The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model
Background: Dyskinesia or abnormal involuntary movements (AIMs) are a disabling effect of chronic l-DOPA administration and consequent pulsatile stimulation of dopamine receptors. This abnormal activation causes maladaptive changes including upregulation of FosB expression in dynorphin containing st...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2014
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| _version_ | 1826288156864937984 |
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| author | Thornton, E Hassall, M Corrigan, F Vink, R |
| author_facet | Thornton, E Hassall, M Corrigan, F Vink, R |
| author_sort | Thornton, E |
| collection | OXFORD |
| description | Background: Dyskinesia or abnormal involuntary movements (AIMs) are a disabling effect of chronic l-DOPA administration and consequent pulsatile stimulation of dopamine receptors. This abnormal activation causes maladaptive changes including upregulation of FosB expression in dynorphin containing striatal cells. Substance P (SP) is co-localized within dynorphin positive cells and is increased within the substantia nigra by l-DOPA (l-3,4-dihydroxyphenylalanine) treatment. Accordingly, we determined if treatment with a SP NK1 receptor antagonist reduced the onset of l-DOPA induced dyskinesia (LID) in the hemi-parkinsonian rodent model. Methods: Adult male Sprague-Dawley rats underwent unilateral 6-OHDA (6-hydroxydopamine-hydrobromide) lesions of the medial forebrain bundle. At day 21, daily administration commenced of either l-DOPA (6mg/kg plus 15mg/kg of benseraside), l-DOPA with the NK1 antagonist N-acetyl- l-tryptophan (NAT) or equal volume of saline. Animals were tested with the rodent AIM scale assessing axial, contralateral forelimb and orolingual AIMs. Assessment of l-DOPA induced turning was undertaken, and motor function determined using the accelerating rotarod and adjusting step test. Dopaminergic neuronal counts and immunoreactivity for SP and FosB were undertaken. Results: All animals treated with l-DOPA alone developed dyskinesia, whereas combined administration of NAT with l-DOPA significantly reduced onset of AIMs and prevented mild to moderate dyskinesia. In non-dyskinetic NAT treated animals, similar numbers of FosB+ striatal cells were recorded as in saline treated animals. Importantly NAT treatment did not interfere with the anti-parkinsonian effect of l-DOPA. Conclusion: Daily administration of a SP NK1 receptor antagonist may represent a novel treatment regime that reduces the onset of LID whilst conserving motor function. © 2014 Elsevier Ltd. |
| first_indexed | 2024-03-07T02:09:28Z |
| format | Journal article |
| id | oxford-uuid:a01f08e6-ed95-4b4a-bfdb-19e7609d4332 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:09:28Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:a01f08e6-ed95-4b4a-bfdb-19e7609d43322022-03-27T02:03:11ZThe NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent modelJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a01f08e6-ed95-4b4a-bfdb-19e7609d4332EnglishSymplectic Elements at OxfordElsevier2014Thornton, EHassall, MCorrigan, FVink, RBackground: Dyskinesia or abnormal involuntary movements (AIMs) are a disabling effect of chronic l-DOPA administration and consequent pulsatile stimulation of dopamine receptors. This abnormal activation causes maladaptive changes including upregulation of FosB expression in dynorphin containing striatal cells. Substance P (SP) is co-localized within dynorphin positive cells and is increased within the substantia nigra by l-DOPA (l-3,4-dihydroxyphenylalanine) treatment. Accordingly, we determined if treatment with a SP NK1 receptor antagonist reduced the onset of l-DOPA induced dyskinesia (LID) in the hemi-parkinsonian rodent model. Methods: Adult male Sprague-Dawley rats underwent unilateral 6-OHDA (6-hydroxydopamine-hydrobromide) lesions of the medial forebrain bundle. At day 21, daily administration commenced of either l-DOPA (6mg/kg plus 15mg/kg of benseraside), l-DOPA with the NK1 antagonist N-acetyl- l-tryptophan (NAT) or equal volume of saline. Animals were tested with the rodent AIM scale assessing axial, contralateral forelimb and orolingual AIMs. Assessment of l-DOPA induced turning was undertaken, and motor function determined using the accelerating rotarod and adjusting step test. Dopaminergic neuronal counts and immunoreactivity for SP and FosB were undertaken. Results: All animals treated with l-DOPA alone developed dyskinesia, whereas combined administration of NAT with l-DOPA significantly reduced onset of AIMs and prevented mild to moderate dyskinesia. In non-dyskinetic NAT treated animals, similar numbers of FosB+ striatal cells were recorded as in saline treated animals. Importantly NAT treatment did not interfere with the anti-parkinsonian effect of l-DOPA. Conclusion: Daily administration of a SP NK1 receptor antagonist may represent a novel treatment regime that reduces the onset of LID whilst conserving motor function. © 2014 Elsevier Ltd. |
| spellingShingle | Thornton, E Hassall, M Corrigan, F Vink, R The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model |
| title | The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model |
| title_full | The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model |
| title_fullStr | The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model |
| title_full_unstemmed | The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model |
| title_short | The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model |
| title_sort | nk1 receptor antagonist n acetyl l tryptophan reduces dyskinesia in a hemi parkinsonian rodent model |
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