Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s disease
Open accessAbstract
Parkinson's disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.
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HDAC5 inhibition attenuates microglial activation and PD-related pathologies in 6-hydroxydopamine-lesioned rats.
“For example, HDAC5 inhibition is effective in attenuating microglial activation and PD-related pathologies in 6-hydroxydopamine (6-OHDA)-lesioned rats.315”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [315]
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Cites
Staging of brain pathology related to sporadic Parkinson’s disease
Braak, H., Tredici, K. D., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00065-9 · Cited by 10,777 · see citing works
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382 · see citing works
Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A.-E., & Lang, A. E. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.13 · Cited by 5,415 · see citing works
Bloem, B. R., Okun, M. S., & Klein, C. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00218-x · Cited by 3,920 · see citing works
AGEING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL SELECTIVITY
FEARNLEY, J. M., & LEES, A. J. (1991) · Brain · doi:10.1093/brain/114.5.2283 · Cited by 3,529 · see citing works
Levodopa and the Progression of Parkinson's Disease
The Parkinson Study Group (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033447 · Cited by 1,844 · see citing works
The SH-SY5Y cell line in Parkinson’s disease research: a systematic review
Xicoy, H., Wieringa, B., & Martens, G. J. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0149-0 · Cited by 1,036 · see citing works
Olsson, M. A., Nikkhah, G., Bentlage, C., & Björklund, A. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-05-03863.1995 · Cited by 625 · see citing works
Recent developments of HDAC inhibitors: Emerging indications and novel molecules
Bondarev, A. D., Attwood, M. M., Jonsson, J., Chubarev, V. N., Tarasov, V. V., & Schiöth, H. B. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14889 · Cited by 440 · see citing works
Greffard, S., Verny, M., Bonnet, A.-M., Beinis, J., Gallinari, C., Meaume, S., Piette, F., Hauw, J., & Duyckaerts, C. J. (2006) · Archives of Neurology · doi:10.1001/archneur.63.4.584 · Cited by 355 · see citing works
Davis, B. M., Salinas‐Navarro, M., Cordeiro, M. F., Moons, L., & Groef, L. D. (2017) · Scientific Reports · doi:10.1038/s41598-017-01747-8 · Cited by 343 · see citing works
Injury-Induced HDAC5 Nuclear Export Is Essential for Axon Regeneration
Cho, Y., Sloutsky, R., Naegle, K. M., & Cavalli, V. (2013) · Cell · doi:10.1016/j.cell.2013.10.004 · Cited by 327 · see citing works
Identification of a Signal-Responsive Nuclear Export Sequence in Class II Histone Deacetylases
McKinsey, T. A., Zhang, C. L., & Olson, E. N. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.18.6312-6321.2001 · Cited by 285 · see citing works
Disease‐modifying strategies for Parkinson's disease
Kalia, L. V., Kalia, S. K., & Lang, A. E. (2015) · Movement Disorders · doi:10.1002/mds.26354 · Cited by 254 · see citing works
Thakur, P. S., Breger, L. S., Lundblad, M., Wan, O. W., Mattsson, B., Luk, K. C., Lee, V. M. ‐., Trojanowski, J. Q., & Björklund, A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710442114 · Cited by 235 · see citing works
Isoform-specific histone deacetylase inhibitors: The next step?
