Akihiro Mouri1,2,3, Hsin-Jung Lee4, Takayoshi Mamiya5, Yuki Aoyama5, Yurie Matsumoto5, Hisayoshi Kubota2, Wei-Jan Huang6, Lih-Chu Chiou4,7,8, Toshitaka Nabeshima1,5,3. 1. Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Toyoake, Japan. 2. Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University, Graduate School of Health Sciences, Toyoake, Japan. 3. Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan. 4. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. 5. Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan. 6. Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan. 7. Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan. 8. Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan.
Abstract
BACKGROUND AND PURPOSE: Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit COMT, a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one of the negative symptoms of schizophrenia. EXPERIMENTAL APPROACH: We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice. KEY RESULTS: In chronic PCP-treated mice, hispidulin (10 mg·kg-1 , i.p.) attenuated social withdrawal similar to that observed with dopamine D1 receptor antagonist (SCH-23390, 0.02 mg·kg-1 , i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mg·kg-1 , i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D1 agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser897 phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser897 -phosphorylation and D1 activation in the PFC exits in both models. CONCLUSIONS AND IMPLICATIONS: Hispidulin attenuated social withdrawal by activating D1 receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.
BACKGROUND AND PURPOSE:Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulinattenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit COMT, a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one of the negative symptoms of schizophrenia. EXPERIMENTAL APPROACH: We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice. KEY RESULTS: In chronic PCP-treated mice, hispidulin (10 mg·kg-1 , i.p.) attenuated social withdrawal similar to that observed with dopamine D1 receptor antagonist (SCH-23390, 0.02 mg·kg-1 , i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mg·kg-1 , i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D1 agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser897 phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser897 -phosphorylation and D1 activation in the PFC exits in both models. CONCLUSIONS AND IMPLICATIONS: Hispidulin attenuated social withdrawal by activating D1 receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.
Authors: Marta Paterlini; Stanislav S Zakharenko; Wen-Sung Lai; Jie Qin; Hui Zhang; Jun Mukai; Koen G C Westphal; Berend Olivier; David Sulzer; Paul Pavlidis; Steven A Siegelbaum; Maria Karayiorgou; Joseph A Gogos Journal: Nat Neurosci Date: 2005-10-23 Impact factor: 24.884
Authors: Ralf Brisch; Arthur Saniotis; Rainer Wolf; Hendrik Bielau; Hans-Gert Bernstein; Johann Steiner; Bernhard Bogerts; Katharina Braun; Anna Katharina Braun; Zbigniew Jankowski; Jaliya Kumaratilake; Jaliya Kumaritlake; Maciej Henneberg; Tomasz Gos Journal: Front Psychiatry Date: 2014-05-19 Impact factor: 4.157