The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy
Open accessPublished version of a preprint
Abstract
Abstract Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [ 18 F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Anavex 2-73 has demonstrated significant benefits in the KO mouse model of FXS where multiple behaviors were improved and deficient BDNF levels were normalized.
“It has demonstrated significant benefits in the KO mouse model of FXS where multiple behaviors were improved and deficient brain derived neurotropic factor (BDNF) levels were normalized [144].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [144]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638
Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands
Innis, R. B., Cunningham, V. J., Delforge, J., Fujita, M., Gjedde, A., Gunn, R. N., Holden, J., Houle, S., Huang, S.-C., Ichise, M., et al. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600493 · Cited by 1,955
Miranda, M., Morici, J. F., Zanoni, M. B., & Bekinschtein, P. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00363 · Cited by 1,416
Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders
Autry, A. E., & Monteggia, L. M. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005108 · Cited by 1,390
Fmr1 knockout mice: A model to study fragile X mental retardation
THEDUTCHBELGIANFRAGILEXCONSOR (1994) · Cell · doi:10.1016/0092-8674(94)90569-x · Cited by 1,108
Advances in the Treatment of Fragile X Syndrome
Hagerman, R. J., Berry-Kravis, E., Kaufmann, W. E., Ono, M. Y., Tartaglia, N., Lachiewicz, A., Kronk, R., Delahunty, C., Hessl, D., Visootsak, J., et al. (2009) · Pediatrics · doi:10.1542/peds.2008-0317 · Cited by 596
Self-citation(1994) · PubMed · Cited by 565
Dysregulation of mTOR signaling in fragile X syndrome
Sharma, A., Hoeffer, C. A., Takayasu, Y., Miyawaki, T., McBride, S. M., Klann, E., & Zukin, R. S. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3696-09.2010 · Cited by 557
Park, S., Park, J. M., Kim, S., Kim, J.-A., Shepherd, J. D., Smith-Hicks, C. L., Chowdhury, S., Kaufmann, W., Kuhl, D., Ryazanov, A. G., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.05.023 · Cited by 516
Self-citationDigging and marble burying in mice: simple methods for in vivo identification of biological impacts
Deacon, R. M. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.20 · Cited by 508
Self-citationThe Hill equation and the origin of quantitative pharmacology
Gesztelyi, R., Zsuga, J., Kemény‐Beke, Á., Varga, B. R., Juhász, B., & Tósaki, Á. (2012) · Archive for History of Exact Sciences · doi:10.1007/s00407-012-0098-5 · Cited by 395
Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Berry-Kravis, E. M., Lindemann, L., Jønch, A. E., Apostol, G., Bear, M. F., Carpenter, R. L., Crawley, J. N., Curie, A., Des Portes, V., Hossain, F., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.221 · Cited by 336
A synaptic perspective of fragile X syndrome and autism spectrum Disorders.
Bagni, C., & Zukin, R. S. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.041 · Cited by 326
The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems
Su, T., Su, T., Nakamura, Y., & Tsai, S. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.01.003 · Cited by 324
Phenotypic variation and FMRP levels in fragile X
Loesch, D. Z., Huggins, R., & Hagerman, R. J. (2004) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.20006 · Cited by 306
The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo
Mientjes, E., Nieuwenhuizen, I. M., Kirkpatrick, L., Zu, T., Hoogeveen‐Westerveld, M., Severijnen, L., Rife, M. F., Willemsen, R., Nelson, D. L., & Oostra, B. A. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.08.019 · Cited by 285
Autism spectrum disorder in fragile X syndrome: cooccurring conditions and current treatment
Kaufmann, W. E., Kidd, S. A., Andrews, H. F., Budimirovic, D. B., Esler, A., Haas-Givler, B., Stackhouse, T., Riley, C., Peacock, G., Sherman, S. L., et al. (2017) · PEDIATRICS · doi:10.1542/peds.2016-1159f · Cited by 268
Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., Brynczka, C., Rush, R., Thomas, A., Paylor, R., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004218 · Cited by 249
Modeling fragile X syndrome in the Fmr1 knockout mouse
Kazdoba, T. M., Leach, P. T., Silverman, J. L., & Crawley, J. N. (2014) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2014.01024 · Cited by 241
Sigma receptors: biology and therapeutic potential
Guitart, X., Codony, X., & Monroy, X. (2004) · Psychopharmacology · doi:10.1007/s00213-004-1920-9 · Cited by 235
Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases
Ryskamp, D. A., Korban, S. A., Zhemkov, V., Kraskovskaya, N., & Борисович, Б. И. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00862 · Cited by 233
de Brouwer, G., Fick, A., Harvey, B. H., & Wolmarans, D. W. (2018) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-018-00653-4 · Cited by 198
What Can We Learn about Autism from Studying Fragile X Syndrome?