Balasubramanian, S., Verner, E. J., & Buggy, J. J. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.02.013 · Cited by 224 · see citing works
Yuan, H., Sarre, S., Ebinger, G., & Michotte, Y. M. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.10.004 · Cited by 210 · see citing works
HDAC5 is a novel injury‐regulated tubulin deacetylase controlling axon regeneration
Cho, Y., & Cavalli, V. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.160 · Cited by 204 · see citing works
Mai, A., Massa, S., Pezzi, R., Simeoni, S., Rotili, D., Nebbioso, A., Scognamiglio, A., Altucci, L., Loidl, P., & Brosch, G. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049002a · Cited by 185 · see citing works
Regulation of Histone Acetylation by Autophagy in Parkinson Disease
Park, G., Tan, J., Garcia, G., Kang, Y., Salvesen, G. S., & Zhang, Z. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.675488 · Cited by 162 · see citing works
Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases
Porter, N. J., & Christianson, D. W. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.01.004 · Cited by 146 · see citing works
Sharma, S., Taliyan, R., & Singh, S. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.05.052 · Cited by 142 · see citing works
The promise and perils of HDAC inhibitors in neurodegeneration
Didonna, A., & Opal, P. (2014) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.147 · Cited by 120 · see citing works
Taniguchi, M., Carreira, M. B., Cooper, Y. A., Bobadilla, A., Heinsbroek, J. A., Koike, N., Larson, E. B., Balmuth, E. A., Hughes, B. W., Penrod, R. D., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.015 · Cited by 118 · see citing works
Harrison, I. F., Smith, A. D., & Dexter, D. T. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.12.037 · Cited by 115 · see citing works
Herrera, A. J., Tomás‐Camardiel, M., Venero, J. L., Cano, J., & Machado, A. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-004-0121-3 · Cited by 103 · see citing works
Neuroprotective effects of short-chain fatty acids in MPTP induced mice model of Parkinson's disease
Hou, Y., Li, X., Liu, C., Zhang, M., Zhang, X., Ge, S., & Zhao, L. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111376 · Cited by 101 · see citing works
Pinho, B. R., Reis, S., Guedes-Dias, P., Leitão-Rocha, A., Quintas, C., Valentão, P., Andrade, P. B., Santos, M. M., & Oliveira, J. M. A. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.11.024 · Cited by 84 · see citing works
Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders
Gupta, R. V., Ambasta, R. K., & Kumar, P. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117278 · Cited by 79 · see citing works
Rane, P., Shields, J., Heffernan, M., Guo, Y., Akbarian, S., & King, J. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.01.026 · Cited by 78 · see citing works
Wu, Q., Yang, X., Zhang, L., Zhang, Y., & Feng, L. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0199-2 · Cited by 66 · see citing works
Ximenes, J. C. M., Neves, K. R. T., Leal, L. K. A. M., do Carmo, M. R. S., Brito, G. A. D. C., Naffah‐Mazzacoratti, M. D. G., Cavalheiro, É. A., & Viana, G. S. D. B. (2015) · Journal of Neurodegenerative Diseases · doi:10.1155/2015/313702 · Cited by 61 · see citing works
Griffin, E. A., Melas, P. A., Zhou, R. W., Li, Y., Mercado, P., Kempadoo, K. A., Stephenson, S. I., Colnaghi, L., Taylor, K. M., Hu, M., et al. (2017) · Science Advances · doi:10.1126/sciadv.1701682 · Cited by 61 · see citing works
Inhibition of HDAC6 activity protects dopaminergic neurons from alpha-synuclein toxicity
Francelle, L., Outeiro, T. F., & Rappold, G. (2020) · Scientific Reports · doi:10.1038/s41598-020-62678-5 · Cited by 60 · see citing works
Harrison, I. F., Powell, N. M., & Dexter, D. T. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14599 · Cited by 59 · see citing works
Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases
Sharma, S., Sarathlal, K. C., & Taliyan, R. (2018) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527317666181004155136 · Cited by 58 · see citing works
