Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency
Abstract
We are testing the hypothesis that exercise is neuroprotective in animal models of the dopamine (DA) deficiency in Parkinson's disease. Our studies include mice or rats provided access to a running wheel and subsequently treated with MPTP (mice) or 6-hydroxydopamine (rats) and monkeys provided access to a treadmill and subsequently treated with MPTP. Typically, the exercise occurs for 3 months prior to the toxin treatment and often for 1-2 months thereafter. Our findings indicate that exercise reduces the behavioral impairments elicited by the dopaminergic neurotoxins as well as the loss of DA neurons as assessed by PET imaging and biochemical or histochemical assessment of tissue samples. Our studies are focused on one of several possible explanations for the beneficial effects of exercise: an exercise-induced increase in the expression of neurotrophic factors, particularly GDNF. Our observations indicate that GDNF can reduce the vulnerability of DA neurons, in part due to the activation of key intracellular cascades. We also find that mild cellular stress itself can provide protection against more intensive stress, a form of preconditioning. We conclude that dopamine neurons have the capacity to respond to intracellular and extracellular signals by triggering endogenous neuroprotective mechanisms. This raises the possibility that some individuals with Parkinson's disease suffer from a reduction of these neuroprotective mechanisms, and that treatments that boost these mechanisms - including exercise - may provide therapeutic benefit.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Exercise-induced myokines influence cell survival, neurogenesis, neuroinflammation, protein homoeostasis, oxidative stress, and protein modification.
“exercise-induced myokines that influence cell survival, neurogenesis, neuroinflammation, protein homoeostasis, oxidative stress, and protein modification.502,503”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [503]
Cites
Exercise: a behavioral intervention to enhance brain health and plasticity
Cotman, C. (2002) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)02143-4 · Cited by 2,739 · see citing works
Exercise builds brain health: key roles of growth factor cascades and inflammation
Cotman, C. W., Berchtold, N. C., & Christie, L.-A. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.06.011 · Cited by 2,268 · see citing works
Goodwin, V. A., Richards, S. H., Taylor, R. S., Taylor, A. H., & Campbell, J. L. (2008) · Movement Disorders · doi:10.1002/mds.21922 · Cited by 922 · see citing works
Compensations after lesions of central dopaminergic neurons: some clinical and basic implications
Zigmond, M. J., Abercrombie, E. D., Berger, T. W., Grace, A. A., & Stricker, E. M. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90112-n · Cited by 609 · see citing works
Self-citationNavarro, A., Gómez, C., López-Cepero, J. M., & Boveris, A. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00208.2003 · Cited by 464 · see citing works
Tillerson, J. L., Caudle, W. M., Reverón, M. E., & Miller, G. W. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00096-4 · Cited by 399 · see citing works
Physical activity and the risk of Parkinson disease
Chen, H., Zhang, S. M., Schwarzschild, M. A., Hernán, M. A., & Ascherio, A. (2005) · Neurology · doi:10.1212/01.wnl.0000151960.28687.93 · Cited by 371 · see citing works
Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine
Tillerson, J. L., Cohen, A. D., Philhower, J., Miller, G. W., Zigmond, M. J., & Schallert, T. J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-12-04427.2001 · Cited by 357 · see citing works
Self-citationPresymptomatic compensation in Parkinson's disease is not dopamine-mediated
Bézard, E., Gross, C. E., & Brotchie, J. M. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(03)00038-9 · Cited by 351 · see citing works
Murphy, L. O., MacKeigan, J. P., & Blenis, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.24.1.144-153.2004 · Cited by 332 · see citing works
Petzinger, G. M., Walsh, J. P., Akopian, G., Hogg, E., Abernathy, A., Arevalo, P., Turnquist, P., Vučković, M., Fisher, B. E., Togasaki, D. M., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1069-07.2007 · Cited by 329 · see citing works
c-fos regulates neuronal excitability and survival
Zhang, J., Zhang, D., McQuade, J. M. S., Behbehani, M. M., Tsien, J. Z., & Xu, M. (2002) · Nature Genetics · doi:10.1038/ng859 · Cited by 328 · see citing works
Effects of Exercise on Gene-Expression Profile in the Rat Hippocampus
Tong, L., Shen, H., Perreau, V. M., Balázs, R., & Cotman, C. W. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0427 · Cited by 325 · see citing works
Fisher, B. E., Petzinger, G. M., Nixon, K., Hogg, E., Bremmer, S., Meshul, C. K., & Jakowec, M. W. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20162 · Cited by 311 · see citing works
Exercise-induced cardioprotection against myocardial ischemia–reperfusion injury
