NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine

Autor(es)

de Almeida, Valeria ; Mendes, Niele Dias ; Zuccoli, Giuliana S. ; Reis-de-Oliveira, Guilherme ; Almeida, Glaucia M. ; Podolsky-Gondim, Guilherme Gozzoli ; Neder, Luciano ; Martins-de-Souza, Daniel ; Sebollela, Adriano

• Tipo de documento: Artigo Científico
• Fonte: Journal of Neurochemistry; v. 168, n. 3, p. 13-pg., 2024-02-08.

Resumo

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to resective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain. (AU)

• Processo FAPESP: 21/12263-2 - Alterações teciduais-moleculares associadas a infecções virais em culturas de fatias de cérebro humano adulto
• Beneficiário: Glaucia Maria de Almeida
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/18242-1 - Vias bioquímicas moduladas por drogas canabinóides em oligodendrócitos humanos
• Beneficiário: Valéria de Almeida
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/06614-4 - Determinação da função neuronal e do perfil metabólico oxidativo em fatias de cérebro humano adulto cultivadas em free-floating
• Beneficiário: Glaucia Maria de Almeida
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 17/25588-1 - Da compreensão básica a biomarcadores clínicos para a esquizofrenia: um estudo multidisciplinar centrado na neuroproteômica
• Beneficiário: Daniel Martins-de-Souza
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/25681-3 - Bases moleculares da toxicidade de oligômeros protéicos associados a amiloidoses do sistema nervoso
• Beneficiário: Adriano Silva Sebollela
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores