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JNK inhibition protects dopamine neurons and provides behavioral improvement in a rat 6-hydroxydopamine model of Parkinson's Disease

Academic Article
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Overview

authors

  • Crocker, C. E.
  • Khan, S.
  • Cameron, Michael
  • Robertson, H. A.
  • Robertson, G. S.
  • LoGrasso, Philip

publication date

  • April 2011

journal

  • ACS Chemical Neuroscience  Journal

abstract

  • Parkinson's disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH(+)) neurons in the SNpc by six-fold and reduced the loss of the TH(+) terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (p<0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately two-fold higher than the cell-based IC(50) for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson's disease.
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Research

keywords

  • 6-OHDA
  • JNK
  • Parkinson's disease
  • neuroprotection
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Identity

PubMed Central ID

  • PMC3110072

International Standard Serial Number (ISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/cn1001107

PubMed ID

  • 21666838
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Additional Document Info

start page

  • 207

end page

  • 212

volume

  • 2

issue

  • 4

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