Gait Deficits and Loss of Striatal Tyrosine Hydroxlase/Trk-B are Restored Following 7,8-Dihydroxyflavone Treatment in a Progressive MPTP Mouse Model of Parkinson’s Disease

• Published in: Neuroscience 2020-05, Vol.433, p.53-71
• Main Authors: Massaquoi, Michelle S., Liguore, William A., Churchill, Madeline J., Moore, Cindy, Melrose, Heather L., Meshul, Charles K.
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 7,8-dihydroxyflavone; Animals; Corpus Striatum - metabolism; Disease Models, Animal; dorsolateral striatum; Flavones; Gait; Mice; Mice, Inbred C57BL; Parkinson Disease; Parkinsonian Disorders - drug therapy; Parkinson’s disease; sprouting; substantia nigra; Substantia Nigra - metabolism; Tyrosine; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.02.046

•DHF causes motor and striatal TH recovery in a progressive MPTP animal model of PD.•DHF induced motor recovery is not facilitated by restoration of dopamine within the nigrostriatal pathway.•DHF treated mice had an increased expression of the sprouting factor, SCG10, in the striatum and midbrain.•Using a restorative PD animal model, DHF may be a useful treatment for patients with PD. Parkinson’s disease (PD) is caused by neurodegeneration of nigrostriatal neurons, resulting in dopamine (DA) stimulated motor deficits. Like brain derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (DHF) is an agonist of the tropomyosin receptor kinase-B (TrkB) and stimulates the same secondary cascades that promote neuronal growth, survival and differentiation. We used our progressive mouse model of PD by administering increasing doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over 4 weeks (5 days/week), and then treated mice with DHF for 4 weeks after the cessation of the toxin injections (i.e., restoration). Mice treated with DHF recovered motorically, even after MPTP administration. Despite a 75% loss of tyrosine hydroxylase (TH) expression in the dorsolateral (DL) striatum in the MPTP group, mice treated with DHF had a recovery comparable to that found in the respective control. There was no recovery of DA tissue levels within the DL striatum. In both the DL striatum and substantia nigra (SN)/midbrain, phosphorylated TrkB and secondary messengers were significantly increased following DHF compared to the MPTP only group. Expression of the sprouting biomarker, superior cervical ganglion 10 (SCG10), was increased ∼20% in the DL striatum and 66% in the SN/midbrain in mice treated with DHF compared to the MPTP only group. We report that after 4 weeks of progressive MPTP administration, DHF can restore motor deficits and TH within the DL striatum in a TrkB-dependent manner. Our data suggests that DHF may help alleviate motor symptoms of PD and restore the loss of DA terminals within the striatum.