Yu-Hsiang Liao1, Hsin-Jung Lee2, Wei-Jan Huang3, Pi-Chuan Fan4, Lih-Chu Chiou5,6,7,8. 1. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. 2. Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, Taipei, 100, Taiwan. 3. Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan. 4. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan. 5. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. lcchiou@ntu.edu.tw. 6. Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, Taipei, 100, Taiwan. lcchiou@ntu.edu.tw. 7. Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan. lcchiou@ntu.edu.tw. 8. Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung, Taiwan. lcchiou@ntu.edu.tw.
Abstract
RATIONALE: Hispidulin is a flavonoid we isolated from Clerodendrum inerme, an herb that effectively remitted a case of intractable motor tic disorders. Hispidulin was shown to be a positive allosteric modulator (PAM) of GABAA receptors, including the α6 subunit-containing subtype (α6GABAAR) that is predominantly expressed in cerebellar granule cells and insensitive to diazepam. OBJECTIVES: We explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders. RESULTS: Hispidulin significantly inhibited methamphetamine-induced hyperlocomotion (MIH) at i.p. doses without affecting apomorphine-induced hyperlocomotion and stereotypy behaviors or having significant benzodiazepine-like effects (BZLE), including sedation, anxiety, and motor impairment. When given by intracerebellar (i.c.b.) microinjection, hispidulin also alleviated MIH and this effect was prevented by i.c.b. coadministration of furosemide, an α6GABAAR antagonist, and mimicked by i.c.b. Ro 15-4513, an α6GABAAR PAM. Conversely, i.c.b. diazepam did not affect MIH while it reduced MIH at i.p. doses having significant BZLE. In a screening assay for 92 neurotransmitter receptors/degradation enzymes/transporters, hispidulin displayed significant (>50 % inhibition of radiolabeled ligand binding at 10 μM) binding affinity only at the benzodiazepine binding site of GABAARs (IC50 0.73∼1.78 μM) and catecholamine-o-methyl-transferase (COMT) (IC50 1.32 μM). OR-486, a more potent COMT inhibitor than hispidulin, did not affect MIH. CONCLUSIONS: It is suggested that hispidulin alleviates MIH via acting as a PAM of cerebellar α6GABAARs, but not through COMT inhibition or affecting dopamine receptor responsiveness. Thus, selective α6GABAAR PAMs may have the potential to be a novel treatment for hyperdopaminergic disorders.
RATIONALE: Hispidulin is a flavonoid we isolated from Clerodendrum inerme, an herb that effectively remitted a case of intractable motor tic disorders. Hispidulin was shown to be a positive allosteric modulator (PAM) of GABAA receptors, including the α6 subunit-containing subtype (α6GABAAR) that is predominantly expressed in cerebellar granule cells and insensitive to diazepam. OBJECTIVES: We explored the action mechanism(s) of hispidulin using hyperdopaminergic mouse models induced by methamphetamine and apomorphine, based on the hyperdopaminergic nature of tic disorders. RESULTS: Hispidulin significantly inhibited methamphetamine-induced hyperlocomotion (MIH) at i.p. doses without affecting apomorphine-induced hyperlocomotion and stereotypy behaviors or having significant benzodiazepine-like effects (BZLE), including sedation, anxiety, and motor impairment. When given by intracerebellar (i.c.b.) microinjection, hispidulin also alleviated MIH and this effect was prevented by i.c.b. coadministration of furosemide, an α6GABAAR antagonist, and mimicked by i.c.b. Ro 15-4513, an α6GABAAR PAM. Conversely, i.c.b. diazepam did not affect MIH while it reduced MIH at i.p. doses having significant BZLE. In a screening assay for 92 neurotransmitter receptors/degradation enzymes/transporters, hispidulin displayed significant (>50 % inhibition of radiolabeled ligand binding at 10 μM) binding affinity only at the benzodiazepine binding site of GABAARs (IC50 0.73∼1.78 μM) and catecholamine-o-methyl-transferase (COMT) (IC50 1.32 μM). OR-486, a more potent COMT inhibitor than hispidulin, did not affect MIH. CONCLUSIONS: It is suggested that hispidulin alleviates MIH via acting as a PAM of cerebellar α6GABAARs, but not through COMT inhibition or affecting dopamine receptor responsiveness. Thus, selective α6GABAAR PAMs may have the potential to be a novel treatment for hyperdopaminergic disorders.
Authors: F Knoflach; D Benke; Y Wang; L Scheurer; H Lüddens; B J Hamilton; D B Carter; H Mohler; J A Benson Journal: Mol Pharmacol Date: 1996-11 Impact factor: 4.436
Authors: Woo-Kyu Park; Daeyoung Jeong; Cheol-Won Yun; Sunghou Lee; Heeyeong Cho; Gun-Do Kim; Hun Yeong Koh; Ae Nim Pae; Yong Seo Cho; Kyung Il Choi; Ji Young Jung; Sun Ho Jung; Jae Yang Kong Journal: Pharmacol Res Date: 2003-12 Impact factor: 7.658
Authors: Irene Neuner; Cornelius J Werner; Jorge Arrubla; Tony Stöcker; Corinna Ehlen; Hans P Wegener; Frank Schneider; N Jon Shah Journal: Front Hum Neurosci Date: 2014-05-28 Impact factor: 3.169
Authors: Marco Treven; David C B Siebert; Raphael Holzinger; Konstantina Bampali; Jure Fabjan; Zdravko Varagic; Laurin Wimmer; Friederike Steudle; Petra Scholze; Michael Schnürch; Marko D Mihovilovic; Margot Ernst Journal: Br J Pharmacol Date: 2017-12-22 Impact factor: 9.473
Authors: Daniel E Knutson; Revathi Kodali; Branka Divović; Marco Treven; Michael R Stephen; Nicolas M Zahn; Vladimir Dobričić; Alec T Huber; Matheus A Meirelles; Ranjit S Verma; Laurin Wimmer; Christopher Witzigmann; Leggy A Arnold; Lih-Chu Chiou; Margot Ernst; Marko D Mihovilovic; Miroslav M Savić; Werner Sieghart; James M Cook Journal: J Med Chem Date: 2018-03-06 Impact factor: 8.039