| Autor: |
Scarborough J; Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland., Mattei D; Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland., Dorner-Ciossek C; Department of CNS Discovery Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany., Sand M; Department of Medicine, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA., Arban R; Department of CNS Discovery Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany., Rosenbrock H; Department of CNS Discovery Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany., Richetto J; Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.; Neuroscience Center Zürich, University of Zürich and ETH Zürich, Zürich, Switzerland., Meyer U; Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland. urs.meyer@vetpharm.uzh.ch.; Neuroscience Center Zürich, University of Zürich and ETH Zürich, Zürich, Switzerland. urs.meyer@vetpharm.uzh.ch. |
| Abstrakt: |
BI 409306, a phosphodiesterase-9 inhibitor under development for treatment of schizophrenia and attenuated psychosis syndrome (APS), promotes synaptic plasticity and cognition. Here, we explored the effects of BI 409306 treatment in the polyriboinosinic-polyribocytidilic acid (poly[I:C])-based mouse model of maternal immune activation (MIA), which is relevant to schizophrenia and APS. In Study 1, adult offspring received BI 409306 0.2, 0.5, or 1 mg/kg or vehicle to establish an active dose. In Study 2, adult offspring received BI 409306 1 mg/kg and/or risperidone 0.025 mg/kg, risperidone 0.05 mg/kg, or vehicle, to evaluate BI 409306 as add-on to standard therapy for schizophrenia. In Study 3, offspring received BI 409306 1 mg/kg during adolescence only, or continually into adulthood to evaluate preventive effects of BI 409306. We found that BI 409306 significantly mitigated MIA-induced social interaction deficits and amphetamine-induced hyperlocomotion, but not prepulse inhibition impairments, in a dose-dependent manner (Study 1). Furthermore, BI 409306 1 mg/kg alone or in combination with risperidone 0.025 mg/kg significantly reversed social interaction deficits and attenuated amphetamine-induced hyperlocomotion in MIA offspring (Study 2). Finally, we revealed that BI 409306 1 mg/kg treatment restricted to adolescence prevented adult deficits in social interaction, whereas continued treatment into adulthood also significantly reduced amphetamine-induced hyperlocomotion (Study 3). Taken together, our findings suggest that symptomatic treatment with BI 409306 can restore social interaction deficits and dopaminergic dysfunctions in a MIA model of neurodevelopmental disruption, lending preclinical support to current clinical trials of BI 409306 in patients with schizophrenia. Moreover, BI 409306 given during adolescence has preventive effects on adult social interaction deficits in this model, supporting its use in people with APS. |
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