Powers, S. K., Quindry, J. C., & Kavazis, A. N. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.02.006 · Cited by 273 · see citing works
Fukunaga, K., & Miyamoto, E. (1998) · Molecular Neurobiology · doi:10.1007/bf02740604 · Cited by 256 · see citing works
Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF
Cohen, A. D., Tillerson, J. L., Smith, A. D., Schallert, T., & Zigmond, M. J. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01657.x · Cited by 243 · see citing works
Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism
Faherty, C. J., Shepherd, K. R., Herasimtschuk, A., & Smeyne, R. J. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.08.008 · Cited by 241 · see citing works
Self-citationImpact of physical therapy for Parkinson's disease: A critical review of the literature
Kwakkel, G., de Goede, C. J. T., & van Wegen, E. E. H. (2007) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(08)70053-1 · Cited by 213 · see citing works
Herman, T., Giladi, N., & Hausdorff, J. M. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-008-0139-z · Cited by 193 · see citing works
Forced Nonuse in Unilateral Parkinsonian Rats Exacerbates Injury
Tillerson, J. L., Cohen, A. D., Caudle, W. M., Zigmond, M. J., Schallert, T. J., & Miller, G. W. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-15-06790.2002 · Cited by 163 · see citing works
Self-citationAscensão, A. A. M. R., Ferreira, R. M., & Magalhães, J. (2006) · International Journal of Cardiology · doi:10.1016/j.ijcard.2006.04.076 · Cited by 160 · see citing works
The Role of Physical Exercise in the Occurrence of Parkinson's Disease
Sasco, A. J., Paffenbarger, R. S., Gendre, I., & Wing, A. L. (1992) · Archives of Neurology · doi:10.1001/archneur.1992.00530280040020 · Cited by 146 · see citing works
Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli
Kavazis, A. N., McClung, J. M., Hood, D. A., & Powers, S. K. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01231.2007 · Cited by 144 · see citing works
Ding, Y. M., Jaumotte, J. D., Signore, A. P., & Zigmond, M. J. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02415.x · Cited by 137 · see citing works
Self-citationHornykiewicz, O. (1993) · PubMed · Cited by 132 · see citing works
Steiner, B., Winter, C., Hosman, K., Siebert, E., Kempermann, G., Petrus, D. S., & Kupsch, A. R. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2005.11.004 · Cited by 127 · see citing works
O’Dell, S. J., Gross, N. B., Fricks, A. N., Casiano, B. D., Nguyen, T. B., & Marshall, J. F. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.10.042 · Cited by 118 · see citing works
Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys
Gash, D. M., Zhang, Z., Cass, W. A., Ovadia, A., Simmerman, L. A., Martin, D., Russell, D. A., Collins, F., Hoffer, B. J., & Gerhardt, G. A. (1995) · The Journal of Comparative Neurology · doi:10.1002/cne.903630302 · Cited by 118 · see citing works
Salvatore, M. F., Zhang, J., Large, D. M., Wilson, P. E., Gash, C. R., Thomas, T. C., Haycock, J. W., Bing, G., Stanford, J. A., Gash, D. M., et al. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02496.x · Cited by 108 · see citing works
Hebert, M. A., & Gerhardt, G. A. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36878-8 · Cited by 108 · see citing works
Treadmill training ameliorates dopamine loss but not behavioral deficits in hemi-Parkinsonian rats
Poulton, N. P., & Muir, G. D. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2004.12.006 · Cited by 104 · see citing works
Glorioso, C. A., Sabatini, M., Unger, T. L., Hashimoto, T., Monteggia, L. M., Lewis, D. A., & Mirnics, K. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001835 · Cited by 100 · see citing works
Self-citationEnriched environment improves motor function in intact and unilateral dopamine-depleted rats
Jadavji, N. M., Kolb, B. E., & Metz, G. A. S. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.03.027 · Cited by 94 · see citing works
Mabandla, M. V., Kellaway, L. A., Gibson, A. S. C., & Russell, V. A. (2004) · Metabolic Brain Disease · doi:10.1023/b:mebr.0000027416.13070.c3 · Cited by 89 · see citing works
Self-citationUgarte, S. D., Lin, E., Klann, E., Zigmond, M. J., & Perez, R. G. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10632 · Cited by 89 · see citing works
Self-citationEnvironmental risk factors of young onset Parkinson's disease: a case-control study
Tsai, C. H., Lo, S. K., See, L., Chen, H. Z., Chen, R., Weng, Y.-H., Chang, F., & Lu, C. (2002) · Clinical Neurology and Neurosurgery · doi:10.1016/s0303-8467(02)00027-6 · Cited by 89 · see citing works
The effects of exercise training on [3H]-spiperone binding in rat striatum
Gilliam, P. E., Spirduso, W. W., Martin, T. P., Walters, J., Wilcox, R. E., & Farrar, R. P. (1984) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(84)90008-x · Cited by 79 · see citing works
Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson's disease
Howells, F. M., Russell, V. A., Mabandla, M. V., & Kellaway, L. A. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.06.044 · Cited by 69 · see citing works
