Funktionelle Bedeutung der Antipsychotika-Anreicherung im Gehirn
Zusammenfassung der Projektergebnisse
Schizophrenia is a severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD’s work only in a limited number of patients and may impair cognition and locomotor activity as accepted side effects. A growing body of evidence points to potential involvement of an abnormal sphingolipid metabolism in the pathophysiology of schizophrenia. In our study, the analysis of human gene polymorphisms and brain gene expression in schizophrenia patients identified an association of two genes and their polymorphisms, coding for sphingolipid controlling proteins, with schizophrenia. In an animal model of schizophrenia, we found a very specific activity increase of one of those enzymes in the prefrontal cortex. Shortterm chronic haloperidol treatment which was able to treat schizophrenia symptoms reversed the enzyme activity increase in the brain back to normal levels. A lipidomic analysis, which focused specifically on sphingolipids, showed an altered ceramide metabolism in the cortex, when schizophrenia is established. Targeting enhanced enzyme activity in schizophrenia with a new potent pharmacological inhibitor cured schizophrenia like behaviour and remitted lipid changes back to normal level. While effective haloperidol treatment led to locomotor decline and cognitive impairments, the novel enzyme inhibitor did not. Altogether, the new data provide a better insight into the brain mechanisms involved in the pathogenesis of schizophrenia and suggest a new effective pharma treatment possibility that shows less side effects than currently used therapies.
Projektbezogene Publikationen (Auswahl)
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Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats. Journal of Psychopharmacology, 35(1), 65-77.
Uzuneser, Taygun C.; Weiss, Eva-Maria; Dahlmanns, Jana; Kalinichenko, Liubov S.; Amato, Davide; Kornhuber, Johannes; Alzheimer, Christian; Hellmann, Jan; Kaindl, Jonas; Hübner, Harald; Löber, Stefan; Gmeiner, Peter; Grömer, Teja W. & Müller, Christian P.
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Pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure. Behavioural Brain Research, 403, 113144.
Chestnykh, Daria A.; Amato, Davide; Kornhuber, Johannes & Müller, Christian P.
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Analysis of hyperforin (St. John’s wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs. Molecular Psychiatry, 27(12), 5070-5085.
El, Hamdaoui Yamina; Zheng, Fang; Fritz, Nikolas; Ye, Lian; Tran, Mai Anh; Schwickert, Kevin; Schirmeister, Tanja; Braeuning, Albert; Lichtenstein, Dajana; Hellmich, Ute A.; Weikert, Dorothee; Heinrich, Markus; Treccani, Giulia; Schäfer, Michael K. E.; Nowak, Gabriel; Nürnberg, Bernd; Alzheimer, Christian; Müller, Christian P. & Friedland, Kristina
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Low income and schizophrenia risk: A narrative review. Behavioural Brain Research, 435, 114047.
Schneider, Miriam; Müller, Christian P. & Knies, Andrea K.
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Serotonin and consciousness – A reappraisal. Behavioural Brain Research, 432, 113970.
Müller, Christian P.
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Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models. Psychopharmacology, 240(4), 1011-1031.
Chestnykh, Daria; Graßl, Fabian; Pfeifer, Canice; Dülk, Jonas; Ebner, Chiara; Walters, Mona; von Hörsten, Stephan; Kornhuber, Johannes; Kalinichenko, Liubov S.; Heinrich, Markus & Müller, Christian P.
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Self-management with alcohol over lifespan: psychological mechanisms, neurobiological underpinnings, and risk assessment. Molecular Psychiatry, 28(7), 2683-2696.
Müller, Christian P.; Schumann, Gunter; Rehm, Jürgen; Kornhuber, Johannes & Lenz, Bernd
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Serotonin Signaling through Lipid Membranes. ACS Chemical Neuroscience, 15(7), 1298-1320.
Kalinichenko, Liubov S.; Kornhuber, Johannes; Sinning, Steffen; Haase, Jana & Müller, Christian P.
