title: Oral treatment with the NADPH oxidase antagonist apocynin mitigates clinical and pathological features of parkinsonism in the MPTP marmoset model.
abstract: This study evaluates the therapeutic efficacy of the NADPH oxidase inhibitor apocynin, isolated as principal bioactive component from the medicinal plant Picrorhiza kurroa, in a marmoset MPTP model of Parkinson's disease (PD). The methoxy-substituted catechol apocynin has a similar structure as homovanillic acid (HVA), a metabolite of dopamine (DA). Apocynin acquires its selective inhibitory capacity of the reactive oxygen species generating NADPH oxidase via metabolic activation by myeloperoxidase (MPO). As MPO is upregulated in activated brain microglia cells of PD patients and in MPTP animal models, the conditions for metabolic activation of apocynin and inhibition of microglia NADPH oxidase are in place. Marmoset monkeys received oral apocynin (100 mg/kg; p.o.) (n = 5) or Gum Arabica (controls; n = 5) three times daily until the end of the study, starting 1 week before PD induction with MPTP (1 mg/kg s.c. for 8 days). Parkinsonian symptoms, motor function, home-cage activity and body weight were monitored to assess the disease development and severity. Post-mortem numbers of the tyrosine hydroxylase expressing DA neurons in the substantia nigra were counted. During the MPTP injections, apocynin limited the body weight loss and relieved parkinsonian symptoms compared to controls (Linear regression, P < 0.05) indicating a reduction of disease progression. During the last test week, apocynin also improved the hand-eye coordination performance compared with vehicle treatment (resp. 39.3 ± 4.5 % and 17.7 ± 6.7 %; P = 0.048) and improved the home cage activity with 32 % (P = 0.029), indicating anti-Parkinson efficacy. Apocynin also increased the number of surviving DA neurons in MPTP-treated marmosets with 8.5 % (P = 0.059), indicating a tendency towards a neuroprotective efficacy. In conclusion, compensation for the loss of DA and its metabolite HVA by apocynin mitigates the PD progression and limits the parkinsonian signs and motor-function deterioration.
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, Lange Kleiweg 161, P.O. Box 3306, 2280 GH, Rijswijk, The Netherlands. philippens@bprc.nl
authors.forename: Ingrid H C H M
authors.initials: IH
authors.lastname: Philippens
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Wubben
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D002144:Callithrix; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; C056165:acetovanillone; D019255:NADPH Oxidases