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Author Notes:

Walter E. Kaufmann, Email: walter.e.kaufmann@emory.edu

F.C., C.Mi., J.S., P.C., R.D. and W.E.K. conceived the experiments. F.C., J.S., C.Mi. and S.R., designed the imaging experiments. P.C. designed the cellular assays and R.D. designed the behavioral experiments. S.R., S.G., B.v.d.W., J.P., J.C., A.M. and F.A. performed the experiments. S.R., R.D., F.A., D.K., L.O., J.R., W.E.K. and F.C. analyzed the data. S.R., J.R., F.A., D.K., W.E.K. and F.C. made the figures. C.Mc. and N.R. contributed intellectually. S.R., P.C., W.E.K. and F.C. wrote the manuscript with the support of all authors. All authors contributed to the article and approved the submitted version.

NR, JS, CMi, DK and WEK are employees of Anavex Life Sciences Corp., while LO is a paid consultant to their company. The imaging studies and data analysis performed at Stanford University by SR, SG, JC, BvdW, JP, AM, JR and FC were funded in part by Anavex Life Sciences Corporation. The behavioral studies and cellular assays performed by FA, PC and RD were funded by FRAXA Research Foundation, FA, PC and RD declare no competing interests. CMc declares no competing interests.

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Research Funding:

This work was supported by the FRAXA Research Foundation, USA (FRAXA-DVI, Chile); Fondecyt 1200928 (PC); Anavex Life Sciences Corporation, USA; NIH R01 HD084214 (FTC); The Ben and Catherine Ivy Foundation, USA; the Stanford Cyclotron & Radiochemistry Facility (CRF); the Stanford Center for Innovations in In vivo Imaging (SCi3) small animal imaging center; NIH S10 OD018130 (FTC); NIH R21 HD095319 (FTC); NIH R01 DA023205 (CMc).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • FMR1 KNOCKOUT MICE
  • MOUSE MODEL
  • AUTISM
  • BDNF
  • RADIOLIGAND
  • GENERATION
  • ANAVEX2-73

Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy

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Journal Title:

SCIENTIFIC REPORTS

Volume:

Volume 11, Number 1

Publisher:

, Pages 17150-17150

Type of Work:

Article | Final Publisher PDF

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 [18F]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.

Copyright information:

© The Author(s) 2021

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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