Your browser doesn't support javascript.
loading
L-proline transporter inhibitor (LQFM215) promotes neuroprotection in ischemic stroke.
Carvalho, Gustavo Almeida; Chiareli, Raphaela Almeida; Marques, Bruno Lemes; Parreira, Ricardo Cambraia; de Souza Gil, Eric; de Carvalho, Flávio Silva; da Rocha, André Luís Batista; Silva, Rafaela Ribeiro; Noël, François; Vaz, Boniek Gontijo; Lião, Luciano Morais; Ahmad, Shabir; Verli, Hugo; Menegatti, Ricardo; Pinto, Mauro Cunha Xavier.
Afiliação
  • Carvalho GA; Department of Pharmacology, Federal University of Goias, Goiânia, GO, Brazil.
  • Chiareli RA; Department of Pharmacology, Federal University of Goias, Goiânia, GO, Brazil.
  • Marques BL; Department of Pharmacology, Federal University of Goias, Goiânia, GO, Brazil.
  • Parreira RC; Department of Pharmacology, Federal University of Goias, Goiânia, GO, Brazil.
  • de Souza Gil E; Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
  • de Carvalho FS; Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
  • da Rocha ALB; Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
  • Silva RR; Department of Pharmacology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
  • Noël F; Department of Pharmacology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
  • Vaz BG; Institute of Chemistry, Federal University of Goias, Goiânia, GO, Brazil.
  • Lião LM; Institute of Chemistry, Federal University of Goias, Goiânia, GO, Brazil.
  • Ahmad S; Center of Biotechnology, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
  • Verli H; Center of Biotechnology, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
  • Menegatti R; Faculty of Pharmacy, Federal University of Goias, Goiânia, GO, Brazil.
  • Pinto MCX; Department of Pharmacology, Federal University of Goias, Goiânia, GO, Brazil. pintomcx@ufg.br.
Pharmacol Rep ; 75(2): 276-292, 2023 Apr.
Article em En | MEDLINE | ID: mdl-36719635
BACKGROUND: L-proline transporter (PROT/SLC6A7) is closely associated with glutamatergic neurotransmission, where L-proline modulates the NMDA receptor (NMDAR) function. NMDAR-mediated excitotoxicity is a primary cause of neuronal death following stroke, which is triggered by the uncontrolled release of glutamate during the ischemic process. After ischemic stroke, L-proline levels show a reduction in the plasma, but high circulating levels of this molecule indicate good functional recovery. This work aimed to produce new PROT inhibitors and explore their effects on ischemic stroke. METHODS: Initially, we built a three-dimensional model of the PROT protein and run a molecular docking with the newly designed compounds (LQFM215, LQFM216, and LQFM217). Then, we synthesized new PROT inhibitors by molecular hybridization, and proline uptake was measured in ex vivo and in vivo models. The behavioral characterization of the treated mice was performed by the open-field test, elevated plus-maze, Y-maze, and forced swimming test. We used the permanent middle cerebral artery occlusion (MCAO) model to study the ischemic stroke damage and analyzed the motor impairment with limb clasping or cylinder tests. RESULTS: LQFM215 inhibited proline uptake in hippocampal synaptosomes, and the LQFM215 treatment reduced proline levels in the mouse hippocampus. LQFM215 reduced the locomotor and exploratory activity in mice and did not show any anxiety-related or working memory impairments. In the MCAO model, LQFM215 pre-treatment and treatment reduced the infarcted area and reduced motor impairments in the cylinder test and limb clasping. CONCLUSIONS: This dataset suggests that the new compounds inhibit cerebral L-proline uptake and that LQFM215 promotes neuroprotection and neuro-repair in the acute ischemic stroke model.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Isquemia Encefálica / AVC Isquêmico Limite: Animals Idioma: En Revista: Pharmacol Rep Assunto da revista: FARMACOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Isquemia Encefálica / AVC Isquêmico Limite: Animals Idioma: En Revista: Pharmacol Rep Assunto da revista: FARMACOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça