Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as l-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

Schizophrenia, Glutamatergic neurotransmission, Drug discovery, Target validation, SLC family transporters, SLC6A7

Zitieren

ISO 690

CARVALHO, Gustavo Almeida, Raphaela Almeida CHIARELI, João Francisco Cordeiro PEDRAZZI, Danyelle SILVA-AMARAL, André Luís Batista DA ROCHA, Onésia Cristina OLIVEIRA-LIMA, Luciano Morais LIÃO, Stefan SCHILDKNECHT, Marcel LEIST, Mauro Cunha Xavier PINTO, 2024. Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia. In: Neurochemical Research. Springer. 2024, 49(1), pp. 170-183. ISSN 0364-3190. eISSN 1573-6903. Available under: doi: 10.1007/s11064-023-04018-3

BibTex

@article{Carvalho2024Novel-67767,
  year={2024},
  doi={10.1007/s11064-023-04018-3},
  title={Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia},
  number={1},
  volume={49},
  issn={0364-3190},
  journal={Neurochemical Research},
  pages={170--183},
  author={Carvalho, Gustavo Almeida and Chiareli, Raphaela Almeida and Pedrazzi, João Francisco Cordeiro and Silva-Amaral, Danyelle and da Rocha, André Luís Batista and Oliveira-Lima, Onésia Cristina and Lião, Luciano Morais and Schildknecht, Stefan and Leist, Marcel and Pinto, Mauro Cunha Xavier}
}

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Universitätsbibliographie

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Begutachtet

Ja