Intervention with 7,8-dihydroxyflavone blocks further striatal terminal loss and restores motor deficits in a progressive mouse model of Parkinson's disease

Neuroscience. 2015 Apr 2:290:454-71. doi: 10.1016/j.neuroscience.2014.12.080. Epub 2015 Feb 2.

Abstract

Parkinson's disease (PD) is a progressive neurological disorder and current therapies help alleviate symptoms, but are not disease modifying. In the flavonoid class of compounds, 7,8-dihydroxyflavone (7,8-DHF) has been reported to elicit tyrosine kinase receptor B (TrkB) dimerization and autophosphorylation that further stimulates signaling cascades to promote cell survival/growth, differentiation, and plasticity. In this study we investigated if 7,8-DHF could prevent further loss of dopaminergic cells and terminals if introduced at the midpoint (i.e. intervention) of our progressive mouse model of PD. In our model, 1-methyl-4phenyl-1,2,3,6-tetrahyrdopyridine (MPTP) is administered with increased doses each week (8, 16, 24, 32-kg/mg) over a 4-week period. We found that despite 4 weeks of MPTP treatment, animals administered 7,8-DHF starting at the 2-week time period maintained 54% of the tyrosine hydroxylase (TH) levels within the dorsolateral (DL) striatum compared to the vehicle group, which was comparable to animals treated with MPTP for 2 weeks and was significantly greater compared to animals treated with MPTP for the full 4 weeks. Animals treated with MPTP and 7,8-DHF also demonstrated increased levels of, a sprouting-associated protein, superior cervical ganglion-10 (SCG10), phosphorylated TrkB (pTrkB), and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) within the DL striatum and substantia nigra (SN) compared to the 4-week MPTP-treated animals. In addition, motor deficits seen in the 2- and 4-week MPTP-treated animals were restored following administration of 7,8-DHF. We are reporting here for the first time that intervention with 7,8-DHF blocks further loss of dopaminergic terminals and restores motor deficits in our progressive MPTP mouse model. Our data suggest that 7,8-DHF has the potential to be a translational therapy in PD.

Keywords: 7,8-dihydroxyflavone; MPTP; Parkinson’s disease; collateral sprouting; motor behavior; mouse model.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology*
  • Calcium-Binding Proteins
  • Corpus Striatum / drug effects*
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology
  • Flavones / pharmacology*
  • Forelimb / drug effects
  • Forelimb / physiopathology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / pathology
  • MPTP Poisoning / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Phosphorylation / drug effects
  • Random Allocation
  • Receptor, trkB / metabolism
  • Stathmin
  • Substantia Nigra / drug effects
  • Substantia Nigra / pathology
  • Substantia Nigra / physiopathology
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • 6,7-dihydroxyflavone
  • Antiparkinson Agents
  • Calcium-Binding Proteins
  • Flavones
  • Intracellular Signaling Peptides and Proteins
  • Stathmin
  • Stmn2 protein, mouse
  • Tyrosine 3-Monooxygenase
  • Receptor, trkB
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3