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Open Access Highly Accessed Research

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Anamitra Ghosh1, Arthi Kanthasamy1, Joy Joseph2, Vellareddy Anantharam1, Pallavi Srivastava1, Brian P Dranka2, Balaraman Kalyanaraman2 and Anumantha G Kanthasamy1*

Author Affiliations

1 Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA, 50011, USA

2 Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

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Journal of Neuroinflammation 2012, 9:241  doi:10.1186/1742-2094-9-241

Published: 23 October 2012

Abstract

Background

Parkinson’s disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.

Methods

Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin.

Results

Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD.

Conclusions

Collectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients.

Keywords:
Parkinson’s disease; Oxidative stress; Neuroinflammation; Neuroprotection; Dopamine; Microglia; Diapocynin; Astrocytes