minocycline and Huntington-Disease

Huntington's disease (HD) is a devastating autosomal dominant disorder characterized by progressive motor and neuropsychological symptoms. Evidence implicating the apoptotic cascades as a possible cause for the neurodegeneration seen in HD has directed researchers toward investigating therapeutic treatments targeting caspases and other proapoptotic factors. Cellular and murine models, which have demonstrated that caspase-mediated cleavage could be the cause for the neurodegeneration seen in HD, have evoked more research investigating the possible inhibition of apoptosis in HD. In particular, minocycline, a tetracycline-derived antibiotic that has been shown to increase survival in transgenic mouse models of HD, exhibits a neuroprotective feature in HD and demonstrates an anti-inflammatory as well as an anti-microbial effect by inhibiting microglial activation known to cause apoptosis.

Topics: Animals; Apoptosis; Humans; Huntington Disease; Minocycline; Models, Biological; Neural Inhibition

Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to the launching of various clinical trials. The present review summarizes the available data supporting the clinical testing of minocycline for these neurodegenerative disorders. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.

Topics: Animals; Apoptosis; Humans; Huntington Disease; Inflammation; Minocycline; Motor Neuron Disease; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease

Topics: Acute Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Apoptosis; Caspases; Cytochrome c Group; Humans; Huntington Disease; Mice; Minocycline; Neurodegenerative Diseases

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In 1993 the mutation that causes HD was identified as an unstable expansion of CAG repeats in the IT15 gene. Since then one of the most important advances in HD research has been the generation of various mouse models that enable the exploration of early pathological, molecular and cellular abnormalities produced by the mutation. In addition, these models have made it possible to test different pharmacological approaches to delay the onset or slow the progression of HD. In this article, insights gained from mouse models towards the understanding of HD and the design of new therapeutic strategies are discussed.

Topics: Animals; Creatine; Dichloroacetic Acid; Enzyme Inhibitors; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Knockout; Mice, Transgenic; Minocycline; Models, Animal; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Proteins; Trinucleotide Repeat Expansion

This study assessed the futility of proceeding with a Phase 3 clinical trial of minocycline as a disease-modifying treatment for Huntington's disease (HD). One hundred fourteen research participants with HD were randomized, 87 to minocycline (200 mg/d) and 27 to placebo. The change in Total Functional Capacity (TFC) score from baseline to Mo 18 was prespecified as the primary measure of HD progression. By using a futility design, we tested the null hypothesis that minocycline would reduce the mean decline in TFC score by at least 25% compared to a fixed value obtained from a historical database, with a one-tailed significance level of 10%. The placebo group was included to facilitate blinding. Rejection of the null hypothesis would discourage a major definitive trial of minocycline in HD. For the primary analysis, missing data were handled by carrying forward the last available observation; a secondary analysis used multiple imputations. The mean TFC decline in the minocycline group was 1.55 (SD 1.85), and futility was not declared (P = 0.12) for the primary analysis. When multiple imputation was used to handle missing data, the mean TFC decline in the minocycline group of 1.71 (SD 1.96, P = 0.07) suggested futility, as was the case for prespecified secondary outcome measures. There were no safety abnormalities attributable to minocycline. Based on the threshold of 25% improvement in TFC, further study of minocycline 200 mg/d in HD was not warranted. Futility designs aid in screening potential therapies for HD.

Topics: Activities of Daily Living; Adult; Anti-Bacterial Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Huntington Disease; Male; Medical Futility; Middle Aged; Minocycline; Treatment Outcome

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Humans; Huntington Disease; Hyperpigmentation; Middle Aged; Minocycline; Neuroprotective Agents; Prevalence

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase (iNOS), and has been shown to delay disease progression in the mouse model R6/2 of Huntington's disease (HD). This safety and tolerability study included 30 patients with HD who were given minocycline over a 6-month period and underwent assessments every 2 months with laboratory studies, the Abnormal Involuntary Movements Scale, the Unified Huntington's Disease Rating Scale, and the Mini-Mental State Examination. Minocycline was well tolerated during this study period and no serious adverse events were noted.