Budimirovic, D. B., & Kaufmann, W. E. (2011) · Developmental Neuroscience · doi:10.1159/000330213 · Cited by 187
Self-citationThe Molecular Function of σ Receptors: Past, Present, and Future
Schmidt, H. R., & Kruse, A. C. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.07.006 · Cited by 177
Lahmy, V., Meunier, J., Malmström, S., Naert, G., Givalois, L., Kim, S. H., Villard, V., Vamvakides, A., & Maurice, T. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.70 · Cited by 164
Guo, W., Murthy, A. C., Zhang, L., Johnson, E. B., Schaller, E., Allan, A. M., & Zhao, X. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr501 · Cited by 160
Updated report on tools to measure outcomes of clinical trials in fragile X syndrome
Budimirovic, D. B., Berry‐Kravis, E., Erickson, C. A., Hall, S. S., Hessl, D. R., Reiss, A. L., King, M. K., Abbeduto, L., & Kaufmann, W. E. (2017) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-017-9193-x · Cited by 159
Self-citationVillard, V., Espallergues, J., Keller, E., Vamvakides, A., & Maurice, T. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881110379286 · Cited by 139
Costa, L., Spatuzza, M., D’Antoni, S., Bonaccorso, C. M., Trovato, C., Musumeci, S. A., Leopoldo, M., Lacivita, E., Catania, M. V., & Ciranna, L. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.06.008 · Cited by 134
Of Men and Mice: Modeling the Fragile X Syndrome
Dahlhaus, R. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00041 · Cited by 132
Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility
Styr, B., Gonen, N., Zarhin, D., Ruggiero, A., Atsmon, R., Gazit, N., Braun, G., Frère, S. G. A., Vertkin, I., Shapira, I., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.045 · Cited by 122
The behavioral phenotype of FMR1 mutations
Boyle, L., & Kaufmann, W. E. (2010) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.30277 · Cited by 118
Self-citationEarly Development of Stereotyped and Self-Injurious Behaviors: I. Incidence
Berkson, G., Tupa, M., & Sherman, L. (2001) · American Journal on Mental Retardation · doi:10.1352/0895-8017(2001)106 · Cited by 95
New Positron Emission Tomography (PET) Radioligand for Imaging σ-1 Receptors in Living Subjects
James, M. L., Shen, B., Zavaleta, C. L., Nielsen, C. H., Mésangeau, C., Vuppala, P. K., Chan, C. T., Avery, B. A., Fishback, J. A., Matsumoto, R. R., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300371c · Cited by 94
Self-citationBDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse
Louhivuori, V., Vicario, A., Uutela, M., Rantamäki, T., Louhivuori, L. M., Ċastrén, E., Tongiorgi, E., Åkerman, K. E. O., & Castrén, M. L. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.018 · Cited by 93
Santini, E., Huynh, T. N., Longo, F., Koo, S. Y., Mojica, E. S., D’Andrea, L., Bagni, C., & Klann, E. (2017) · Science Signaling · doi:10.1126/scisignal.aan0665 · Cited by 92
Uutela, M., Lindholm, J., Louhivuori, V., Wei, H., Louhivuori, L. M., Pertovaara, A., Åkerman, K. E. O., Ċastrén, E., & Castrén, M. L. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00784.x · Cited by 91
Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome
Bostrom, C. A., Yau, S., Majaess, N. M., Vetrici, M. A., Gil‐Mohapel, J., & Christie, B. R. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.033 · Cited by 87
