title: Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson's disease.
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.
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011, USA.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.forename: Pallavi
authors.initials: P
authors.lastname: Srivastava
authors.forename: Brian P
authors.initials: BP
authors.lastname: Dranka
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology; D005452:Fluoresceins; D020267:MPTP Poisoning / Q000150:complications / Q000188:drug therapy*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018377:Neurotransmitter Agents / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009930:Organic Chemicals; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D005452:Fluoresceins; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D009930:Organic Chemicals; C527766:diapocynin; C435731:fluoro jade; C002744:3-nitrotyrosine; D014443:Tyrosine; C056165:acetovanillone; D052247:Nitric Oxide Synthase Type II; D014446:Tyrosine 3-Monooxygenase; D019255:NADPH Oxidases; D004298:Dopamine