Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson’s disease
Open accessAbstract
Increasing the function of residual dopaminergic neurons in the nigra of PD patients is an important area of research as it may eventually compensate the loss. Although tyrosine hydroxylase (TH) is the rate-limiting enzyme in the dopamine (DA) biosynthesis pathway, there are no effective drugs/molecules to upregulate TH and increase the production of DA in nigral dopaminergic neurons. This study underlines the importance of aspirin in stimulating the expression of TH and increasing the level of DA in dopaminergic neurons. At low doses, aspirin increased the expression of TH and the production of DA in mouse MN9D dopaminergic neuronal cells. Accordingly, oral administration of aspirin increased the expression of TH in the nigra and upregulated the level of DA in striatum of normal C57/BL6 mice and aged A53T α-syn transgenic mice. Oral aspirin also improved locomotor activities of normal mice and A53T transgenic mice. While investigating mechanisms, we found the presence of cAMP response element (CRE) in the promoter of TH gene and the rapid induction of cAMP response element binding (CREB) activation by aspirin in dopaminergic neuronal cells. Aspirin treatment also increased the level of phospho-CREB in the nigra of C57/BL6 mice. The abrogation of aspirin-induced expression of TH by siRNA knockdown of CREB and the recruitment of CREB to the TH gene promoter by aspirin suggest that aspirin stimulates the transcription of TH in dopaminergic neurons via CREB. These results highlight a new property of aspirin in stimulating the TH-DA pathway, which may be beneficial in PD patients. Graphical Abstract ᅟ.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
CREB is directly involved in regulating TH expression in PD.
“Among the mechanisms related to exercise-dependent neuroplasticity, CREB is directly involved in regulating TH expression in PD [193,194].”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [194]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs
VANE, J. R. (1971) · Nature New Biology · doi:10.1038/newbio231232a0 · Cited by 8,605 · see citing works
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469 · see citing works
Lang, A. E., & Lozano, A. M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199810083391506 · Cited by 2,041 · see citing works
Inhibition of NF-κB by Sodium Salicylate and Aspirin
Kopp, E. B., & Ghosh, S. (1994) · Science · doi:10.1126/science.8052854 · Cited by 1,765 · see citing works
ETIOLOGY AND PATHOGENESIS OF PARKINSON'S DISEASE
Olanow, C. W., & Tatton, W. G. (1999) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.22.1.123 · Cited by 1,394 · see citing works
The mechanism of action of aspirin
Vane, J. R., & Botting, R. M. (2003) · Thrombosis Research · doi:10.1016/s0049-3848(03)00379-7 · Cited by 1,225 · see citing works
Selective neuronal vulnerability in Parkinson disease
Surmeier, D. J., Obeso, J. A., & Halliday, G. M. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.178 · Cited by 1,120 · see citing works
Rothwell, P. M., Wilson, M., Price, J. F., Belch, J. F., Meade, T. W., & Mehta, Z. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60209-8 · Cited by 984 · see citing works
Ghosh, A., Roy, A., Liu, X., Kordower, J. H., Mufson, E. J., Hartley, D. M., Ghosh, S., Mosley, R. L., Gendelman, H. E., & Pahan, K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704908104 · Cited by 438 · see citing works
Self-citationAspirin: a review of its neurobiological properties and therapeutic potential for mental illness
Berk, M., Dean, O. M., Drexhage, H. A., McNeil, J. J., Moylan, S., O'Neil, A. E., Davey, C. G., Sanna, L., & Maes, M. H. J. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-74 · Cited by 392 · see citing works
MARSDEN, C. D. (1990) · The Lancet · doi:10.1016/0140-6736(90)91006-v · Cited by 363 · see citing works
Anti-inflammatory drugs and risk of Parkinson disease
Gagne, J. J., & Power, M. C. (2010) · Neurology · doi:10.1212/wnl.0b013e3181d5a4a3 · Cited by 323 · see citing works
Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease
Benner, E. J., Mosley, R. L., Destache, C. J., Lewis, T. B., Jackson-Lewis, V. R., Gorantla, S., Nemachek, C., Green, S. R., Przedborski, S., & Gendelman, H. E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400569101 · Cited by 321 · see citing works
Parkinsonian signs and substantia nigra neuron density in decendents elders without PD
Ross, G. W., Petrovitch, H., Abbott, R. D., Nelson, J. R., Markesbery, W. R., Davis, D. G., Hardman, J. M., Launer, L. J., Masaki, K., Tanner, C. M., et al. (2004) · Annals of Neurology · doi:10.1002/ana.20226 · Cited by 260 · see citing works
Genetic clues to the pathogenesis of Parkinson's disease
Vila, M., & Przedborski, S. (2004) · Nature Medicine · doi:10.1038/nm1068 · Cited by 254 · see citing works
Aspirin and Salicylate Protect Against MPTP‐Induced Dopamine Depletion in Mice
Aubin, N., Curet, O., Deffois, A., & Carter, C. J. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71041635.x · Cited by 214 · see citing works
Up-regulation of Microglial CD11b Expression by Nitric Oxide
Roy, A., Fung, Y. K., Liu, X., & Pahan, K. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600236200 · Cited by 214 · see citing works
Self-citationRoy, A., Jana, M., Kundu, M., Corbett, G. T., Rangaswamy, S. B., Mishra, R. K., Luan, C., Gonzalez, F. J., & Pahan, K. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.022 · Cited by 160 · see citing works
Self-citationBrahmachari, S., Jana, A., & Pahan, K. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803336 · Cited by 159 · see citing works
Self-citationKhasnavis, S., & Pahan, K. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9286-3 · Cited by 138 · see citing works
Self-citationChandra, S., Jana, M., & Pahan, K. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.0054-18.2018 · Cited by 134 · see citing works
Self-citationJana, A., Modi, K. K., Roy, A., Anderson, J. A. D., van Breemen, R. B., & Pahan, K. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9447-7 · Cited by 129 · see citing works
Self-citationKhasnavis, S., Jana, A., Roy, A., Mazumder, M., Bhushan, B., Wood, T., Ghosh, S., Watson, R. L., & Pahan, K. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.338012 · Cited by 117 · see citing works
Self-citationKhasnavis, S., & Pahan, K. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9552-2 · Cited by 112 · see citing works
Self-citationEmerging Roles of CREB-Regulated Transcription Coactivators in Brain Physiology and Pathology
Saura, C. A., & Cardinaux, J. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.10.002 · Cited by 110 · see citing works
Nilsson, S. E., Johansson, B., Takkinen, S., Zarit, S., McClearn, G., Melander, A., & Berg, S. (2003) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-003-0618-y · Cited by 104 · see citing works
Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory
Patel, D. R., Roy, A., Kundu, M., Jana, M., Luan, C.-H., Gonzalez, F. J., & Pahan, K. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802021115 · Cited by 93 · see citing works
Self-citationClinical Use of Aspirin in Treatment and Prevention of Cardiovascular Disease
Dai, Y., & Ge, J. (2011) · Thrombosis · doi:10.1155/2012/245037 · Cited by 92 · see citing works
Brahmachari, S., & Pahan, K. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.1.275 · Cited by 91 · see citing works
Self-citationDasgupta, S., Jana, M., Liu, X., & Pahan, K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301789200 · Cited by 66 · see citing works
Self-citationPPARα Signaling in the Hippocampus: Crosstalk Between Fat and Memory
Roy, A., & Pahan, K. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9582-9 · Cited by 61 · see citing works
Self-citationCorbett, G. T., Roy, A., & Pahan, K. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102624 · Cited by 60 · see citing works
Self-citationResveratrol promotes neurotrophic factor release from astroglia
Zhang, F., Lu, Y., Wu, Q., Liu, J., & Shi, J. (2012) · Experimental Biology and Medicine · doi:10.1258/ebm.2012.012044 · Cited by 57 · see citing works