Lahmy, V., Long, R., Morin, D., Villard, V., & Maurice, T. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00463 · Cited by 85
Sawicka, K., Pyronneau, A., Chao, M., Bennett, M. V. L., & Zukin, R. S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610812113 · Cited by 84
Hampel, H., Williams, C., Etcheto, A., Goodsaid, F., Parmentier, F., Sallantin, J., Kaufmann, W. E., Missling, C. U., & Afshar, M. (2020) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12013 · Cited by 84
Self-citationCyclic AMP metabolism in fragile X syndrome
Berry‐Kravis, E., & Huttenlocher, P. R. (1992) · Annals of Neurology · doi:10.1002/ana.410310105 · Cited by 81
NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome
Deacon, R. M. J., Glass, L., Snape, M., Hurley, M. J., Altimiras, F. J., Biekofsky, R. R., & Cogram, P. (2015) · NeuroMolecular Medicine · doi:10.1007/s12017-015-8341-2 · Cited by 78
Christ, M., Huesmann, H., Nagel, H., Kern, A., & Behl, C. (2019) · Cells · doi:10.3390/cells8030211 · Cited by 74
Maurice, T. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.09.020 · Cited by 69
Castrén, M. L., & Ċastrén, E. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.018 · Cited by 68
Francardo, V., Geva, M., Bez, F., Denis, Q., Steiner, L., Hayden, M. R., & Cenci, M. A. (2019) · Neurotherapeutics · doi:10.1007/s13311-018-00699-9 · Cited by 68
Verrilli, M. A. L., Pirola, C. J., Pascual, M. M., Dominici, F. P., Turyn, D., & Gironacci, M. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05912.x · Cited by 65
Gaudissard, J., Ginger, M. R., Premoli, M., Memo, M., Frick, A., & Pietropaolo, S. (2017) · Autism Research · doi:10.1002/aur.1814 · Cited by 64
Smith-Dijak, A., Nassrallah, W. B., Zhang, L. Y. J., Geva, M., Hayden, M. R., & Raymond, L. A. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00209 · Cited by 59
Kaufmann, W. E., Sprouse, J., Rebowe, N., Hanania, T., Klamer, D., & Missling, C. U. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.172796 · Cited by 54
Self-citationVisualizing Nerve Injury in a Neuropathic Pain Model with [18F]FTC-146 PET/MRI
Shen, B., Behera, D., James, M. L., Reyes, S. T., Andrews, L., Cipriano, P. W., Klukinov, M., Lutz, A. B., Mavlyutov, T. A., Rosenberg, J., et al. (2017) · Theranostics · doi:10.7150/thno.19378 · Cited by 53
Self-citationGaboxadol Normalizes Behavioral Abnormalities in a Mouse Model of Fragile X Syndrome
Cogram, P., Deacon, R. M. J., Warner‐Schmidt, J. L., von Schimmelmann, M. J., Abrahams, B. S., & During, M. J. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00141 · Cited by 53
Self-citationPET imaging for receptor occupancy: meditations on calculation and simplification
Zhang, Y., & Fox, G. B. (2012) · Journal of Biomedical Research · doi:10.1016/s1674-8301(12)60014-1 · Cited by 52
Evaluation of σ-1 Receptor Radioligand18F-FTC-146 in Rats and Squirrel Monkeys Using PET
James, M. L., Shen, B., Nielsen, C. H., et al. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.113.120261 · Cited by 48
Biodistribution and Radiation Dosimetry of 18F-FTC-146 in Humans
Hjørnevik, T., Cipriano, P. W., Shen, B., Park, J. H., Gulaka, P., Holley, D., Gandhi, H., Yoon, D., Mittra, E., Zaharchuk, G., et al. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.117.192641 · Cited by 41
Self-citationRepurposing available drugs for neurodevelopmental disorders: The fragile X experience
