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  1. Article ; Online: Prominent Efficacy of Amantadine against Human Borna Disease Virus Infection In Vitro and In Vivo. Comment on Fink et al. Amantadine Inhibits SARS-CoV-2 In Vitro.

    Bode, Liv / Dietrich, Detlef E / Spannhuth, Carsten W / Ludwig, Hanns

    Viruses

    2022  Volume 14, Issue 3

    Abstract: Amantadine (1-amino-adamantane) is a versatile antiviral compound which has been licensed for decades against influenza viruses. During the Corona pandemic, its effect to inhibit SARS-CoV-2 in vitro has been investigated. However, an in vivo oral ... ...

    Abstract Amantadine (1-amino-adamantane) is a versatile antiviral compound which has been licensed for decades against influenza viruses. During the Corona pandemic, its effect to inhibit SARS-CoV-2 in vitro has been investigated. However, an in vivo oral inapplicability was concluded due to ID
    MeSH term(s) Amantadine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Borna disease virus ; COVID-19/drug therapy ; Humans ; SARS-CoV-2
    Chemical Substances Antiviral Agents ; Amantadine (BF4C9Z1J53)
    Language English
    Publishing date 2022-02-28
    Publishing country Switzerland
    Document type Journal Article ; Comment
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v14030494
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Prominent Efficacy of Amantadine against Human Borna Disease Virus Infection In Vitro and In Vivo. Comment on Fink et al. Amantadine Inhibits SARS-CoV-2 In Vitro. Viruses 2021, 13, 539

    Bode, Liv / Dietrich, Detlef E. / Spannhuth, Carsten W. / Ludwig, Hanns

    Viruses. 2022 Feb. 28, v. 14, no. 3

    2022  

    Abstract: Amantadine (1-amino-adamantane) is a versatile antiviral compound which has been licensed for decades against influenza viruses. During the Corona pandemic, its effect to inhibit SARS-CoV-2 in vitro has been investigated. However, an in vivo oral ... ...

    Abstract Amantadine (1-amino-adamantane) is a versatile antiviral compound which has been licensed for decades against influenza viruses. During the Corona pandemic, its effect to inhibit SARS-CoV-2 in vitro has been investigated. However, an in vivo oral inapplicability was concluded due to ID₅₀ doses exceeding eight times the estimated maximum tolerable plasma levels reached by 600 mg orally daily. In contrast, amantadine has been shown to be extraordinarily efficient against human neurotropic Borna disease virus (BoDV-1), presenting with both anti-depressive and anti-viral efficacy against a placebo, achieved by a well-tolerated low oral daily dose of 200 mg amantadine.
    Keywords Borna disease virus ; Severe acute respiratory syndrome coronavirus 2 ; antiviral agents ; humans ; influenza ; pandemic ; placebos
    Language English
    Dates of publication 2022-0228
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2516098-9
    ISSN 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v14030494
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: The biology of bornavirus.

    Ludwig, Hanns

    APMIS. Supplementum

    2008  , Issue 124, Page(s) 14–20

    MeSH term(s) Animals ; Antigens, Viral/blood ; Antigens, Viral/cerebrospinal fluid ; Borna Disease/epidemiology ; Borna Disease/virology ; Borna disease virus/physiology ; Brain/physiopathology ; Brain/virology ; Cell Line ; Evoked Potentials ; Genome, Viral ; Humans ; Mental Disorders/blood ; Mental Disorders/cerebrospinal fluid ; Mental Disorders/physiopathology ; Mental Disorders/virology ; Mice ; Rats
    Chemical Substances Antigens, Viral
    Language English
    Publishing date 2008-09-03
    Publishing country Denmark
    Document type Journal Article ; Review
    ISSN 0903-465X
    ISSN 0903-465X
    DOI 10.1111/j.1600-0463.2008.000m2.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Essentials in bornavirus virology--an epilogue.

    Ludwig, Hanns

    APMIS. Supplementum

    2008  , Issue 124, Page(s) 94–97

    MeSH term(s) Animals ; Borna Disease/blood ; Borna Disease/drug therapy ; Borna Disease/physiopathology ; Borna disease virus/pathogenicity ; Borna disease virus/physiology ; Brain/physiopathology ; Humans ; Inflammation/pathology ; Mental Disorders/blood ; Mental Disorders/physiopathology ; Neurons/metabolism ; Virulence ; Virus Cultivation
    Language English
    Publishing date 2008-09-03
    Publishing country Denmark
    Document type Journal Article ; Review
    ISSN 0903-465X
    ISSN 0903-465X
    DOI 10.1111/j.1600-0463.2008.00m18.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Word recognition memory and serum levels of Borna disease virus specific circulating immune complexes in obsessive-compulsive disorder.

