PMID- 37046989 OWN - NLM STAT- MEDLINE DCOM- 20230825 LR - 20230825 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 7 DP - 2023 Mar 23 TI - Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia. LID - 10.3390/ijms24076016 [doi] LID - 6016 AB - 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. FAU - Vila, Elia AU - Vila E AUID- ORCID: 0000-0003-2790-5400 AD - Parc Sanitari Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Spain. FAU - Pinacho, Raquel AU - Pinacho R AUID- ORCID: 0000-0001-6417-5983 AD - Parc Sanitari Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Spain. FAU - Prades, Roger AU - Prades R AD - Iproteos S.L., Baldiri i Reixac, 10, 08028 Barcelona, Spain. FAU - Tarrago, Teresa AU - Tarrago T AD - Iproteos S.L., Baldiri i Reixac, 10, 08028 Barcelona, Spain. AD - Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, 08028 Barcelona, Spain. FAU - Castro, Elena AU - Castro E AD - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, Avda. Cardenal Herrera Oria s/n, 39011 Santander, Spain. AD - Centro de Investigacion Biomedica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Institute of Health Carlos III, 28029 Madrid, Spain. FAU - Munarriz-Cuezva, Eva AU - Munarriz-Cuezva E AUID- ORCID: 0000-0003-1943-3642 AD - Centro de Investigacion Biomedica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Institute of Health Carlos III, 28029 Madrid, Spain. AD - Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Spain. AD - Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain. FAU - Meana, J Javier AU - Meana JJ AUID- ORCID: 0000-0002-7913-6714 AD - Centro de Investigacion Biomedica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Institute of Health Carlos III, 28029 Madrid, Spain. AD - Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Spain. AD - Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain. FAU - Eugui-Anta, Ania AU - Eugui-Anta A AD - Parc Sanitari Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Spain. FAU - Roldan, Monica AU - Roldan M AUID- ORCID: 0000-0002-9530-6234 AD - Unitat de Microscopia Confocal i Imatge Cel.lular, Servei de Medicina Genetica i Molecular, Institut Pediatric de Malaties Rares (IPER), Hospital Sant Joan de Deu, 08950 Esplugues de Llobregat, Spain. FAU - Vera-Montecinos, America AU - Vera-Montecinos A AD - Parc Sanitari Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Spain. FAU - Ramos, Belen AU - Ramos B AUID- ORCID: 0000-0002-4577-2106 AD - Parc Sanitari Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Spain. AD - Centro de Investigacion Biomedica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Institute of Health Carlos III, 28029 Madrid, Spain. AD - Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autonoma de Barcelona, Bellaterra, 08193 Barcelona, Spain. AD - Faculty of Medicine, University of Vic-Central University of Catalonia, 08500 Vic, Spain. LA - eng GR - MS16/00153-CP16/00153/Instituto de Salud Carlos III/ GR - FI19/00080/Instituto de Salud Carlos III/ GR - PI18/00213/Instituto de Salud Carlos III/ GR - FPU17/06000/Spanish Ministry of Education, culture and sports/ GR - 72160426/CONICYT-Doctorado Becas Chile/ PT - Journal Article DEP - 20230323 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - 0 (Prohibitins) RN - EC 3.4.21.26 (Prolyl Oligopeptidases) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Phb2 protein, rat) SB - IM MH - Animals MH - Rats MH - Cognition MH - *Cognitive Dysfunction/drug therapy/etiology MH - Dizocilpine Maleate/pharmacology MH - Prohibitins MH - Prolyl Oligopeptidases/metabolism MH - *Psychotic Disorders MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - *Schizophrenia/drug therapy/metabolism PMC - PMC10093989 OTO - NOTNLM OT - DLPFC OT - PHB2 OT - cognitive deficits OT - dizocilpine OT - postmortem OT - prolyl oligopeptidase OT - schizophrenia COIS- R. Prades and T. Tarrago are former employees of Iproteos S.L. and inventors of the patent application WO 2014/072498A1, which protects IPR19 and its derivates. In 2020, Iproteos S.L. was integrated into Accure Therapeutics S.L., which is the current owner of the patent application. The other authors declare no competing interests. EDAT- 2023/04/14 06:00 MHDA- 2023/04/14 06:41 PMCR- 2023/03/23 CRDT- 2023/04/13 01:09 PHST- 2022/11/29 00:00 [received] PHST- 2023/03/10 00:00 [revised] PHST- 2023/03/16 00:00 [accepted] PHST- 2023/04/14 06:41 [medline] PHST- 2023/04/13 01:09 [entrez] PHST- 2023/04/14 06:00 [pubmed] PHST- 2023/03/23 00:00 [pmc-release] AID - ijms24076016 [pii] AID - ijms-24-06016 [pii] AID - 10.3390/ijms24076016 [doi] PST - epublish SO - Int J Mol Sci. 2023 Mar 23;24(7):6016. doi: 10.3390/ijms24076016.