Choong, C., Sasaki, T., Hayakawa, H., Yasuda, T., Baba, K., Hirata, Y., Uesato, S., & Mochizuki, H. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.10.001 · Cited by 53 · see citing works
Jian, W., Wei, X., Chen, L., Wang, Z., Sun, Y., Zhu, S., Lou, H., Yan, S., Li, X., Zhou, J., et al. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.08.029 · Cited by 52 · see citing works
Li, B., Yang, Y., Wang, Y., Zhang, J., Ding, J., Liu, X.-Y., Jin, Y., Lian, B.-L., Ling, Y., & Sun, C. (2021) · iScience · doi:10.1016/j.isci.2021.102302 · Cited by 36 · see citing works
Collins, L., Adriaanse, L. J., Theratile, S. D., Hegarty, S. V., Sullivan, A. M., & O’Keeffe, G. W. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8820-8 · Cited by 35 · see citing works
Self-citationMazzocchi, M., Goulding, S. R., Wyatt, S. L., Collins, L., Sullivan, A. M., & O’Keeffe, G. W. (2021) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2021.103642 · Cited by 33 · see citing works
Self-citationGuida, N., Laudati, G., Mascolo, L., Cuomo, O., Anzilotti, S., Sirabella, R., Santopaolo, M., Galgani, M., Montuori, P., Renzo, G. D., et al. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw157 · Cited by 30 · see citing works
Han, X. H., Wang, Z., Su, L., Liang, D., Kuang, S., & Dong, Q. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.265562 · Cited by 29 · see citing works
Johnston, T. H., Huot, P., Damude, S., Fox, S. H., Jones, S. W., Rusche, J. R., & Brotchie, J. M. (2012) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2012.07.001 · Cited by 28 · see citing works
Mazzocchi, M., Wyatt, S. L., Mercatelli, D., Morari, M., Morales‐Prieto, N., Collins, L., Sullivan, A. M., & O’Keeffe, G. W. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00191 · Cited by 20 · see citing works
Self-citationLai, C.-L., Lu, C.-C., Lin, H.-C., Sung, Y.-F., Wu, Y.-P., Hong, J.-S., & Peng, G.-S. (2019) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2018.06.017 · Cited by 18 · see citing works
Early Versus Delayed Initiation of Pharmacotherapy in Parkinson’s Disease
Löhle, M., Ramberg, C.-J., Reichmann, H., et al. (2014) · Drugs · doi:10.1007/s40265-014-0209-5 · Cited by 18 · see citing works
Goulding, S. R., Concannon, R. M., Morales‐Prieto, N., et al. (2020) · Brain · doi:10.1093/brain/awaa367 · Cited by 18 · see citing works
Self-citationProtocol for evaluation of neurotrophic strategies in Parkinson
Hegarty, S. V., Sullivan, A. M., & O’Keeffe, G. W. (2016) · Journal of Biological Methods · doi:10.14440/jbm.2016.124 · Cited by 11 · see citing works
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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Role of histone deacetylases and their inhibitors in neurological diseases
Zhang, L.-Y., Zhang, S.-Y., Wen, R., Zhang, T.-N., & Yang, N. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107410 · Cited by 84 · see citing works
- Authors
- Mazzocchi, M., Goulding, S. R., Morales-Prieto, N., Foley, T., Collins, L. M., Sullivan, A. M., & O'Keeffe, G. W.
- Affiliations
- University College Cork (IE)
- Corresponding author
- Sullivan, Aideen M.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 102
- Pages
- 151-160
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W4213390936
- Cited by
- 32
- References
- 49
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 6 · 2022: 4
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cork Open Research Archive (University College Cork, Ireland) (submittedVersion, cc-by)
- Funders
- Science Foundation Ireland
- Irish Research Council
- Maria Curie-Sklodowska University
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, HDAC5, peripheral administration, 6-hydroxydopamine, neuroprotection, protein kinase C, microglial activation, substantia nigra, striatum, akinesia, dopaminergic neurons
- MeSH terms
- Animals, Corpus Striatum, Disease Models, Animal, Histone Deacetylases, Hydroxamic Acids, Parkinson Disease, Pyrroles, Substantia Nigra, Oxidopamine, Neuroprotective Agents, Neurodegenerative Diseases, Rats, Histone Deacetylase Inhibitors, Dopaminergic Neurons
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