BCI-838, an orally active mGluR2/3 receptor antagonist pro-drug, rescues learning behavior deficits in the PS19 MAPTP301S mouse model of tauopathy

Georgina Perez-Garcia, Mesude Bicak, Jean Vianney Haure-Mirande, Gissel M. Perez, Alena Otero-Pagan, Miguel A. Gama Sosa, Rita De Gasperi, Mary Sano, Carrolee Barlow, Fred H. Gage, Benjamin Readhead, Michelle E. Ehrlich, Sam Gandy, Gregory A. Elder

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Abstract

Tauopathies are a heterogeneous group of neurodegenerative disorders that are clinically and pathologically distinct from Alzheimer's disease (AD) having tau inclusions in neurons and/or glia as their most prominent neuropathological feature. BCI-838 (MGS00210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APPE693Q) transgenic mice, a model of the pathological accumulation of Aβ oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPTP301S associated with human frontotemporal lobar degeneration (FTLD). These mice develop an aging-related tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle, (2) PS19 mice treated with vehicle and (3) PS19 mice treated with 5 mg/kg BCI-838. Groups of 10–13 mice were utilized. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Behavioral testing consisting of a novel object recognition task was conducted after drug administration. Two studies were performed beginning treatment of mice at 3 or 7 months of age. One month of BCI-838 treatment rescued deficits in recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as their underlying basis. They also suggest an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice.

Original languageEnglish
Article number137080
JournalNeuroscience Letters
Volume797
DOIs
StatePublished - 16 Feb 2023

Keywords

  • BCI-838
  • Frontotemporal dementia
  • Metabotropic glutamate receptors 2/3
  • Tauopathy
  • Transgenic mice
  • microtubule associated protein tau (MAPT)

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