The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model

Journal article

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.

Authors: Thornton, E; Hassall, M; Corrigan, F; Vink, R

• Publisher: Elsevier
• Journal: Parkinsonism and Related Disorders
• Volume: 20
• Issue: 5
• Pages: 508-513
• Publication date: 2014-01-01
• DOI: 10.1016/j.parkreldis.2014.02.008
• EISSN: 1873-5126
• ISSN: 1353-8020
• Language: English
• Keywords: Dyskinesia; Motor function; FosB; L-DOPA; Substance P; Tachykinin NK1 receptor