PMID- 38332572 OWN - NLM STAT- MEDLINE DCOM- 20240223 LR - 20240321 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 168 IP - 3 DP - 2024 Mar TI - NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine. PG - 238-250 LID - 10.1111/jnc.16059 [doi] AB - 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 respective 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. CI - (c) 2024 International Society for Neurochemistry. FAU - de Almeida, Valeria AU - de Almeida V AD - Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil. FAU - Mendes, Niele Dias AU - Mendes ND AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. AD - Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. AD - Division of Neurosurgery, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. FAU - Zuccoli, Giuliana S AU - Zuccoli GS AUID- ORCID: 0000-0002-7604-9279 AD - Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil. FAU - Reis-de-Oliveira, Guilherme AU - Reis-de-Oliveira G AD - Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil. FAU - Almeida, Glaucia M AU - Almeida GM AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. FAU - Podolsky-Gondim, Guilherme Gozzoli AU - Podolsky-Gondim GG AD - Division of Neurosurgery, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. FAU - Neder, Luciano AU - Neder L AD - Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. FAU - Martins-de-Souza, Daniel AU - Martins-de-Souza D AD - Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil. AD - Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION) Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Sao Paulo, Brazil. AD - Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, Sao Paulo, Brazil. AD - D'Or Institute for Research and Education (IDOR), Sao Paulo, Brazil. FAU - Sebollela, Adriano AU - Sebollela A AUID- ORCID: 0000-0002-7444-9156 AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. LA - eng GR - 302453/2017-2/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ GR - 2014/25681-3/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ GR - 2017/18242-1/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ GR - 2017/25588-1/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ GR - 2018/06614-4/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ GR - 2021/12263-2/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ GR - 1709-16349/Instituto Serrapilheira/ GR - 1656470/Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/ GR - Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240208 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - J60AR2IKIC (Clozapine) RN - J6292F8L3D (Haloperidol) RN - 0 (Excitatory Amino Acid Antagonists) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - 0 (Proteome) RN - 6384-92-5 (N-Methylaspartate) RN - 3KX376GY7L (Glutamic Acid) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Antipsychotic Agents) SB - IM MH - Animals MH - Humans MH - *Clozapine/pharmacology MH - Haloperidol/pharmacology MH - Excitatory Amino Acid Antagonists/pharmacology MH - Dizocilpine Maleate/pharmacology MH - Proteome/metabolism MH - N-Methylaspartate MH - Glutamic Acid/metabolism MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Proteomics MH - *Antipsychotic Agents/pharmacology MH - Brain/metabolism OTO - NOTNLM OT - NMDAr hypofunction OT - antipsychotics OT - clozapine OT - haloperidol OT - organotypic culture OT - schizophrenia EDAT- 2024/02/09 06:43 MHDA- 2024/02/23 06:43 CRDT- 2024/02/09 01:23 PHST- 2023/11/27 00:00 [revised] PHST- 2023/08/20 00:00 [received] PHST- 2024/01/04 00:00 [accepted] PHST- 2024/02/23 06:43 [medline] PHST- 2024/02/09 06:43 [pubmed] PHST- 2024/02/09 01:23 [entrez] AID - 10.1111/jnc.16059 [doi] PST - ppublish SO - J Neurochem. 2024 Mar;168(3):238-250. doi: 10.1111/jnc.16059. Epub 2024 Feb 8.