Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice
Treating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocanna...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/14/11400 |
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| author | Marta Kruk-Slomka Bartlomiej Adamski Tomasz Slomka Grazyna Biala |
| author_facet | Marta Kruk-Slomka Bartlomiej Adamski Tomasz Slomka Grazyna Biala |
| author_sort | Marta Kruk-Slomka |
| collection | DOAJ |
| description | Treating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL)). Here, the aim of the experiments was to evaluate the impact of inhibitors of endocannabinoids’ enzymatic degradation in the brain: KML-29 (MAGL inhibitor), JZL-195 (MAGL/FAAH inhibitor) and PF-3845 (FAAH inhibitor), on the memory disturbances typical for schizophrenia in an acute N-methyl-D-aspartate (NMDA) receptor hypofunction animal model of schizophrenia (i.e., injection of MK-801, an NMDA receptor antagonist). The memory-like responses were assessed in the passive avoidance (PA) test. A single administration of KML-29 or PF-3845 had a positive effect on the memory processes, but an acute administration of JZL-195 impaired cognition in mice in the PA test. Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids’ concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia. |
| first_indexed | 2024-03-11T01:00:26Z |
| format | Article |
| id | doaj.art-2d82031241114947a983a856b1cf24e4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:00:26Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2d82031241114947a983a856b1cf24e42023-11-18T19:38:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141140010.3390/ijms241411400Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in MiceMarta Kruk-Slomka0Bartlomiej Adamski1Tomasz Slomka2Grazyna Biala3Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, PolandDepartment of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, PolandDepartment of Medical Informatics and Statistics with E-Health Lab, Medical University of Lublin, Jaczewskiego 4 Street, 20-954 Lublin, PolandDepartment of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, PolandTreating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL)). Here, the aim of the experiments was to evaluate the impact of inhibitors of endocannabinoids’ enzymatic degradation in the brain: KML-29 (MAGL inhibitor), JZL-195 (MAGL/FAAH inhibitor) and PF-3845 (FAAH inhibitor), on the memory disturbances typical for schizophrenia in an acute N-methyl-D-aspartate (NMDA) receptor hypofunction animal model of schizophrenia (i.e., injection of MK-801, an NMDA receptor antagonist). The memory-like responses were assessed in the passive avoidance (PA) test. A single administration of KML-29 or PF-3845 had a positive effect on the memory processes, but an acute administration of JZL-195 impaired cognition in mice in the PA test. Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids’ concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia.https://www.mdpi.com/1422-0067/24/14/11400endocannabinoidsschizophrenia-like cognitive disordersFAAH and MAGL inhibitorNMDA receptor hypofunctionpassive avoidance testmice |
| spellingShingle | Marta Kruk-Slomka Bartlomiej Adamski Tomasz Slomka Grazyna Biala Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice International Journal of Molecular Sciences endocannabinoids schizophrenia-like cognitive disorders FAAH and MAGL inhibitor NMDA receptor hypofunction passive avoidance test mice |
| title | Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice |
| title_full | Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice |
| title_fullStr | Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice |
| title_full_unstemmed | Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice |
| title_short | Inhibitors of Endocannabinoids’ Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice |
| title_sort | inhibitors of endocannabinoids enzymatic degradation as a potential target of the memory disturbances in an acute n methyl d aspartate nmda receptor hypofunction model of schizophrenia in mice |
| topic | endocannabinoids schizophrenia-like cognitive disorders FAAH and MAGL inhibitor NMDA receptor hypofunction passive avoidance test mice |
| url | https://www.mdpi.com/1422-0067/24/14/11400 |
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