Stephen G Nuara1, Jim C Gourdon1, Shawn Maddaford2, Philippe Huot3,4,5. 1. Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada. 2. Talon Pharmaceuticals, Mississauga, ON, Canada. 3. Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, H3A 2B4, Canada. philippe.huot@mcgill.ca. 4. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. philippe.huot@mcgill.ca. 5. Department of Neuroscience, Division of Neurology, Movement Disorder Clinic, McGill University Health Centre, Montreal, QC, Canada. philippe.huot@mcgill.ca.
Abstract
PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.
PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.
Authors: Susan H Fox; Regina Katzenschlager; Shen-Yang Lim; Bernard Ravina; Klaus Seppi; Miguel Coelho; Werner Poewe; Olivier Rascol; Christopher G Goetz; Cristina Sampaio Journal: Mov Disord Date: 2011-10 Impact factor: 10.338
Authors: Imane Frouni; Adjia Hamadjida; Cynthia Kwan; Dominique Bédard; Vaidehi Nafade; Fleur Gaudette; Stephen G Nuara; Jim C Gourdon; Francis Beaudry; Philippe Huot Journal: Neuropharmacology Date: 2019-07-25 Impact factor: 5.250
Authors: Fleur Gaudette; Adjia Hamadjida; Dominique Bédard; Stephen G Nuara; Francis Beaudry; Philippe Huot Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2017-07-15 Impact factor: 3.205
Authors: Miguel Fribourg; José L Moreno; Terrell Holloway; Davide Provasi; Lia Baki; Rahul Mahajan; Gyu Park; Scott K Adney; Candice Hatcher; José M Eltit; Jeffrey D Ruta; Laura Albizu; Zheng Li; Adrienne Umali; Jihyun Shim; Alexandre Fabiato; Alexander D MacKerell; Vladimir Brezina; Stuart C Sealfon; Marta Filizola; Javier González-Maeso; Diomedes E Logothetis Journal: Cell Date: 2011-11-23 Impact factor: 41.582
Authors: Fleur Gaudette; Adjia Hamadjida; Dominique Bédard; Stephen G Nuara; Jim C Gourdon; Véronique Michaud; Francis Beaudry; Philippe Huot Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2018-06-19 Impact factor: 3.205
Authors: Javier González-Maeso; Rosalind L Ang; Tony Yuen; Pokman Chan; Noelia V Weisstaub; Juan F López-Giménez; Mingming Zhou; Yuuya Okawa; Luis F Callado; Graeme Milligan; Jay A Gingrich; Marta Filizola; J Javier Meana; Stuart C Sealfon Journal: Nature Date: 2008-02-24 Impact factor: 49.962
Authors: Adjia Hamadjida; Stephen G Nuara; Dominique Bédard; Fleur Gaudette; Francis Beaudry; Jim C Gourdon; Philippe Huot Journal: Neuropharmacology Date: 2018-06-30 Impact factor: 5.250