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

Autor: Carvalho GA; Laboratório de Neuroquímica e Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Av. Esperança, S/N, UFG, Prédio ICB II, Sala 114, Goiânia, GO, 74690-900, Brazil., Chiareli RA; Laboratório de Neuroquímica e Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Av. Esperança, S/N, UFG, Prédio ICB II, Sala 114, Goiânia, GO, 74690-900, Brazil., Pedrazzi JFC; Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), São Paulo, Brazil., Silva-Amaral D; Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), São Paulo, Brazil., da Rocha ALB; Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil., Oliveira-Lima OC; Laboratório de Neuroquímica e Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Av. Esperança, S/N, UFG, Prédio ICB II, Sala 114, Goiânia, GO, 74690-900, Brazil., Lião LM; Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil., de Souza-Fagundes EM; Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Schildknecht S; Faculty of Life Sciences, Albstadt-Sigmaringen University, 72488, Sigmaringen, Germany., Leist M; In Vitro Toxicology and Biomedicine, Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany., Del-Bel EA; Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), São Paulo, Brazil., Gomez RS; Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Birbrair A; Department of Dermatology, Medical Sciences Center, University of Wisconsin-Madison, Rm 4385, 1300 University Avenue, Madison, WI, 53706, USA., Menegatti R; Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil., Pinto MCX; Laboratório de Neuroquímica e Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Av. Esperança, S/N, UFG, Prédio ICB II, Sala 114, Goiânia, GO, 74690-900, Brazil. pintomcx@gmail.com.
Jazyk: angličtina
Zdroj: Neurochemical research [Neurochem Res] 2024 Jan; Vol. 49 (1), pp. 170-183. Date of Electronic Publication: 2023 Sep 09.
DOI: 10.1007/s11064-023-04018-3
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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