Topics: Adult; Aged; Caspase Inhibitors; Cognition Disorders; Enzyme Inhibitors; Female; Humans; Huntington Disease; Male; Middle Aged; Minocycline; Neuropsychological Tests; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pilot Projects

Minocycline is an antibiotic with anti-inflammatory and antiapoptotic properties that prolongs survival in a transgenic Huntington disease (HD) mouse model. In a double-blind, randomized, placebo-controlled study of minocycline in 60 HD patients, the authors determined that over 8 weeks, minocycline at 100 and 200 mg/day was well tolerated and safe in HD patients. Tolerability and adverse event frequency were similar between treatment and placebo groups.

Topics: Adult; Apoptosis; Caspase 3; Caspase Inhibitors; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Huntington Disease; Male; Middle Aged; Minocycline; Patient Dropouts; Treatment Failure; Treatment Outcome

Huntington's disease (HD), a relentlessly progressive neurodegenerative disorder, is characterized by a clinical triad of psychiatric, cognitive and motor disturbances. The antibiotic minocycline, a caspase inhibitor exhibiting antiapoptotic properties, has been shown to prolong survival in the transgenic mouse model of HD. We administrated minocycline to 14 patients with genetically confirmed HD. The patients were psychiatrically, neurologically and neuropsychologically evaluated at baseline, and after 6 and 24 months of treatment, using the Unified HD Rating Scale and a neuropsychological test battery. After 12 months, three patients were lost to follow-up so that 11 patients were analysed at the endpoint. Minocycline was well tolerated. Unlike the expected natural course of HD, patients exhibited stabilization in general motor and neuropsychological function at endpoint, after improving in the first 6 months. Moreover, we found a significant amelioration of psychiatric symptoms that was not apparent after the first 6 months. In detail, the Mini-Mental State Examination, the Total Motor Score, the Total Functional Capacity Scale and the Independence Scale, as the most prominent scales in HD, were stabilized after 3 years of treatment. Our results confirm previous animal studies and indicate a neuroprotective effect of this agent in HD. A long-term, double-blind, placebo-controlled trial appears highly warranted for definitively establishing the value of minocycline in HD.

Topics: Adult; Female; Humans; Huntington Disease; Male; Middle Aged; Minocycline; Neuroprotective Agents; Neuropsychological Tests; Pilot Projects; Psychomotor Performance; Treatment Outcome

Topics: Activities of Daily Living; Adult; Caspase Inhibitors; Double-Blind Method; Female; Humans; Huntington Disease; Male; Minocycline; Single-Blind Method; Treatment Outcome

Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials.. We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal.. Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models.. Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies.. The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

Topics: Acetamides; Female; Humans; Huntington Disease; Kaplan-Meier Estimate; Male; Middle Aged; Minocycline; Neuroprotective Agents; Neuropsychological Tests; Patient Dropouts; Proportional Hazards Models; Randomized Controlled Trials as Topic; Ubiquinone

Emerging evidences indicate hesperidin, a citrus flavanone, attenuates neurodegenerative processes and related complications. Besides its anti-oxidant properties, the other probable mechanisms which underpin its neuroprotective potential are still not clear. In light of emerging role of flavonoids in modulating oxidative stress and neuro-inflammation, the study has been designed to explore the possible neuroprotective effect of hesperidin and its combination with minocycline (microglial inhibitor), against quinolinic acid (QA) induced Huntington's disease (HD) like symptoms in rats. Unilateral intrastriatal administration of QA (300 nmol/4 µl) significantly reduced body weight, impaired behavior (locomotor activity, beam balance and memory performance), caused oxidative damage (increased lipid peroxidation, nitrite concentration, depleted super oxide dismutase and reduced glutathione), demonstrated mitochondrial dysfunction (decreased Complex-I, II, III, and IV activities), increased striatal lesion volume and altered the levels of TNF-α, caspase-3 as well as BDNF expression, as compared to sham group. Meanwhile, chronic hesperidin (100mg/kg, p.o.) and minocycline (25mg/kg, p.o.) treatment for 21 days significantly attenuated the behavioral, biochemical and cellular alterations as compared to QA treated (control) animals, whereas hesperidin (50mg/kg, p.o.) treatment was found to be non-significant. However, treatment of hesperidin (50mg/kg) in combination with minocycline (25mg/kg) potentiated their neuroprotective effect, which was significant as compared to their effects per se in QA treated animals. Taken altogether, the results of the present study suggest a possible interplay of microglial modulation and anti-oxidant effect in neuroprotective potential of hesperidin against QA induced HD like symptoms in rats.

