title: Benserazide dosing regimen affects the response to L-3,4-dihydroxyphenylalanine in the 6-hydroxydopamine-lesioned rat.
abstract: Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We now assess the effect of dose, timing, and supplemental administration of benserazide on the rotational response induced by L-DOPA in unilateral 6-hydroxydopamine-lesioned rats. L-DOPA (12.5 mg/kg, p.o.) concomitant with benserazide (3.125-15 mg/kg, p.o.) produced a dose-dependent increase in contraversive rotation compared with the effects of L-DOPA alone. The optimal L-DOPA response was achieved with 10 mg/kg of benserazide and this dose was used in subsequent experiments. When L-DOPA treatment was delayed for 1, 2, or 3 h after benserazide, the rotational response declined suggesting loss of AADC inhibition. Unexpectedly, there was also a progressive decline in response when benserazide and L-DOPA were given together but at increasingly later time points of 08.00, 09.00, 10.00, and 11.00 h. To assess supplemental administration of benserazide, an additional dose was given 2 h after the initial benserazide/L-DOPA treatment. This produced a further increase in the number of contralateral rotations indicating that the effect of benserazide declines while plasma levels of L-DOPA are maintained. Therefore, optimization of the dose and timing of benserazide administration is essential to achieve a consistent L-DOPA response in 6-hydroxydopamine-lesioned rats. These findings may have implications for the way in which peripheral AADC inhibitors are used in the treatment of PD.
authors.affiliation: Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK.
authors.forename: Kayhan A
authors.initials: KA
authors.lastname: Tayarani-Binazir
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jackson
authors.forename: Isobel
authors.initials: I
authors.lastname: Strang
authors.forename: Mark
authors.initials: M
authors.lastname: Jairaj
authors.forename: Sarah
authors.initials: S
authors.lastname: Rose
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
mesh_terms: D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001545:Benserazide / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007980:Levodopa / Q000008:administration & dosage / Q000819:agonists*; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004791:Enzyme Inhibitors; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine