having rosacea. The IRs of Parkinson disease per 10 000 person-years were 3.54 (95% CI, 3.49-3.59) in the reference population and 7.62 (95% CI, 6.78-8.57) in patients with rosacea. The adjusted IRR of Parkinson disease was 1.71 (95%, CI 1.52-1.92) in patients with rosacea compared with the reference population. There was a 2-fold increased risk of Parkinson disease in patients classified as having ocular rosacea (adjusted IRR, 2.03 [95% CI, 1.67-2.48]), and tetracycline therapy appeared to reduce the risk of Parkinson disease (adjusted IRR, 0.98 [95% CI, 0.97-0.99]).. Rosacea constitutes an independent risk factor for Parkinson disease. This association could be due to shared pathogenic mechanisms involving elevated matrix metalloproteinase activity. The clinical consequences of this association require further study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Community Health Planning; Denmark; Female; Humans; Male; Middle Aged; Parkinson Disease; Rosacea; Severity of Illness Index; Tetracycline; Young Adult

The ability to safely control transgene expression from viral vectors is a long-term goal in the gene therapy field. We have previously reported tight regulation of GFP expression in rat brain using a self-regulating tet-off rAAV vector. The immune responses against tet regulatory elements observed by other groups in nonhuman primates after intramuscular injection of tet-on encoding vectors raise concerns about the clinical value of tet-regulated vectors. However, previous studies have not examined immune responses following injection of AAV vectors into brain. Therefore, rat striatum was injected with tet-off rAAV harboring a therapeutic gene for Parkinson's disease, either hAADC or hGDNF. The expression of each gene was tightly controlled by the tet-off regulatory system. Using an ELISA developed with purified GST-tTA protein, no detectable immunogenicity against tTA was observed in sera of rats that received an intrastriatal injection of either vector. In contrast, sera from rats intradermally injected with an adenovirus containing either tTA or rtTA, as positive controls, had readily detectable antibodies. These observations suggest that tet-off rAAV vectors do not elicit an immune response when injected into rat brain and that these may offer safer vectors for Parkinson's disease than vectors with constitutive expression.

Topics: Animals; Aromatic-L-Amino-Acid Decarboxylases; Basal Ganglia; Dependovirus; Gene Expression Regulation; Genetic Therapy; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Immunity, Humoral; Male; Parkinson Disease; Rats; Rats, Inbred F344; Recombinant Fusion Proteins; Response Elements; Tetracycline; Trans-Activators; Transgenes

In this study, a tetracycline-regulated lentiviral vector system, based on the tetracycline-dependent transactivator rtTA2(S)-M2, was developed for controlled expression of glial cell line-derived neurotrophic factor (GDNF) in the rat brain. Expression of the marker gene green fluorescent protein (GFP) and GDNF was tightly regulated in a dose-dependent manner in neural cell lines in vitro. Injection of high-titer lentiviral vectors into the rat striatum resulted in a 7-fold induction of GDNF tissue levels (1060 pg/mg tissue), when doxycycline (a tetracycline analog) was added to the drinking water. However, low levels of GDNF (150 pg/mg tissue) were also detected in animals that did not receive doxycycline, indicating a significant background leakage from the vector system in vivo. The level of basal expression was markedly reduced when a 10-fold lower dose of the tetracycline-regulated GDNF vector was injected into the striatum (3-11 pg/mg tissue), and doxycycline-induced GDNF tissue levels obtained in these animals were about 190 pg/mg tissue. Doxycycline-induced expression of GDNF resulted in a significant downregulation of the tyrosine hydroxylase (TH) protein in the intact striatum. Removal of doxycycline from the drinking water rapidly (within 3 days) turned off transgenic GDNF mRNA expression and GDNF protein levels in the tissue were completely reduced by 2 weeks, demonstrating the dynamics of the system in vivo. Accordingly, TH protein expression returned to normal by 2-8 weeks after removal of doxycycline, indicating that GDNF-induced downregulation of TH is a reversible event.

Topics: Animals; Corpus Striatum; Dopamine Agonists; Down-Regulation; Doxycycline; Enzyme-Linked Immunosorbent Assay; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Green Fluorescent Proteins; Lentivirus; Microscopy, Confocal; Models, Genetic; Nerve Growth Factors; Neurons; Parkinson Disease; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tetracycline; Time Factors; Transgenes; Tyrosine 3-Monooxygenase

Conditional expression systems for 4-repeat wild-type (WT) tau or the corresponding mutants V337M and R406W were established in human neuroglioma H4 cells to study the effect of tau mutations on the physicochemical properties of tau, and to develop a cellular model for the formation of filamentous tau characteristic of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease. Upon induction tau expression increased, reaching maximal levels at 5 to 7 days. WT tau was phosphorylated at amino acids T181, S202/T205, T231, and S396/S404. The R406W mutation decreased tau phosphorylation at each of these sites as did the V337M mutation except for S396/S404 sites that increased. Most tau in postnuclear cell lysates was recovered in the supernatant fraction after centrifugation at 200,000 x g. The amount of tau in the pellet fraction increased more in mutant transfectants compared to WT when the induction was extended beyond 5 days. This particulate tau could be partially extracted with salt, Triton X-100, or sarkosyl. Of the transfectants, R406W had the highest proportion of sarkosyl-insoluble tau by day 7. This insoluble fraction was thioflavin S-positive and contained 15- to 5-nm-wide filaments with tau immunoreactivities. The R406W filaments were more abundant than those detected in similar preparations from WT or V337M transfectants. At the light microscopy level, most tau was found with microtubules, or diffusely distributed in the cytoplasm, but none of this appeared thioflavin S-positive. The results suggest that conditional tau transfectants are in a pretangle stage making them an attractive model system for studying intracellular tangle accumulation and for testing potential therapeutic agents as inhibitors for tau aggregation.

Topics: Chromosomes, Human, Pair 17; Dementia; Gene Expression Regulation; Glioma; Humans; Immunoblotting; Immunohistochemistry; Inclusion Bodies; Kinetics; Microscopy, Fluorescence; Microtubule-Associated Proteins; Mutation; Parkinson Disease; Phosphorylation; tau Proteins; Tetracycline; Transfection; Tumor Cells, Cultured

Parkinson's disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD. We established inducible PC12 cell lines in which wild-type or mutant alpha-synuclein can be de-repressed by removing doxycycline. Differentiated PC12 cell lines expressing mutant alpha-synuclein showed decreased activity of proteasomes without direct toxicity. Cells expressing mutant alpha-synuclein showed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A. These data suggest that expression of mutant alpha-synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.

Topics: Acetylcysteine; alpha-Synuclein; Animals; Apoptosis; Blotting, Western; Caspase 3; Caspase 9; Caspases; Cyclosporine; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Gene Expression Regulation; Immunoenzyme Techniques; Membrane Potentials; Mitochondria; Multienzyme Complexes; Mutation; Nerve Tissue Proteins; Parkinson Disease; PC12 Cells; Proteasome Endopeptidase Complex; Rats; Synucleins; Tetracycline; Transfection

Topics: Acne Vulgaris; Aged; Dihydroxyphenylalanine; Fatty Acids, Nonesterified; Female; Humans; Lipid Metabolism; Lipids; Male; Middle Aged; Parkinson Disease; Sebum; Skin; Tetracycline; Time Factors

Topics: Adolescent; Adult; Aged; Chlamydia; Consciousness; Encephalitis; Female; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease; Psittacosis; Tetracycline; Tremor