Topics: Animals; Behavior, Animal; Brain; Caspase 3; Disease Models, Animal; Drug Synergism; Electron Transport Complex IV; Glutathione; Hesperidin; Huntington Disease; Male; Maze Learning; Minocycline; Motor Activity; Neuroprotective Agents; Nitrites; Quinolinic Acid; Quinone Reductases; Rats; Rats, Wistar; Succinate Dehydrogenase; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Recent experimental and clinical reports support the fact that the minocycline exhibits significant neuroprotective activity in neurodegenerative diseases. However, its mechanism of neuroprotection is still far from our understanding. Besides, minocycline does not always produce neuroprotective effect. Therefore, this study has been designed to explore the possible mechanism of minocycline in experimental model of HD in rats. Intrastriatal administration of quinolinic acid caused a significant reduction in body weight, motor dysfunction (impaired locomotor activity, rotarod performance, and beam walk test), oxidative damage (as evidenced by increase in lipid peroxidation, nitrite concentration, and depletion of super oxide dismutase and catalase), increased TNF-α and IL-6 levels as compared to the sham-treated animals. Minocycline (25, 50, and 100 mg/kg) treatment (for 21 days) significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, attenuated TNF-α and IL-6 levels as compared to quinolinic-acid (QA)-treated animals. This study provides evidence that minocycline might have neuroprotective effect against QA-induced Huntington-like behavioral, biochemical alterations, and neuroinflammation in rats.

Topics: Analysis of Variance; Animals; Body Weight; Catalase; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Huntington Disease; Lipid Peroxidation; Male; Minocycline; Motor Activity; Nitrites; Oxidative Stress; Psychomotor Performance; Quinolinic Acids; Rats; Rats, Wistar; Rotarod Performance Test; Statistics as Topic; Superoxide Dismutase

Minocycline is a tetracycline family antibiotic that has anti-inflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4(+) T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4(+) T cell activation: NF-κB, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca(2+) flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent.

Topics: Active Transport, Cell Nucleus; Anti-Bacterial Agents; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Calcium Signaling; CD4-Positive T-Lymphocytes; Cell Nucleus; Cells, Cultured; Enzyme Activation; Enzyme Activators; Glycogen Synthase Kinase 3; Humans; Huntington Disease; Lymphocyte Activation; Minocycline; Multiple Sclerosis; NF-kappa B; NFATC Transcription Factors; Phosphorylation; Protein Isoforms; Transcription Factor AP-1

Protein-protein interactions play an important role in regulating the expression of huntingtin protein (htt). Expansion of polyglutamine tracts in htt results in neurodegenerative Huntington disease. Huntingtin interacting protein (HIP14) is an important interacting partner of htt and the altered interactions have been proposed to play an important role in disease progression. In the present study, an attempt has been made to explore the potential of several known Huntington inhibitors to inhibit HIP14. The docking studies have resulted in the identification of a novel binding site for these inhibitors distinct from the previously known ankyrin repeat domain. The results have been validated using geometry based docking transformations against the other binding pocket. The specificity of binding has been determined with high values of both accuracy and precision. Nine potential inhibitors obtained after screening belong to three distinct classes of compounds viz, carbohydrates (deoxy-glucose), alcohols (including phenolic scaffold) and tetracycline. The compounds form stable complex with protein exhibiting optimal intermolecular and Gibbs free energy. The hydrogen bonding and hydrophobic interactions predominantly contribute to the stability of these complexes. The present study identifies metoprolol, minocyclines and 18 F fluorodeoxyglucose as the best inhibitors that bind specifically to the new site. Therefore, these compounds can further be exploited for their potential to serve in the diagnosis and treatment of Huntington disease. The quantitative predictions provide a scope for experimental testing in future.