    Zhang, Yuanyuan / Alwin Prem Anand, A / Bode, Liv / Ludwig, Hanns / Emrich, Hinderk M / Dietrich, Detlef E

    BMC psychiatry

    2022  Volume 22, Issue 1, Page(s) 597

    Abstract: Background: Borna disease virus 1 (BoDV-1) is a non-segmented, negative-strand RNA virus that persistently infects mammals including humans. BoDV-1 worldwide occurring strains display highly conserved genomes with overlapping genetic signatures between ... ...

    Abstract Background: Borna disease virus 1 (BoDV-1) is a non-segmented, negative-strand RNA virus that persistently infects mammals including humans. BoDV-1 worldwide occurring strains display highly conserved genomes with overlapping genetic signatures between those of either human or animal origin. BoDV-1 infection may cause behavioral and cognitive disturbances in animals but has also been found in human major depression and obsessive-compulsive disorder (OCD). However, the impact of BoDV-1 on memory functions in OCD is unknown.
    Method: To evaluate the cognitive impact of BoDV-1 in OCD, event-related brain potentials (ERPs) were recorded in a continuous word recognition paradigm in OCD patients (n = 16) and in healthy controls (n = 12). According to the presence of BoDV-1-specific circulating immune complexes (CIC), they were divided into two groups, namely group H (high) and L (low), n = 8 each. Typically, ERPs to repeated items are characterized by more positive waveforms beginning approximately 250 ms post-stimulus. This "old/new effect" has been shown to be relevant for memory processing. The early old/new effect (ca. 300-500 ms) with a frontal distribution is proposed to be a neural correlate of familiarity-based recognition. The late old/new effect (post-500 ms) is supposed to reflect memory recollection processes.
    Results: OCD patients were reported to show a normal early old/new effect and a reduced late old/new effect compared to normal controls. In our study, OCD patients with a high virus load (group H) displayed exactly these effects, while patients with a low virus load (group L) did not differ from healthy controls.
    Conclusion: These results confirmed that OCD patients had impaired memory recollection processes compared to the normal controls which may to some extent be related to their BoDV-1 infection.
    MeSH term(s) Animals ; Antigen-Antibody Complex ; Borna Disease ; Borna disease virus/genetics ; Evoked Potentials ; Humans ; Mammals ; Obsessive-Compulsive Disorder ; Recognition, Psychology
    Chemical Substances Antigen-Antibody Complex
    Language English
    Publishing date 2022-09-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2050438-X
    ISSN 1471-244X ; 1471-244X
    ISSN (online) 1471-244X
    ISSN 1471-244X
    DOI 10.1186/s12888-022-04208-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial.

    Dietrich, Detlef E / Bode, Liv / Spannhuth, Carsten W / Hecker, Hartmut / Ludwig, Hanns / Emrich, Hinderk M

    BMC pharmacology & toxicology

    2020  Volume 21, Issue 1, Page(s) 12

    Abstract: Background: Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to ... ...

    Abstract Background: Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine.
    Methods: The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2-3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC).
    Results: Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen's d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4-10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL).
    Conclusions: Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs.
    Trial registration: The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do.
    MeSH term(s) Adult ; Amantadine/pharmacology ; Amantadine/therapeutic use ; Animals ; Antibodies, Viral/blood ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Antigens, Viral/blood ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Bipolar Disorder/drug therapy ; Borna Disease/drug therapy ; Borna Disease/virology ; Borna disease virus/drug effects ; Borna disease virus/physiology ; Cells, Cultured ; Cross-Over Studies ; Depressive Disorder, Major/drug therapy ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Rabbits ; Virus Replication/drug effects
    Chemical Substances Antibodies, Viral ; Antidepressive Agents ; Antigens, Viral ; Antiviral Agents ; Amantadine (BF4C9Z1J53)
    Keywords covid19
    Language English
    Publishing date 2020-02-17
    Publishing country England
    Document type Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 2680259-4
    ISSN 2050-6511 ; 2050-6511
    ISSN (online) 2050-6511
    ISSN 2050-6511
    DOI 10.1186/s40360-020-0391-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates.

    Gosztonyi, Georg / Ludwig, Hanns / Bode, Liv / Kao, Moujahed / Sell, Manfred / Petrusz, Peter / Halász, Béla

    Brain structure & function

    2020  Volume 225, Issue 5, Page(s) 1459–1482

    Abstract: Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity ... ...

