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Epigenetics as a new therapeutic target for postoperative cognitive dysfunction
Medical Hypotheses 80 (2013) 249–251
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Epigenetics as a new therapeutic target for postoperative cognitive dysfunction Yun Wang a, Zhijun Chen b, Yujie Zhao a, Rong Shi a, Yue Wang a, Jie Xu a, Anshi Wu a, Roger A. Johns c,⇑, Yun Yue a,⇑ a
Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China c Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA b
a r t i c l e
i n f o
Article history: Received 12 August 2012 Accepted 27 November 2012
a b s t r a c t Persistent memory and learning disabilities may occur postoperatively and may be related to neurodegenerative processes. Epigenetic dysregulation has been implicated to abnormal brain function and neurodegenerative diseases. Some risk factors contributing to postoperative cognitive disorder (POCD) have been identified, including exposure to general anesthesia, hypotension, hypoxia, psychoactive drugs, hippocampal inflammation induced by the surgical intervention, etc. The current evidence supports these risk factors might induce epigenetic dysfunction in the brain. It is possible that epigenetic regulation might be the common downstream pathway of these risk factors, since the chromatin remodeling is necessary for the memory-associated gene transcription and expression. Here, we present our hypothesis that the epigenetic dysregulation might be a critical mechanism underlying POCD. Our hypothesis may lead to a new therapeutic strategy of epigenetic intervention for POCD. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction An impairment of cognition may occur after surgery, and is referred to as postoperative cognitive dysfunction (POCD) [1]. POCD affects a wide variety of cognitive domains, such as attention, memory, executive function and speed of information processing, resulting in significant long-term morbidity and an overall reduced quality of life. POCD affects surgical patients in all age groups on a short-term basis, but resolves faster in the younger population and can last for months in the elderly. An international multicenter study on POCD (ISPOCD) reported memory impairments in 25.8% of patients 1 week after noncardiac surgery and in 9.9% after 3 months in patients older than 60 years [2]. Studies have sought to identify factors that may contribute to POCD, including exposure to general anesthesia, hyperventilation, hypotension, hypoxia, psychoactive drugs, and hippocampal inflammation induced by the surgical intervention, etc. [2]. Epigenetics refers to alterations in gene expression due to histone modification and DNA methylation at the promoter regions of genes. Although there are very few studies investigating the role ⇑ Corresponding authors. Addresses: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 361, Baltimore, MD 21205, USA. Tel.: +1 410 614 1810; fax: +1 410 614 7711 (R.A. Johns). Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongtinan Road, Chaoyang District, Beijing 100020, China. Tel.: +86 10 85231463 (Y. Yue). E-mail addresses: [email protected] (R.A. Johns), [email protected] (Y. Yue). 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.11.041
of epigenetic factors in POCD, there is an increasing line of experimental evidence that epigenetic signals play a critical role in synaptic plasticity, learning and memory [3,4]. Epigenetic dysregulation has been implicated to abnormal brain function and neurodegenerative diseases [5,6]. POCD is a prolonged change in cognition, with clinical manifestations similar to those seen in neurodegenerative disorders. Therefore, we speculate that similar epigenetic dysregulation might be also involved in the development of POCD and become an attractive drug target. The hypothesis The hypothesis we propose here is that the epigenetic regulation of chromatin remodeling might be a critical mechanism underlying POCD, which might lead to a new therapeutic strategy of epigenetic intervention for POCD. Evaluation of the hypothesis A series of studies demonstrate that the changes in the epigenetic modification of chromatin may be the molecular basis for memory decline [7]. Until now a number of DNA binding transcription factors involved in gene expression regulation during learning have been described [8]. The chromatin modification (remodeling) is necessary for the gene expression induced by activation of transcription factors [9]. Some processes of chromatin remodeling are considered to be epigenetic. Histone phosphorylation, methylation and acetylation, as well as DNA methylation play the most
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Y. Wang et al. / Medical Hypotheses 80 (2013) 249–251
important role in chromatin remodeling [10]. Dysfunction of these processes leads to the inability to form long-term memory. Pharmacologic inhibitors of epigenetic processes have had documented effects on long-term potentiation (LTP), an increase in efficiency of synaptic transmission, in the mammalian brain. The DNA methyltransferase (DNMT) inhibitors, such as zebularine, impair induction of LTP in mouse hippocampus, while histone deacetylase (HDAC) inhibitors, such as sodium butyrate and trichostatin A (TSA), have been shown to enhance LTP in rat hippocampus and amygdala [11–13]. Peleg et al. [14] showed that intrahippocampal infusion of mice with suberoylanilide hydroxamic acid, an HDAC, increased memory-associated histone H4 lysine 12 (H4K12) acetylation in the central nervous system, restored memory-associated transcriptional regulation, and improved behavioral memory function in aged animals. Elevation of histone acetylation via administration of HDAC inhibitors is currently being pursued as a novel therapeutic avenue to treat memory impairment linked to Alzheimer’s disease (AD) [6]. Taken together, these experimental evidence suggest that epigenetic regulation is essential for neural and brain functioning. Some risk factors contributing to POCD have been identified, including exposure to general anesthesia, hypotension, hypoxia, psychoactive