Topics: Acyltransferases; Adaptor Proteins, Signal Transducing; Binding Sites; Enzyme Inhibitors; Fluorodeoxyglucose F18; Humans; Huntingtin Protein; Huntington Disease; Hydrogen Bonding; Metoprolol; Minocycline; Models, Molecular; Nerve Tissue Proteins; Nuclear Proteins; Peptides; Protein Binding; Protein Structure, Tertiary; Tetracycline; Thermodynamics

Minocycline (7-dimethylamino-6-dimethyl-6-deoxytetracycline) is a second-generation tetracycline that can cross the blood-brain barrier and has anti-inflammatory and neuroprotective effects. The potential of minocycline as a drug for treating Huntington's disease has been studied; however, the molecular mechanism underlying the neuroprotective properties of minocycline remains elusive. In this study, we tested the hypothesis that a principal cellular target of minocycline is Apaf-1, a key protein in the formation of the apoptosome, a multiprotein complex involved in caspase activation. Minocycline binds to Apaf-1, as shown by nuclear magnetic resonance spectroscopy, and inhibits apoptosome activity in vitro and in ex vivo models. As a consequence, minocycline-treated cells as well as Apaf-1 knock-out cells are resistant to the development of mutant huntingtin-dependent protein aggregation.

Topics: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Cell Death; Cell Line; Down-Regulation; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Knockout; Minocycline; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Protein Binding

Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington's disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington's disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival. We were thus unable to confirm the previously reported benefits for these two drugs, and we discuss potential reasons for these discrepancies, such as the effects of husbandry and nutrition.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Body Weight; Disease Models, Animal; Female; Hand Strength; Huntington Disease; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Minocycline; Motor Skills; Ubiquinone

Cannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB(1) cannabinoid receptors attenuates excitotoxic glutamatergic neurotransmission, triggers prosurvival signalling pathways and palliates motor symptoms in animal models of neurodegenerative disorders. However, in Huntington's disease there is a very early downregulation of CB(1) receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB(1) receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB(2) cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB(2) receptors in R6/2 mice, that express human mutant huntingtin exon 1, enhanced microglial activation, aggravated disease symptomatology and reduced mice lifespan. Likewise, induction of striatal excitotoxicity in CB(2) receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB(2) receptor-selective agonists to wild-type mice subjected to excitotoxicity reduced neuroinflammation, brain oedema, striatal neuronal loss and motor symptoms. Studies on ganciclovir-induced depletion of astroglial proliferation in transgenic mice expressing thymidine kinase under the control of the glial fibrillary acidic protein promoter excluded the participation of proliferating astroglia in CB(2) receptor-mediated actions. These findings support a pivotal role for CB(2) receptors in attenuating microglial activation and preventing neurodegeneration that may pave the way to new therapeutic strategies for neuroprotection in Huntington's disease as well as in other neurodegenerative disorders with a significant excitotoxic component.

Topics: Animals; Anti-Bacterial Agents; Biomarkers; Corpus Striatum; Humans; Huntingtin Protein; Huntington Disease; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Minocycline; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Nuclear Proteins; Quinolinic Acid; Receptor, Cannabinoid, CB2; Rotarod Performance Test; Seizures