Up-regulation of Ciliary Neurotrophic Factor in Astrocytes by Aspirin
Modi, K. K., Sendtner, M., & Pahan, K. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.447268 · Cited by 55 · see citing works
Self-citationCREB at the Crossroads of Activity-Dependent Regulation of Nervous System Development and Function
Belgacem, Y. H., & Borodinsky, L. N. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-62817-2_2 · Cited by 55 · see citing works
Khasnavis, S., Roy, A., Ghosh, S., Watson, R. L., & Pahan, K. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9503-3 · Cited by 54 · see citing works
Self-citationGemfibrozil, a Lipid-lowering Drug, Induces Suppressor of Cytokine Signaling 3 in Glial Cells
Ghosh, A., & Pahan, K. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.346932 · Cited by 50 · see citing works
Self-citationMondal, S., Roy, A., & Pahan, K. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0801734 · Cited by 45 · see citing works
Self-citationKern, S., Skoog, I. G., Östling, S., Kern, J., & Börjesson‐Hanson, A. (2012) · BMJ Open · doi:10.1136/bmjopen-2012-001288 · Cited by 43 · see citing works
Testing NF-κB-based Therapy in Hemiparkinsonian Monkeys
Mondal, S., Roy, A., Jana, A., Ghosh, S., Kordower, J. H., & Pahan, K. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9377-9 · Cited by 42 · see citing works
Self-citationChandra, G., Kundu, M., Rangasamy, S. B., Dasarathi, S., Ghosh, S., Watson, R. L., & Pahan, K. (2017) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-017-9771-4 · Cited by 33 · see citing works
Self-citationJana, M., Ghosh, S., & Pahan, K. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2435-1 · Cited by 23 · see citing works
Self-citationRoy, A. (2013) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899.1000158 · Cited by 22 · see citing works
Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement
Modi, K. K., Rangasamy, S. B., Dasarathi, S., Roy, A., & Pahan, K. (2016) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-016-9693-6 · Cited by 22 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
BDNF as a Promising Therapeutic Agent in Parkinson’s Disease
Palasz, E., Wysocka, A., Gasiorowska, A., Chalimoniuk, M., Niewiadomski, W., & Niewiadomska, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031170 · Cited by 504 · see citing works
Dodiya, H. B., Forsyth, C. B., Voigt, R. M., Engen, P. A., Patel, J., Shaikh, M., Green, S. J., Naqib, A., Roy, A., Kordower, J. H., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.12.012 · Cited by 305 · see citing works
Self-citation
- Authors
- Rangasamy, S. B., Dasarathi, S., Pahan, P., Jana, M., & Pahan, K.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Pahan, Kalipada
- Venue
- Journal of Neuroimmune Pharmacology
- Published
- 2018-09-05
- Volume
- 14
- Issue
- 2
- Pages
- 173-187
- ISSN
- 1557-1890 (ISSN-L)
- 1557-1904
- PMC
- PMC6401361
- OpenAlex
- W2892271175
- Cited by
- 49
- References
- 45
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 2 · 2021: 14 · 2020: 4 · 2019: 4 · 2018: 2
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-03-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Neuroimmune Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX002174, I01BX003033)
- National Institutes of Health (NS083054)
- 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 › Neurotransmitter Receptor Influence on Behavior
- Keywords
- low-dose aspirin, tyrosine hydroxylase, dopamine synthesis, dopaminergic neurons, Parkinson's disease, CREB, cAMP response element, gene transcription, substantia nigra, striatum, locomotor activity, MN9D cells
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Cell Line, Dopamine, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Parkinson Disease, Tyrosine 3-Monooxygenase, Transcriptional Activation, Up-Regulation, Cyclic AMP Response Element-Binding Protein, RNA, Small Interfering, Mice, alpha-Synuclein, Dopaminergic Neurons
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
