Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia
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 pharmacologic...
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| Veröffentlicht in: | International journal of molecular sciences 2023-03, Vol.24 (7), p.6016 |
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| creator | Vila, Èlia Pinacho, Raquel Prades, Roger Tarragó, Teresa Castro, Elena Munarriz-Cuezva, Eva Meana, J Javier Eugui-Anta, Ania Roldan, Mònica Vera-Montecinos, América Ramos, Belén |
| description | 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. |
| doi_str_mv | 10.3390/ijms24076016 |
| format | Article |
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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.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms24076016</identifier><identifier>PMID: 37046989</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Analysis ; Animal cognition ; Animals ; Antagonists ; Antipsychotics ; Aspartate ; Astrocytes ; Brain research ; Cognition ; Cognitive Dysfunction - drug therapy ; Cognitive Dysfunction - etiology ; Confounding (Statistics) ; Cytoplasm ; Dizocilpine ; Dizocilpine Maleate - pharmacology ; Gene expression ; Glutamic acid receptors ; Hypotheses ; Immunocytochemistry ; Inhibition (psychology) ; Mental disorders ; Methyl aspartate ; Mitochondria ; N-Methyl-D-aspartic acid receptors ; Neurons ; Oligopeptidase ; Pathophysiology ; Phencyclidine ; Prefrontal cortex ; Prohibitin ; Prohibitins ; Prolyl oligopeptidase ; Prolyl Oligopeptidases - metabolism ; Proteins ; Psychosis ; Psychotic Disorders ; Psychotropic drugs ; Rats ; Receptors, N-Methyl-D-Aspartate - metabolism ; Schizophrenia ; Schizophrenia - drug therapy ; Schizophrenia - metabolism ; State finance</subject><ispartof>International journal of molecular sciences, 2023-03, Vol.24 (7), p.6016</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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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.</description><subject>Analysis</subject><subject>Animal cognition</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Antipsychotics</subject><subject>Aspartate</subject><subject>Astrocytes</subject><subject>Brain research</subject><subject>Cognition</subject><subject>Cognitive Dysfunction - drug therapy</subject><subject>Cognitive Dysfunction - etiology</subject><subject>Confounding (Statistics)</subject><subject>Cytoplasm</subject><subject>Dizocilpine</subject><subject>Dizocilpine Maleate - pharmacology</subject><subject>Gene expression</subject><subject>Glutamic acid receptors</subject><subject>Hypotheses</subject><subject>Immunocytochemistry</subject><subject>Inhibition (psychology)</subject><subject>Mental disorders</subject><subject>Methyl aspartate</subject><subject>Mitochondria</subject><subject>N-Methyl-D-aspartic acid receptors</subject><subject>Neurons</subject><subject>Oligopeptidase</subject><subject>Pathophysiology</subject><subject>Phencyclidine</subject><subject>Prefrontal cortex</subject><subject>Prohibitin</subject><subject>Prohibitins</subject><subject>Prolyl oligopeptidase</subject><subject>Prolyl Oligopeptidases - metabolism</subject><subject>Proteins</subject><subject>Psychosis</subject><subject>Psychotic Disorders</subject><subject>Psychotropic drugs</subject><subject>Rats</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Schizophrenia</subject><subject>Schizophrenia - drug therapy</subject><subject>Schizophrenia - metabolism</subject><subject>State finance</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptUk2P0zAQjRCIXRZunJElLhzoMrGTOOaCVuVrpaJd8XG2XHvcuErtYKeVyj_gX-PQZeki5INHb9579jxNUTwt4ZwxAa_cepNoBbyBsrlXnJYVpTOAht8_qk-KRymtASijtXhYnDAOVSNacVr8vPSdW7rRBU-CJdcx9PueXPVuFQYcRmdUQvIZ0xgipql9YHtCyQJ32CeS6-u0111ILpFPwWTsdVb0avJMnRvIGMg8rHyW7ZC8Reu0G3_rvujO_QhDF9E79bh4YFWf8MnNfVZ8e__u6_zjbHH14XJ-sZjpqoVxphkKswRbtw2npgZgzFSW6zYjgMLSJRitamBCccpFro2xmpYtGGsFanZWvDn4DtvlBo1GP0bVyyG6jYp7GZSTdzvedXIVdrIEECyHlh1e3DjE8H2bs5EblzT2vfIYtknSNmdOBbAqU5__Q12HbfR5Ppk_J3jZ1A39y1qpHqXzNuSH9WQqL3hdClpzOnmd_4eVj8GN08HnYDN-R_DyINAxpBTR3g5Zgpx2Rx7vTqY_Ow7mlvxnWdgvcV3CBA</recordid><startdate>20230323</startdate><enddate>20230323</enddate><creator>Vila, Èlia</creator><creator>Pinacho, Raquel</creator><creator>Prades, Roger</creator><creator>Tarragó, Teresa</creator><creator>Castro, Elena</creator><creator>Munarriz-Cuezva, Eva</creator><creator>Meana, J Javier</creator><creator>Eugui-Anta, Ania</creator><creator>Roldan, Mònica</creator><creator>Vera-Montecinos, América</creator><creator>Ramos, Belén</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2790-5400</orcidid><orcidid>https://orcid.org/0000-0003-1943-3642</orcidid><orcidid>https://orcid.org/0000-0002-9530-6234</orcidid><orcidid>https://orcid.org/0000-0001-6417-5983</orcidid><orcidid>https://orcid.org/0000-0002-7913-6714</orcidid><orcidid>https://orcid.org/0000-0002-4577-2106</orcidid></search><sort><creationdate>20230323</creationdate><title>Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia</title><author>Vila, Èlia ; Pinacho, Raquel ; Prades, Roger ; Tarragó, Teresa ; Castro, Elena ; Munarriz-Cuezva, Eva ; Meana, J Javier ; Eugui-Anta, Ania ; Roldan, Mònica ; Vera-Montecinos, América ; Ramos, Belén</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c480t-c3e9db0f58672d50033d4f7c8f580e9f2b0dca5039a7279dcaddfc2180dff9ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Analysis</topic><topic>Animal cognition</topic><topic>Animals</topic><topic>Antagonists</topic><topic>Antipsychotics</topic><topic>Aspartate</topic><topic>Astrocytes</topic><topic>Brain research</topic><topic>Cognition</topic><topic>Cognitive Dysfunction - 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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. 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| ispartof | International journal of molecular sciences, 2023-03, Vol.24 (7), p.6016 |
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| subjects | Analysis Animal cognition Animals Antagonists Antipsychotics Aspartate Astrocytes Brain research Cognition Cognitive Dysfunction - drug therapy Cognitive Dysfunction - etiology Confounding (Statistics) Cytoplasm Dizocilpine Dizocilpine Maleate - pharmacology Gene expression Glutamic acid receptors Hypotheses Immunocytochemistry Inhibition (psychology) Mental disorders Methyl aspartate Mitochondria N-Methyl-D-aspartic acid receptors Neurons Oligopeptidase Pathophysiology Phencyclidine Prefrontal cortex Prohibitin Prohibitins Prolyl oligopeptidase Prolyl Oligopeptidases - metabolism Proteins Psychosis Psychotic Disorders Psychotropic drugs Rats Receptors, N-Methyl-D-Aspartate - metabolism Schizophrenia Schizophrenia - drug therapy Schizophrenia - metabolism State finance |
| title | Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia |
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