According to the recent controversy regarding the effects of minocycline in the R6/2 transgenic model of Huntington's disease (HD), this tetracycline has been re-evaluated in another model, the N171-82Q strain. Ten miligrams per kilogram minocycline was given daily from the age of 2 mo, corresponding to an early symptomatic stage. We did not observe improvement in survival, weight loss, or motor function in treated transgenic mice. In addition, minocycline failed to mitigate the ventricle enlargement as well as the striatal and cortical atrophies induced by the transgene. Using high-performance liquid chromatography, it was observed that minocycline was similarly present in the plasma and the brain of both wild-type and N171-82Q mice following 14 daily injections. Using Western blot, we show that the increased expression of procaspase-1 induced by the transgene in the cortex was significantly reduced by the antibiotic. Combining together these data support that despite minocycline crosses blood-brain barrier in N171-82Q mice and displays an expected effect on procaspase-1 expression, it does not provide protection in this HD model. These in vivo results are in accordance with in vitro data, since minocycline failed to protect against mutated Huntingtin in an inducible PC12-clone expressing exon1 of mutated Huntingtin103Q. Altogether, the present data does not support minocycline as a beneficial drug for HD.

Topics: Animals; Anti-Bacterial Agents; Brain; Caspase 1; Cell Line; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Minocycline; Mutation; Nerve Tissue Proteins; Nuclear Proteins; PC12 Cells; Rats

Huntington's disease (HD) is a fatal neurodegenerative disorder of genetic origin with no known therapeutic intervention that can slow or halt disease progression. Transgenic murine models of HD have significantly improved the ability to assess potential therapeutic strategies. The R6/2 murine model of HD, which recapitulates many aspects of human HD, has been used extensively in pre-clinical HD therapeutic treatment trials. Of several potential therapeutic candidates, both minocycline and coenzyme Q10 (CoQ10) have been demonstrated to provide significant improvement in the R6/2 mouse. Given the specific cellular targets of each compound, and the broad array of abnormalities thought to underlie HD, we sought to assess the effects of combined minocycline and CoQ10 treatment in the R6/2 mouse. Combined minocycline and CoQ10 therapy provided an enhanced beneficial effect, ameliorating behavioral and neuropathological alterations in the R6/2 mouse. Minocycline and CoQ10 treatment significantly extended survival and improved rotarod performance to a greater degree than either minocycline or CoQ10 alone. In addition, combined minocycline and CoQ10 treatment attenuated gross brain atrophy, striatal neuron atrophy, and huntingtin aggregation in the R6/2 mice relative to individual treatment. These data suggest that combined minocycline and CoQ10 treatment may offer therapeutic benefit to patients suffering from HD.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Body Weight; Coenzymes; Cytoprotection; Disease Models, Animal; Drug Therapy, Combination; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Microglia; Minocycline; Nerve Tissue Proteins; Nuclear Proteins; Survival Rate; Ubiquinone

The combination effects of minocycline (MC), a second-generation tetracycline compound and pyruvate (PY), a glycolysis end metabolite with antioxidant activity were investigated in the rat striatum following an excitotoxic insult. Striatal injection of quinolinic acid (QUIN) resulted in marked inflammation characterized by microgliosis, astrogliosis and enhanced expressions of pro-inflammatory enzymes inducible nitric oxide synthase and cyclooxygenase-2. Inflammatory responses were attenuated with administration of either MC or PY, however, the combination of both compounds was significantly more effective in reducing inflammation relative to MC or PY applied alone. Immunohistochemical analysis at 7 days post-intrastriatal QUIN injection showed extensive oxidative stress evident as lipid peroxidation, oxidative DNA damage and reactive oxygen species formation which was partially decreased by each agent applied separately but markedly inhibited with the combination of the two compounds. In addition, combination treatments significantly reduced neuronal loss in QUIN-injected striatum compared with the agents applied separately. Furthermore, long-term combination treatment decreased striatal lesions and inflammation after QUIN injection. These results demonstrate that MC and PY confer a considerably enhanced anti-inflammatory and neuroprotective efficacy when applied together and suggest this combinatorial procedure as a novel therapeutic strategy in neurodegenerative disorders such as Huntington's disease which exhibit excitotoxic insults.