drugs, hippocampal inflammation induced by the surgical intervention, etc. It is possible that epigenetic regulation might be the common downstream pathway of these risk factors, since the chromatin remodeling is necessary for the memoryassociated gene transcription and expression. Recently, our unpublished data showed that the commonly-used volatile agent, isoflurane, significantly inhibited the H3 acetylation level in the aged rat hippocampus and caused the cognitive impairment after emerge from anesthesia, suggesting exposure to general anesthesia might contribute to POCD through epigenetic mechanism. Hypoxia, an important risk factor of POCD, has been demonstrated to increase the cellular amyloid b production when used combined with desflurane and the increased amyloid b production in the brain might be associated with POCD [15,16]. In the recent study, Wang et al. [17] showed that hypoxia might induce the downregulation of neprilysin, an enzyme to degrade amyloid b, by increasing H3K9 demethylation and decreasing H3 acetylation modulation in mouse primary cortical and hippocampal neurons, suggesting hypoxia might be associated with POCD through histone remodeling. Cognitive decline accompanies surgical trauma, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response, which may alter the permeability of blood–brain barrier via release of inflammatory factors and facilitates the migration of macrophages into the hippocampus [18]. Accumulated evidence has suggested that surgery-related neuroinflammation is another pivotal trigger of POCD [18,19]. The studies in different tissues have shown that inflammation might induce the changes of chromatin modification. For example, in mouse colonic epithelial cells, inflammation could induce aberrant trimethylation of H3K27 [20]. However, so far, no study indicates the direct evidence that surgery-induced hippocampal inflammation may trigger epigenetic dysregualtions of memory-associated genes. It deserves our future investigation. Based on these data, we may propose an emerging hypothesis that risk-factors-induced changes in the epigenetic modification of chromatin remodeling in the central nervous system drive cognitive decline following surgery.
Consequences of the hypothesis and discussion So far, there is no potent drug for the treatment of POCD in clinical practice. Our hypothesis may lead to a new epigenetic intervention for POCD. Epigenetic drug strategies are currently
employed to treat a collection of cancer subtypes, and these medications are now being considered in the treatment of psychiatric or neurodegenerative disease, as well [21]. The DNMT inhibitor, doxorubicin, has been used to increase reelin and GAD67 expression in neuronal precursor cells, and it was shown that reelin gene expression correlated with the dissociation of DNMT1 and MeCP2 from its promoter, as well as an increased level of histone H3 acetylation [22]. Other studies have shown that HDAC inhibition enhances learning and memory following neurodegeneration induced by traumatic brain injury and also shows some therapeutic efficacy in rodent models of neurodegenerative conditions, such as Huntington’s disease, multiple sclerosis, and Parkinson’s disease [5,21]. Recent successes of therapeutic intervention in chronic inflammatory diseases using epigenetic modifiers such as HDAC inhibitors and inhibitors of DNA methylation suggest that the epigenetic intervention will be very promising for POCD in the near future. A substantial challenge to the epigenetic intervention of POCD involves the identification and verification of inhibitors for specific histone-modifying enzymes [23–25]. Once developed, these compounds should provide higher therapeutic efficiency versus the nonspecific therapeutics that are currently used for cancer treatment. Importantly, epigenetic processes are reversible and may provide an excellent therapeutic target for POCD. In conclusion, epigenetic mechanisms play a critical role in synaptic plasticity, learning and memory. The risk-factors of POCD, such as exposure to isoflurane anesthesia, hypoxia, neuroinflammation, etc., might trigger the epigenetic dysregulation of cognition-associated genes (chromatin remodeling), which would fail to initiate a hippocampal gene expression program associated with memory consolidation and consequently lead to cognitive impairment following surgery. Restoration of abnormal chromatin remodeling will be a viable approach to therapeutic intervention in POCD. Conflict of interest statement None declares. Acknowledgement This work was supported by National Natural Science Foundation of China (81171055/H0903), Natural Science Foundation of Beijing (7112054) and New Century Excellent Talents Program from Ministry of Education, China (NCET-10-0014). References [1] Terrando N, Brzezinski M, Degos V, et al. Perioperative cognitive decline in the aging population. Mayo Clin Proc 2011;86(9):885–93. [2] Moller JT, Cluitmans P, Rasmussen LS, et al. ISPOCD investigators. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998;351(9106):857–61. [3] Haberman RP, Quigley C, Gallagher M. Characterization of CpG island DNA methylation of impairment-related genes in a rat model of cognitive aging. Epigenetics 2012. PMID: 22869088. [4] Kosik KS, Rapp PR, Raz N, Small SA, Sweatt JD, Tsai LH. Mechanisms of agerelated cognitive change and targets for intervention: epigenetics. J Gerontol A Biol Sci Med Sci 2012;67(7):741–6. [5] Dash PK, Orsi SA, Moore AN. Histone deacetylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury. Neuroscience 2009;163(1):1–8. [6] Govindarajan N, Agis-Balboa RC, Walter J, Sananbenesi F, Fischer A. Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression. J Alzheimers Dis 2011;26(1):187–97. [7] Sweatt JD. Epigenetics and cognitive aging. Science 2010;328(5979):701–2. [8] Chwang WB, Arthur JS, Schumacher A, et al. The nuclear kinase mitogen- and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation. J Neurosci 2007;27(46):12732–42. [9] Roth TL, Sweatt JD. Regulation of chromatin structure in memory formation. Curr Opin Neurobiol 2009;19(3):336–42.