Tranfaglia, M. R., Thibodeaux, C., Mason, D. J., Brown, D., Roberts, I., Smith, R. J., Guilliams, T., & Cogram, P. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.05.004 · Cited by 41
Self-citationFurther validation to support clinical translation of [18F]FTC-146 for imaging sigma-1 receptors
Shen, B., James, M. L., Andrews, L., Lau, C., Chen, S., Palner, M., Miao, Z., Arksey, N., Shuhendler, A. J., Scatliffe, S., et al. (2015) · EJNMMI Research · doi:10.1186/s13550-015-0122-2 · Cited by 30
Self-citationSears, J. C., Choi, W. J., & Broadie, K. S. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.004 · Cited by 30
Lovastatin, Not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model
Muscas, M., Louros, S. R., & Osterweil, E. K. (2019) · eneuro · doi:10.1523/eneuro.0097-19.2019 · Cited by 30
Relationship between Sigma-1 receptor and BDNF in the visual system
Mysona, B., Zhao, J., Smith, S. L., & Bollinger, K. (2017) · Experimental Eye Research · doi:10.1016/j.exer.2017.10.012 · Cited by 28
Pharmacological Rescue of Hippocampal Fear Learning Deficits in Fragile X Syndrome
Martinez, L. A., & Tejada-Simon, M. V. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0819-5 · Cited by 14
Miller (1999) · doi:10.1002/(sici)1096-8628(19990402)83:4
Flagged first, then by citations
Cited by
Sorted by citations
An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
Aishworiya, R., Valica, T., Hagerman, R., & Restrepo, B. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01183-1 · Cited by 233
Metadata
- Authors
- Reyes, S. T., Deacon, R. M. J., Guo, S. G., Altimiras, F. J., Castillo, J. B., van der Wildt, B., Morales, A. P., Park, J. H., Klamer, D., Rosenberg, J., Oberman, L. M., Rebowe, N., Sprouse, J., Missling, C. U., McCurdy, C. R., Cogram, P., Kaufmann, W. E., & Chin, F. T.
- Affiliations
- Stanford University (US)
- Fraunhofer Chile Research Foundation (CL)
- University of the Americas (CL)
- Anavex Life Sciences Corp. (United States) (US)
- Uniformed Services University of the Health Sciences (US)
- University of Florida (US)
- Emory University (US)
- Stanford Medicine (US)
- Corresponding author
- Kaufmann, Walter E.
- Chin, Frederick T.
- ORCID
- Venue
- Scientific Reports
- Published
- 2021-08-25
- Volume
- 11
- Issue
- 1
- Pages
- 17150-17150
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8387417
- OpenAlex
- W3134568897
- Cited by
- 22
- References
- 63
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 1
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion, other-oa)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of Child Health and Human Development (R21 HD095319)
- National Institutes of Health (S10 OD018130)
- Anavex Life Sciences Corp.
- FRAXA Research Foundation
- Fondecyt (1200928)
- National Institute on Drug Abuse (R01 DA023205)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- fragile X syndrome, sigma-1 receptor agonist, receptor occupancy, hyperactivity, anxiety, marble-burying behavior, contextual fear conditioning, associative learning, brain-derived neurotrophic factor, hippocampus, positron emission tomography, neurodevelopmental disorders, synaptic function
- MeSH terms
- Sigma-1 Receptor, Animals, Fragile X Syndrome, Furans, Hippocampus, Male, Mice, Inbred C57BL, Phenotype, Protein Binding, Receptors, sigma, Neuroprotective Agents, Maze Learning, Brain-Derived Neurotrophic Factor, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