Topics: Analysis of Variance; Animals; Blotting, Western; Cell Death; Cyclooxygenase 2; Disease Models, Animal; Drug Synergism; Huntington Disease; Immunohistochemistry; Inflammation; Male; Minocycline; Nerve Tissue Proteins; Neurons; Nitric Oxide Synthase Type II; Oxidative Stress; Pyruvic Acid; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Minocycline has been shown to be neuroprotective in various models of neurodegenerative diseases. However, its potential in Huntington's disease (HD) models characterized by calpain-dependent degeneration and inflammation has not been investigated. Here, we have tested minocycline in phenotypic models of HD using 3-nitropropionic acid (3NP) intoxication and quinolinic acid (QA) injections. In the 3NP rat model, where the development of striatal lesions involves calpain, we found that minocycline was not protective, although it attenuated the development of inflammation induced after the onset of striatal degeneration. The lack of minocycline activity on calpain-dependent cell death was also confirmed in vitro using primary striatal cells. Conversely, we found that minocycline reduced lesions and inflammation induced by QA. In cultured cells, minocycline protected against mutated huntingtin and staurosporine, stimulations known to promote caspase-dependent cell death. Altogether, these data suggested that, in HD, minocycline may counteract the development of caspase-dependent neurodegeneration, inflammation, but not calpain-dependent neuronal death.

Topics: Animals; Calpain; Caspases; Cell Death; Cells, Cultured; Corpus Striatum; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Glutamic Acid; Huntingtin Protein; Huntington Disease; Male; Minocycline; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Nitro Compounds; Nuclear Proteins; Phenotype; Propionates; Quinolinic Acid; Rats; Rats, Inbred Lew; Rats, Wistar; Staurosporine

Topics: Anti-Bacterial Agents; Cognition Disorders; Exons; Humans; Huntington Disease; Minocycline; Movement Disorders; Neuropsychological Tests

Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.

Topics: Animals; Cells, Cultured; Convulsants; Corpus Striatum; Disease Models, Animal; Female; Huntington Disease; Immunohistochemistry; Macaca fascicularis; Male; Mice; Minocycline; Nerve Degeneration; Neurons; Neuroprotective Agents; Nitro Compounds; Parkinsonian Disorders; Propionates

Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Doxycycline; Female; Genotype; Hippocampus; Huntingtin Protein; Huntington Disease; Hyperglycemia; Immunohistochemistry; Male; Mice; Minocycline; Nerve Tissue Proteins; Nuclear Proteins; Organ Culture Techniques; Peptides; Phenotype; Postural Balance; Tetracycline

Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspase-independent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects.

Topics: Animals; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins; Caspase Inhibitors; Caspases; Cell Death; Cell Line; Disease Models, Animal; Humans; Huntington Disease; Mice; Minocycline; Mitochondria; Neuroprotective Agents; Tumor Necrosis Factor-alpha

Topics: Animals; Disease Models, Animal; Huntington Disease; Mice; Minocycline; Neuroprotective Agents

Topics: Animals; Disease Models, Animal; Huntington Disease; Mice; Minocycline; Neuroprotective Agents; Phenotype

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Cognition; Humans; Huntington Disease; Minocycline; Motor Activity

We present the case of a patient with advanced Huntington's disease treated with minocycline. Minocycline (but not tetracycline which does not cross the blood-brain barrier) appears to increase longevity in an animal model for Huntington's disease. The patient has been maintained on minocycline for more than 1 year with positive effects. Cessation of minocyclin for 3 weeks resulted in an exacerbation of symptoms. The animal studies have suggested that minocycline may prevent progression of Huntington's disease and other neurological disorders. By contrast, this present result suggests that minocycline may benefit those with advanced Huntington's disease and can be used safely in these patients.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Apoptosis; Clozapine; Female; Humans; Huntington Disease; Minocycline

Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.

Topics: Animals; Anti-Bacterial Agents; Caspase 1; Caspase 3; Caspases; Disease Models, Animal; Disease Progression; Enzyme Activation; Evaluation Studies as Topic; Gene Expression Regulation; Huntington Disease; Mice; Mice, Transgenic; Minocycline; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Transcription, Genetic

Topics: Animals; Caspase Inhibitors; Clinical Trials as Topic; Foundations; Humans; Huntingtin Protein; Huntington Disease; Mice; Minocycline; Nerve Tissue Proteins; Nuclear Proteins