24ab1cf437ac424fd2aee63895ecb62c pmc_10093989.pdf 113fa6cc6fd48c50815e886dadd4cc3e30a6c060 pmc_10093989.pdf b5e45fb63196f938f90f0144df84c898518b06c822cd49976491ac2a3f07cbbf pmc_10093989.pdf Title: Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia Subject: Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia. Keywords: schizophrenia; PHB2; cognitive deficits; postmortem; DLPFC; prolyl oligopeptidase; dizocilpine Author: Èlia Vila, Raquel Pinacho, Roger Prades, Teresa Tarragó, Elena Castro, Eva Munarriz-Cuezva, J. Javier Meana, Ania Eugui-Anta, Mònica Roldan, América Vera-Montecinos and Belén Ramos Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Mar 23 03:14:17 2023 CET ModDate: Thu Mar 23 03:18:01 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1260849 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YSAOHE+VnURWPalladioL Type 1 Custom yes yes no 10 0 GXNDYW+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 XJRUOH+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 UZJPPT+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 SEOSIR+CMSY10 Type 1 Builtin yes yes no 28 0 OADQVB+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 50 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 53 0 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TrueType MacRoman yes yes no 169 0 EKOFEG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 185 0 EKOFEH+PalatinoLinotype CID TrueType Identity-H yes yes yes 188 0 EKOFEI+PalatinoLinotype TrueType WinAnsi yes yes no 194 0 EKOFEK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 197 0 EKOGJE+PalatinoLinotype TrueType MacRoman yes yes no 200 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 220 0 SYVAVM+VnURWPalladioL-Italic Type 1 Custom yes yes no 236 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-08-11 02:27:39 CEST RepresentationInformation: pmc_10093989.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-08-01 02:37:55 CEST Size: 1260849 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 468 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Analysis of PHB2 Levels in Postmortem Dorsolateral Prefrontal Cortex in Schizophrenia Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Modulation of PHB2 Protein Levels by NMDA Receptor Activity and the Prolyl Oligopeptidase Inhibitor IPR19 in Rodents Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Modulation of PHB2 Protein Levels by NMDA Receptor Activity and the Prolyl Oligopeptidase Inhibitor IPR19 in Rat Cortical Astrocytes and Neurons Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Acute Treatments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Subchronic Treatments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Characterization of PHB2 in Cortical Neuron Cultures Treated with NMDA Receptor Antagonist and the Inhibitor IPR19 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Brain Tissue Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Rat Cortical Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Protein Extraction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Immunoblotting Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Reverse Transcription Quantitative PCR (RT-qPCR) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Immunocytochemistry and Confocal Imaging Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Info: Title: Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia Author: Èlia Vila, Raquel Pinacho, Roger Prades, Teresa Tarragó, Elena Castro, Eva Munarriz-Cuezva, J. Javier Meana, Ania Eugui-Anta, Mònica Roldan, América Vera-Montecinos and Belén Ramos Subject: Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia. 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