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The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson's disease.
J Neurochem. 2019 01; 148(1):136-156.JN

Abstract

Histone hypoacetylation is associated with dopaminergic neurodegeneration in Parkinson's disease (PD), because of an imbalance in the activities of the enzymes responsible for histone (de)acetylation. Correction of this imbalance, with histone deacetylase (HDAC) inhibiting agents, could be neuroprotective. We therefore hypothesize that nicotinamide, being a selective inhibitor of HDAC class III as well as having modulatory effects on mitochondrial energy metabolism, would be neuroprotective in the lactacystin rat model of PD, which recapitulates the formation of neurotoxic accumulation of altered proteins within the substantia nigra to cause progressive dopaminergic cell death. Rats received nicotinamide for 28 days, starting 7 days after unilateral injection of the irreversible proteasome inhibitor, lactacystin, into the substantia nigra. Longitudinal motor behavioural testing and structural magnetic resonance imaging were used to track changes in this model of PD, and assessment of nigrostriatal integrity, histone acetylation and brain gene expression changes post-mortem used to quantify nicotinamide-induced neuroprotection. Counterintuitively, nicotinamide dose-dependently exacerbated neurodegeneration of dopaminergic neurons, behavioural deficits and structural brain changes in the lactacystin-lesioned rat. Nicotinamide treatment induced histone hyperacetylation and over-expression of numerous neurotrophic and anti-apoptotic factors in the brain, yet failed to result in neuroprotection, rather exacerbated dopaminergic pathology. These findings highlight the importance of inhibitor specificity within HDAC isoforms for therapeutic efficacy in PD, demonstrating the contrasting effects of HDAC class III inhibition upon cell survival in this animal model of the disease. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Authors+Show Affiliations

UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK. Parkinson's Disease Research Group, Division of Brain Sciences, Department of Medicine, Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, UK.UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK. Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.Parkinson's Disease Research Group, Division of Brain Sciences, Department of Medicine, Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30269333

Citation

Harrison, Ian F., et al. "The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson's Disease." Journal of Neurochemistry, vol. 148, no. 1, 2019, pp. 136-156.
Harrison IF, Powell NM, Dexter DT. The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson's disease. J Neurochem. 2019;148(1):136-156.
Harrison, I. F., Powell, N. M., & Dexter, D. T. (2019). The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson's disease. Journal of Neurochemistry, 148(1), 136-156. https://doi.org/10.1111/jnc.14599
Harrison IF, Powell NM, Dexter DT. The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson's Disease. J Neurochem. 2019;148(1):136-156. PubMed PMID: 30269333.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson's disease. AU - Harrison,Ian F, AU - Powell,Nicholas M, AU - Dexter,David T, Y1 - 2018/11/26/ PY - 2018/04/26/received PY - 2018/08/14/revised PY - 2018/09/21/accepted PY - 2018/10/1/pubmed PY - 2019/10/29/medline PY - 2018/10/1/entrez KW - Parkinson's disease KW - histone deacetylase inhibitor KW - lactacystin KW - neurodegeneration KW - nicotinamide KW - sirtuins SP - 136 EP - 156 JF - Journal of neurochemistry JO - J Neurochem VL - 148 IS - 1 N2 - Histone hypoacetylation is associated with dopaminergic neurodegeneration in Parkinson's disease (PD), because of an imbalance in the activities of the enzymes responsible for histone (de)acetylation. Correction of this imbalance, with histone deacetylase (HDAC) inhibiting agents, could be neuroprotective. We therefore hypothesize that nicotinamide, being a selective inhibitor of HDAC class III as well as having modulatory effects on mitochondrial energy metabolism, would be neuroprotective in the lactacystin rat model of PD, which recapitulates the formation of neurotoxic accumulation of altered proteins within the substantia nigra to cause progressive dopaminergic cell death. Rats received nicotinamide for 28 days, starting 7 days after unilateral injection of the irreversible proteasome inhibitor, lactacystin, into the substantia nigra. Longitudinal motor behavioural testing and structural magnetic resonance imaging were used to track changes in this model of PD, and assessment of nigrostriatal integrity, histone acetylation and brain gene expression changes post-mortem used to quantify nicotinamide-induced neuroprotection. Counterintuitively, nicotinamide dose-dependently exacerbated neurodegeneration of dopaminergic neurons, behavioural deficits and structural brain changes in the lactacystin-lesioned rat. Nicotinamide treatment induced histone hyperacetylation and over-expression of numerous neurotrophic and anti-apoptotic factors in the brain, yet failed to result in neuroprotection, rather exacerbated dopaminergic pathology. These findings highlight the importance of inhibitor specificity within HDAC isoforms for therapeutic efficacy in PD, demonstrating the contrasting effects of HDAC class III inhibition upon cell survival in this animal model of the disease. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/30269333/The_histone_deacetylase_inhibitor_nicotinamide_exacerbates_neurodegeneration_in_the_lactacystin_rat_model_of_Parkinson's_disease_ L2 - https://doi.org/10.1111/jnc.14599 DB - PRIME DP - Unbound Medicine ER -