Self-citationUrakawa, S., Hida, H., Masuda, T., Misumi, S., Kim, T.-S., & Nishino, H. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.10.038 · Cited by 63 · see citing works
The mechanism by which exercise modifies brain function
Sutoo, D., & Akiyama, K. (1996) · Physiology & Behavior · doi:10.1016/0031-9384(96)00011-x · Cited by 57 · see citing works
Anstrom, K. K., Schallert, T. J., Woodlee, M. T., Shattuck, A., & Roberts, D. C. S. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.01.028 · Cited by 46 · see citing works
Effect of exercise on dopamine neuron survival in prenatally stressed rats
Mabandla, M. V., Kellaway, L. A., Daniels, W. M. U., & Russell, V. A. (2009) · Metabolic Brain Disease · doi:10.1007/s11011-009-9161-6 · Cited by 38 · see citing works
Self-citationLeak, R. K., Liou, A. K. F., & Zigmond, M. J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04149.x · Cited by 36 · see citing works
Self-citationLindgren, N., Leak, R. K., Carlson, K. M., Smith, A. D., & Zigmond, M. J. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21641 · Cited by 32 · see citing works
Self-citationBarnea, A., Roberts, J., & Croll, S. D. (2004) · Brain Research · doi:10.1016/j.brainres.2004.06.018 · Cited by 25 · see citing works
Adaptation to chronic MG132 reduces oxidative toxicity by a CuZnSOD‐dependent mechanism
Leak, R. K., Zigmond, M. J., & Liou, A. K. F. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05459.x · Cited by 24 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The influence of skeletal muscle on systemic aging and lifespan
Demontis, F., Piccirillo, R., Goldberg, A. L., & Perrimon, N. (2013) · Aging Cell · doi:10.1111/acel.12126 · Cited by 238 · see citing works
It Is Not About the Bike, It Is About the Pedaling: Forced Exercise and Parkinson's Disease
Alberts, J. L., Linder, S. M., Penko, A. L., Lowe, M. J., & Phillips, M. (2011) · Exercise and Sport Sciences Reviews · doi:10.1097/jes.0b013e31822cc71a · Cited by 192 · see citing works
Rothman, S. M., Griffioen, K. J., Wan, R., & Mattson, M. P. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06525.x · Cited by 185 · see citing works
Fox, C., Ebersbach, G., Ramig, L., & Sapir, S. (2012) · Parkinson's Disease · doi:10.1155/2012/391946 · Cited by 178 · see citing works
Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
Real, C. C., Ferreira, A. F. B., Chaves-Kirsten, G. P., Torrão, A. S., Pires, R. S., & Britto, L. R. G. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.01.060 · Cited by 109 · see citing works
Immune system gene dysregulation in autism and schizophrenia
Michel, M., Schmidt, M. J., & Mirnics, K. (2012) · Developmental Neurobiology · doi:10.1002/dneu.22044 · Cited by 107 · see citing works
Self-citationSleep Disturbances in Alzheimer’s and Parkinson’s Diseases
Rothman, S. M., & Mattson, M. P. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8181-2 · Cited by 102 · see citing works
Neurotrophic factors in Parkinson’s disease are regulated by exercise: Evidence-based practice
da Silva, P. G. C., Domingues, D. D., de Carvalho, L. A., Allodi, S., & Correa, C. L. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.02.017 · Cited by 87 · see citing works
Exercise does not protect against MPTP-induced neurotoxicity in BDNF happloinsufficent mice
Gerecke, K. M., Jiao, Y., Pagala, V., & Smeyne, R. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043250 · Cited by 53 · see citing works
Self-citationGerecke, K. M., Kolobova, A., Allen, S., & Fawer, J. L. (2013) · Brain Research · doi:10.1016/j.brainres.2013.02.027 · Cited by 37 · see citing works
- Authors
- Zigmond, M. J., Cameron, J. L., Leak, R. K., Mirnics, K., Russell, V. A., Smeyne, R. J., & Smith, A. D.
- Affiliations
- University of Pittsburgh (US)
- University of Cape Town (ZA)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Zigmond, Michael J.
- Venue
- Parkinsonism & Related Disorders
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 15
- Pages
- S42-S45
- ISSN
- 1353-8020 (ISSN-L)
- OpenAlex
- W2164459320
- Cited by
- 121
- References
- 47
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 5 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 8 · 2013: 18 · 2012: 13
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Parkinsonism & Related Disorders (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Army
- U.S. Public Health Service (TW008040, DA018087, MH067234, NS053471, NS45698, NS045906, AG021494, NS19608)
- National Parkinson Foundation
- American Parkinson's Disease Foundation
- Michael J. Fox Foundation for Parkinson's Research
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- physical activity, neuroprotection
- MeSH terms
- Animals, Disease Models, Animal, Dopamine, Humans, Neurons, Parkinson Disease, Secondary, Physical Conditioning, Animal, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Oxidopamine, Glial Cell Line-Derived Neurotrophic Factor, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
