Parkinson's disease (PD) affects at least 1 million individuals in the US alone. Although much is known about its pathophysiology and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained impact on the prevention of PD or on attenuation of its progress. However, clinical evidence suggests that physical exercise is such a treatment, and this is supported by studies of animal models of the dopamine (DA) deficiency associated with the motor symptoms of PD. Moreover, exercise is a practical and sustainable therapeutic intervention likely to act simultaneously on most if not all of the cellular events capable of protecting DA neurons and restoring DA function. This proposal is designed test the hypothesis that exercise increases DA function and protects DA neurons against toxic insult due in part to increased neurotrophic factor (NTF) signaling, protection of mitochondrial respiration, and stimulation of angiogenesis. An MPTP mouse model will be used to test this hypothesis.
Aim 1. To determine the effects of exercise on the impact of MPTP on dopaminergic function (1a) the optimal temporal relationship between exercise and toxin exposure will first be established, thus exploring both protection (exercise before toxin) and rescue (exercise after toxin). (1b) The impact of the optimal exercise paradigm on DA cell loss and on changes in pre- and post-synaptic DA receptors will then be assessed. (1c) Levels of DA and metabolites in striatal tissue and extracellular fluid will be measured in MPTP animals treated with exercise as dictated by Aim 1a. (1d) Mitochondrial respiration will be assessed after MPTP exercise.
Aim 2. To assess the role of NTFs in exercise-induced protection members of four distinct NTF families known to protect DA neurons will be examined: GDNF, BDNF, MANF, and VEGF. (2a) The temporal and anatomical profile of NTF changes will be determined after exercise, MPTP, and the optimal combination of MPTP and exercise. (b) The ability of exogenous NTF to mimic the effects of exercise identified in Aim 1 will then be assessed. (2c) The NTFs and/or their receptors suggested by Aim 2a and 2b will be conditionally knocked out to determine if this increases the toxin impact of MPTP and reduces the protective impact of exercise, thereby strengthening the hypothesis of a causal relationship between NTF and exercise-induced protection.
Aim 3. To examine the role of angiogenesis in exercise- and NTF-induced neuroprotection, (a) vasculature be assessed in substantia nigra, striatum, and cortex using BrdU to measure new cells and PECAM-1 (CD31), to mark blood vessels. (3b) FITC-conjugated tomato lectin will be used to detect patent blood vessels. (3c) A 3-dimensional analysis of vascular density will be performed. (3d) Finally, expression of angiogenesis-promoting proteins, including angiopoetins 1 and 2, will be measured. These results will provide the basis for the next iteration of a research program focusing on additional mechanisms underlying exercise-induced protection, provide stronger evidence for exercise-induced protection in PD, and establish targets for pharmacological treatment of the condition.

Public Health Relevance

Parkinson's disease affects well over a million individuals in the US alone. Although we know a good deal about how the brain is affected by the disease, there are no pharmacological treatments shown to have a significant and sustained impact on the prevention of the disease or on the attenuation of its progress. Such treatments are urgently needed. Clinical evidence suggests that physical exercise is just such a treatment, and studies of animal models of the dopamine loss associated with the motor symptoms of the condition further support this hypothesis. This study is designed to test that hypothesis. Such a demonstration would not only strengthen the case for advising individuals to engage in exercise, but may also provide insights into drug development for the condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070825-02
Application #
8337710
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sieber, Beth-Anne
Project Start
2011-09-30
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$581,902
Indirect Cost
$83,920
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jaumotte, Juliann D; Wyrostek, Stephanie L; Zigmond, Michael J (2016) Protection of cultured dopamine neurons from MPP(+) requires a combination of neurotrophic factors. Eur J Neurosci 44:1691-9
Ayadi, Amina El; Zigmond, Michael J; Smith, Amanda D (2016) IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases. Exp Brain Res 234:1863-1873
Smeyne, M; Sladen, P; Jiao, Y et al. (2015) HIF1? is necessary for exercise-induced neuroprotection while HIF2? is needed for dopaminergic neuron survival in the substantia nigra pars compacta. Neuroscience 295:23-38
Kopra, Jaakko; Vilenius, Carolina; Grealish, Shane et al. (2015) GDNF is not required for catecholaminergic neuron survival in vivo. Nat Neurosci 18:319-22
Shan, Lufei; Diaz, Oscar; Zhang, Yajun et al. (2015) L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or L-Dopa history. Brain Res 1618:261-9
Zigmond, Michael J; Smeyne, Richard J (2014) Exercise: is it a neuroprotective and if so, how does it work? Parkinsonism Relat Disord 20 Suppl 1:S123-7
Eakin, Katharine; Baratz-Goldstein, Renana; Pick, Chiam G et al. (2014) Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One 9:e90617
Stetler, R Anne; Leak, Rehana K; Gan, Yu et al. (2014) Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance. Prog Neurobiol 114:58-83
Jaumotte, Juliann D; Zigmond, Michael J (2014) Comparison of GDF5 and GDNF as neuroprotective factors for postnatal dopamine neurons in ventral mesencephalic cultures. J Neurosci Res 92:1425-33
Parmar, Mayur S; Jaumotte, Juliann D; Wyrostek, Stephanie L et al. (2014) Role of ERK1, 2, and 5 in dopamine neuron survival during aging. Neurobiol Aging 35:669-79

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