    Abstract Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity which might help to better understand underlying processes in human obesity. Eighty Wistar rats, between 30 and 60 days of age, were intracerebrally inoculated with Borna disease virus (BDV-1), a neurotropic negative-strand RNA virus infecting an unusually broad host spectrum including humans. Half of the rats developed fatal encephalitis, while the other half, after 3-4 months, continuously gained weight. At tripled weights, rats were sacrificed by trans-cardial fixative perfusion. Neuropathology revealed prevailing inflammatory infiltrates in the median eminence (ME), progressive degeneration of neurons of the paraventricular nucleus, the entorhinal cortex and the amygdala, and a strikingly high-grade involution of the hippocampus with hydrocephalus. Immune histology revealed that major BDV-1 antigens were preferentially present at glutamatergic receptor sites, while GABAergic areas remained free from BDV-1. Virus-induced suppression of the glutamatergic system caused GABAergic predominance. In the hypothalamus, this shifted the energy balance to the anabolic appetite-stimulating side governed by GABA, allowing for excessive fat accumulation in obese rats. Furthermore, inflammatory infiltrates in the ME and ventro-medial arcuate nucleus hindered free access of appetite-suppressing hormones leptin and insulin. The hormone transport system in hypothalamic areas outside the ME became blocked by excessively produced leptin, leading to leptin resistance. The resulting hyperleptinemic milieu combined with suppressed glutamatergic mechanisms was a characteristic feature of the found metabolic pathology. In conclusion, the study provided clear evidence that BDV-1 induced obesity in the rat model is the result of interdependent structural and functional metabolic changes. They can be explained by an immunologically induced hypothalamic microcirculation-defect, combined with a disturbance of neurotransmitter regulatory systems. The proposed mechanism may also have implications for human health. BDV-1 infection has been frequently found in depressive patients. Independently, comorbidity between depression and obesity has been reported, either. Future studies should address the exciting question of whether BDV-1 infection could be a link, whatsoever, between these two conditions.
    MeSH term(s) Animals ; Borna Disease/complications ; Borna Disease/metabolism ; Borna Disease/pathology ; Borna disease virus/physiology ; Brain/metabolism ; Brain/pathology ; Brain/virology ; Encephalitis, Viral/pathology ; Hypothalamus/metabolism ; Hypothalamus/pathology ; Hypothalamus/virology ; Neurons/metabolism ; Neurons/pathology ; Neurons/virology ; Neuropeptides/metabolism ; Obesity/metabolism ; Obesity/pathology ; Obesity/virology ; Rats, Wistar
    Chemical Substances Neuropeptides
    Language English
    Publishing date 2020-05-11
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2273162-3
    ISSN 1863-2661 ; 1863-2653
    ISSN (online) 1863-2661
    ISSN 1863-2653
    DOI 10.1007/s00429-020-02063-0
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  8. Article ; Online: Are human Borna disease virus 1 infections zoonotic and fatal?

    Bode, Liv / Xie, Peng / Dietrich, Detlef E / Zaliunaite, Violeta / Ludwig, Hanns

    The Lancet. Infectious diseases

    2020  Volume 20, Issue 6, Page(s) 650–651

    MeSH term(s) Animals ; Borna disease virus ; Encephalitis ; Humans ; Zoonoses
    Language English
    Publishing date 2020-05-26
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 2061641-7
    ISSN 1474-4457 ; 1473-3099
    ISSN (online) 1474-4457
    ISSN 1473-3099
    DOI 10.1016/S1473-3099(20)30380-7
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  9. Article: The Biology of Bornavirus

    LUDWIG, HANNS

    APMIS. 2008 June., v. 116, suppl. 124

    2008  

    Language English
    Dates of publication 2008-06
    Size p. 14-20.
    Publisher Blackwell Publishing Ltd
    Publishing place Oxford, UK
    Document type Article
    ISSN 0108-0172 ; 0903-465X ; 0903-4641
    ISSN 0108-0172 ; 0903-465X ; 0903-4641
    DOI 10.1111/j.1600-0463.2008.000m2.x
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  10. Article: Essentials in Bornavirus Virology - an Epilogue

    LUDWIG, HANNS

    APMIS. 2008 June., v. 116, suppl. 124

    2008  

    Language English
    Dates of publication 2008-06
    Size p. 94-97.
    Publisher Blackwell Publishing Ltd
    Publishing place Oxford, UK
    Document type Article
    ISSN 0108-0172 ; 0903-465X ; 0903-4641
    ISSN 0108-0172 ; 0903-465X ; 0903-4641
    DOI 10.1111/j.1600-0463.2008.00m18.x
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