title: Intervention with 7,8-dihydroxyflavone blocks further striatal terminal loss and restores motor deficits in a progressive mouse model of Parkinson's disease.
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.
authors: Research Services, VA Medical Center/Portland, Mail Code: RD-29, 3710 S.W. Veterans Hospital Road, Portland, OR 97239, United States.
authors: M D
authors: MD
authors: Sconce
authors: Research Services, VA Medical Center/Portland, Mail Code: RD-29, 3710 S.W. Veterans Hospital Road, Portland, OR 97239, United States.
authors: M J
authors: MJ
authors: Churchill
authors: Research Services, VA Medical Center/Portland, Mail Code: RD-29, 3710 S.W. Veterans Hospital Road, Portland, OR 97239, United States.
authors: C
authors: C
authors: Moore
authors: Research Services, VA Medical Center/Portland, Mail Code: RD-29, 3710 S.W. Veterans Hospital Road, Portland, OR 97239, United States; Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States; Department of Pathology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States. Electronic address: meshulc@ohsu.edu.
authors: C K
authors: CK
authors: Meshul
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002135:Calcium-Binding Proteins; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D047309:Flavones / Q000494:pharmacology*; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D020813:Receptor, trkB / Q000378:metabolism; D050777:Stathmin; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C485383:6,7-dihydroxyflavone; D000978:Antiparkinson Agents; D002135:Calcium-Binding Proteins; D047309:Flavones; D047908:Intracellular Signaling Peptides and Proteins; D050777:Stathmin; C512849:Stmn2 protein, mouse; D014446:Tyrosine 3-Monooxygenase; D020813:Receptor, trkB; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: 7,8-dihydroxyflavone; MPTP; Parkinson’s disease; collateral sprouting; motor behavior; mouse model