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.

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

“…The substantia nigra was analyzed for the presence of tyrosine hydroxylase (TH)-neuronal profiles as previously described [22]. In short, serial sections of 7 μm were stained for TH (Sigma- Aldrich, 1:100).…”

In-vivo evaluation of apocynin for prevention of Helicobacter pylori-induced gastric carcinogenesis

“…In a mouse model of zymosan-induced acute arthritis, oral administration of apocynin significantly improved proteoglycan synthesis in the knee-joint (Hougee et al, 2006). Apocynin treatment in a marmoset model of Parkinson's disease mitigated the disease progression, limiting the parkinsonian signs and motor-function deterioration (Philippens et al, 2013). Moreover, a clinical trial using nebulized apocynin demonstrated a reduction of ROS concentrations in the exhaled breath condensate of asthma patients (Stefanska et al, 2012).…”

Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease

“…15 h post L‐DOPA dose during treatment phase (OFF scores), and during the last 10 days also 2 h post dose (ON scores) 15. Body weight was measured every week and every time before drug administration and expressed relative to individual baseline (i.e.…”

“…Dopamine positive neurons of the Substantia nigra pars compacta (SNpc) were counted with tyrosine hydroxylase immune reactive (TH‐IR) staining by a blinded technician 15, 16…”