Tatyana Strekalova1, João P Costa-Nunes2, Ekaterina Veniaminova3, Aslan Kubatiev4, Klaus-Peter Lesch5, Vladimir P Chekhonin6, Matthew C Evans7, Harry W M Steinbusch8. 1. Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands. Electronic address: t.strekalova@maastrichtuniversity.nl. 2. Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal. 3. Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia. 4. Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia. 5. Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstr. 15, 97080 Wuerzburg, Germany. 6. Serbsky National Research Center for Social and Forensic Psychiatry, Department of Fundamental and Applied Neurobiology, per. Kropotkin 23, Moscow 119034, Russian Federation. 7. Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK. 8. Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands.
Abstract
BACKGROUND: High cholesterol intake in mice induces hepatic lipid dystrophy and inflammation, signs of non-alcoholic fatty liver disease (NAFLD), depressive- and anxiety-like behaviors, and the up-regulation of brain and liver Toll-like receptor 4 (Tlr4). Here, we investigated whether dicholine succinate (DS), an insulin receptor sensitizer and mitochondrial complex II substrate would interact with these effects. METHODS: C57BL/6J mice were given a 0.2%-cholesterol diet for 3 weeks, alone or along with oral DS administration, or a control feed. Outcomes included behavioral measures of anxiety/depression, and Tlr4 and peroxisome-proliferator-activated-receptor-gamma coactivator-1b (PPARGC1b) expression. RESULTS: 50mg/kg DS treatment for 3 weeks partially ameliorated the cholesterol-induced anxiety- and depressive-like changes. Mice were next treated at the higher dose (180mg/kg), either for the 3-week period of dietary intervention, or for the last two weeks. Three-week DS administration normalized behaviors in the forced swim and O-maze tests and abolished the Tlr4 up-regulation in the brain and liver. The delayed, 2-week DS treatment had similar effects on Tlr4 expression and largely rescued the above-mentioned behaviors. Suppression of PPARGC1b, a master regulator of mitochondrial biogenesis, by the high cholesterol diet, was prevented with the 3-week administration, and markedly diminished by the a 2-week administration of DS. None of treatments prevented hepatic dystrophy and triglyceride accumulation. LIMITATIONS: Other conditions have to be tested to define possible limitations of reported effects of DS. CONCLUSIONS: DS treatment did not alter the patho-morphological substrates of NAFLD syndrome in mice, but ameliorated its molecular and behavioral consequences, likely by activating mitochondrial functions and anti-inflammatory mechanisms.
BACKGROUND: High cholesterol intake in mice induces hepatic lipid dystrophy and inflammation, signs of non-alcoholic fatty liver disease (NAFLD), depressive- and anxiety-like behaviors, and the up-regulation of brain and liver Toll-like receptor 4 (Tlr4). Here, we investigated whether dicholine succinate (DS), an insulin receptor sensitizer and mitochondrial complex II substrate would interact with these effects. METHODS: C57BL/6J mice were given a 0.2%-cholesterol diet for 3 weeks, alone or along with oral DS administration, or a control feed. Outcomes included behavioral measures of anxiety/depression, and Tlr4 and peroxisome-proliferator-activated-receptor-gamma coactivator-1b (PPARGC1b) expression. RESULTS: 50mg/kg DS treatment for 3 weeks partially ameliorated the cholesterol-induced anxiety- and depressive-like changes. Mice were next treated at the higher dose (180mg/kg), either for the 3-week period of dietary intervention, or for the last two weeks. Three-week DS administration normalized behaviors in the forced swim and O-maze tests and abolished the Tlr4 up-regulation in the brain and liver. The delayed, 2-week DS treatment had similar effects on Tlr4 expression and largely rescued the above-mentioned behaviors. Suppression of PPARGC1b, a master regulator of mitochondrial biogenesis, by the high cholesterol diet, was prevented with the 3-week administration, and markedly diminished by the a 2-week administration of DS. None of treatments prevented hepatic dystrophy and triglyceride accumulation. LIMITATIONS: Other conditions have to be tested to define possible limitations of reported effects of DS. CONCLUSIONS:DS treatment did not alter the patho-morphological substrates of NAFLD syndrome in mice, but ameliorated its molecular and behavioral consequences, likely by activating mitochondrial functions and anti-inflammatory mechanisms.
Authors: Igor Pomytkin; João P Costa-Nunes; Vladimir Kasatkin; Ekaterina Veniaminova; Anna Demchenko; Alexey Lyundup; Klaus-Peter Lesch; Eugene D Ponomarev; Tatyana Strekalova Journal: CNS Neurosci Ther Date: 2018-04-24 Impact factor: 5.243
Authors: Yasodha Krishnasamy; Venkat K Ramshesh; Monika Gooz; Rick G Schnellmann; John J Lemasters; Zhi Zhong Journal: PLoS One Date: 2016-09-27 Impact factor: 3.240