title: The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats.
abstract: The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets. Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia. H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Papathanou
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Iravani
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Jackson
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Stockwell
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Strang
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK.
authors.forename: Bai-Yun
authors.initials: BY
authors.lastname: Zeng
authors.affiliation: Abbott Healthcare B.V., (formerly Solvay Pharmaceuticals Research Laboratories), Weesp, The Netherlands.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McCreary
authors.affiliation: Neurodegenerative Disease Research Group, School of Biomedical Sciences, King׳s College London, Hodgkin Building, London, SE1 1UL, UK. Electronic address: sarah.rose@kcl.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rose
mesh_terms: D000818:Animals; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D020820:Dyskinesias / Q000188:drug therapy* / Q000503:physiopathology; D017442:Histamine Agonists / Q000627:therapeutic use*; D007093:Imidazoles / Q000627:therapeutic use*; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017442:Histamine Agonists; D007093:Imidazoles; D010880:Piperidines; C085755:4-(1H-imidazol-4-ylmethyl)piperidine; D007980:Levodopa; D016627:Oxidopamine
keywords: 5HT(1A) and H(3) receptors; Dyskinesia; NMDA; Parkinson׳s disease; l-Dopa