Parkinson's disease is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substanfia nigra pars compacta, resulfing in severe motor symptoms, which include a tremor at rest, rigidity, bradykinesia, akinesia and postural instability. In addition to motor deficits, there are a variety of non-motor symptoms associated with Parkinson's disease, including olfactory deficits, problems with gastrointesfinal mofility, sleep disturbances, sympathefic denervafion, anxiety, and depression. One of the promising areas of Parkinson's disease therapeufics is the administrafion of growth factors, such as glial cell derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF). Unfortunately, trials with GDNF and BDNF have not been successful, which is due, in part, to drug delivery and pharmacokinefic limitations. In collaboration with the Ye laboratory at Emory University, we have identified a class of orally active TrkB agonists that appear to recapitulate many of the actions of BDNF. Here we propose to test these novel compounds for their ability to restore funcfion in several animal models of Parkinson's disease. Based on preliminary evidence, we hypothesize that our novel orally-active TrkB agonists will restore function in these animal models. To test this hypothesis we propose to determine the ability of the novel TrkB agonists to restore funcfion in the MPTP mouse model (aim 1), to determine the anfiparkinsonian efficacy of the TrkB agonists in a chronic and progressive animal model of the disease that displays motor and non-motor deficits (VMAT2 LO mice, aim 2), and to determine the ability of these compounds to activate TrkB and alleviate symptoms in a non-human primate model of PD. Complefion of these specific aims will help us to determine the potential utility of selecfive and orally-acfive TrkB agonists as a therapeufic intervenfion for Parkinson's disease and posifion us to apply for further support from the NINDS Translafional Research Program.
Parkinson's disease afflicts over one million U.S. citizens. Current dopaminergic treatments have limited efficacy, and often problematic side effects. This project is designed to test a new potential therapeutic intervenfion for the treatment of Parkinson's disease.
|Smith, Yoland; Wichmann, Thomas (2015) The cortico-pallidal projection: an additional route for cortical regulation of the basal ganglia circuitry. Mov Disord 30:293-5|
|Smith, Yoland; Wichmann, Thomas; DeLong, Mahlon R (2014) Corticostriatal and mesocortical dopamine systems: do species differences matter? Nat Rev Neurosci 15:63|
|Larimore, Jennifer; Zlatic, Stephanie A; Gokhale, Avanti et al. (2014) Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes. J Biol Chem 289:14291-300|
|Conn, P Jeffrey; Lindsley, Craig W; Meiler, Jens et al. (2014) Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov 13:692-708|
|Gyoneva, Stefka; Davalos, Dimitrios; Biswas, Dipankar et al. (2014) Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia 62:1345-60|
|Galvan, Adriana; Hu, Xing; Rommelfanger, Karen S et al. (2014) Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys. J Neurophysiol 112:467-79|
|Foster, Daniel J; Gentry, Patrick R; Lizardi-Ortiz, Jose E et al. (2014) M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor's location. J Neurosci 34:3253-62|
|Pancani, Tristano; Bolarinwa, Caroline; Smith, Yoland et al. (2014) M4 mAChR-mediated modulation of glutamatergic transmission at corticostriatal synapses. ACS Chem Neurosci 5:318-24|
|Villalba, R M; Wichmann, T; Smith, Y (2014) Neuronal loss in the caudal intralaminar thalamic nuclei in a primate model of Parkinson's disease. Brain Struct Funct 219:381-94|
|Devergnas, Annaelle; Pittard, Damien; Bliwise, Donald et al. (2014) Relationship between oscillatory activity in the cortico-basal ganglia network and parkinsonism in MPTP-treated monkeys. Neurobiol Dis 68:156-66|
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