Faculty Collaboration Database

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson's disease. J Neuroinflammation 2012 Oct 23;9:241

Date

10/25/2012

Pubmed ID

23092448

Pubmed Central ID

PMC3488558

DOI

10.1186/1742-2094-9-241

Scopus ID

2-s2.0-84867670576 (requires institutional sign-in at Scopus site)   93 Citations

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.

Author List

Ghosh A, Kanthasamy A, Joseph J, Anantharam V, Srivastava P, Dranka BP, Kalyanaraman B, Kanthasamy AG

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetophenones
Animals
Anti-Inflammatory Agents
Biphenyl Compounds
Chromatography, High Pressure Liquid
Corpus Striatum
Disease Models, Animal
Disease Progression
Dopamine
Dopaminergic Neurons
Dose-Response Relationship, Drug
Encephalitis
Fluoresceins
MPTP Poisoning
Male
Mass Spectrometry
Mice
Mice, Inbred C57BL
Motor Activity
NADPH Oxidases
Neuroglia
Neuroprotective Agents
Neurotransmitter Agents
Nitric Oxide Synthase Type II
Organic Chemicals
Tyrosine
Tyrosine 3-Monooxygenase