Y. Wang et al. / Medical Hypotheses 80 (2013) 249–251 [10] Graff J, Mansuy IM. Epigenetic codes in cognition and behaviour. Behav Brain Res 2008;192(1):70–87. [11] Levenson JM, Roth TL, Lubin FD, et al. Evidence that DNA (sytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 2006;281(23):15763–73. [12] Yeh SH, Lin CH, Gean PW. Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol Pharmacol 2004;65(5):1286–92. [13] Levenson JM, O’Riordan KJ, Brown KD, et al. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 2004;279(39):40545–59. [14] Peleg S, Sananbenesi F, Zovoilis A, et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 2010;328(5979):753–6. [15] Zhang B, Dong Y, Zhang G, et al. The inhalation anesthetic desflurane induces caspase activation and increases amyloid beta levels under hypoxic conditions. J Biol Chem 2008;283(18):11866–75. [16] Xie Z, Tanzi RE. Alzheimer’s disease and postoperative cognitive dysfunction. Exp Gerontol 2006;41(4):346–59. [17] Wang Z, Yang D, Zhang X, et al. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLos One 2011;6(4):e19229.
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[18] Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA 2010;107(47):20518–22. [19] Cibelli M, Fidalgo AR, Terrando N, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010;68(3):360–8. [20] Takeshima H, Ikegami D, Wakabayashi M, Niwa T, Kim YJ, Ushijima T. Induction of aberrant trimethylation of histone H3 lysine 27 by inflammation in mouse colonic epithelial cells. Carcinogenesis 2012;(12):2384–90. [21] Ptak C, Petronis A. Epigenetic approaches to psychiatric disorders. Dialogues Clin Neurosci 2010;12(1):25–35. [22] Kundakovic M, Chen Y, Costa E, Grayson DR. DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol 2007;71(3):644–53. [23] Kim MS, Akhtar MW, Adachi M, et al. An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J Neurosci 2012;32(32): 10879–86. [24] Kilgore M, Miller CA, Fass DM, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacol 2010;35(4):870–80. [25] Chen S, Shi Y. Small molecules that inhibit a specific subfamily of histone demethylases: A new horizon for epigenetic medicine? Cell Res 2012. PMID:22986503.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Epigenetics as a new therapeutic target for postoperative cognitive dysfunction Yun Wang a, Zhijun Chen b, Yujie Zhao a, Rong Shi a, Yue Wang a, Jie Xu a, Anshi Wu a, Roger A. Johns c,⇑, Yun Yue a,⇑ a
Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China c Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA b
a r t i c l e
i n f o
Article history: Received 12 August 2012 Accepted 27 November 2012
a b s t r a c t Persistent memory and learning disabilities may occur postoperatively and may be related to neurodegenerative processes. Epigenetic dysregulation has been implicated to abnormal brain function and neurodegenerative diseases. Some risk factors contributing to postoperative cognitive disorder (POCD) have been identified, including exposure to general anesthesia, hypotension, hypoxia, psychoactive drugs, hippocampal inflammation induced by the surgical intervention, etc. The current evidence supports these risk factors might induce epigenetic dysfunction in the brain. It is possible that epigenetic regulation might be the common downstream pathway of these risk factors, since the chromatin remodeling is necessary for the memory-associated gene transcription and expression. Here, we present our hypothesis that the epigenetic dysregulation might be a critical mechanism underlying POCD. Our hypothesis may lead to a new therapeutic strategy of epigenetic intervention for POCD. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction An impairment of cognition may occur after surgery, and is referred to as postoperative cognitive dysfunction (POCD) [1]. POCD affects a wide variety of cognitive domains, such as attention, memory, executive function and speed of information processing, resulting in significant long-term morbidity and an overall reduced quality of life. POCD affects surgical patients in all age groups on a short-term basis, but resolves faster in the younger population and can last for months in the elderly. An international multicenter study on POCD (ISPOCD) reported memory impairments in 25.8% of patients 1 week after noncardiac surgery and in 9.9% after 3 months in patients older than 60 years [2]. Studies have sought to identify factors that may contribute to POCD, including exposure to general anesthesia, hyperventilation, hypotension, hypoxia, psychoactive drugs, and hippocampal inflammation induced by the surgical intervention, etc. [2]. Epigenetics refers to alterations in gene expression due to histone modification and DNA methylation at the promoter regions of genes. Although there are very few studies investigating the role ⇑ Corresponding authors. Addresses: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 361, Baltimore, MD 21205, USA. Tel.: +1 410 614 1810; fax: +1 410 614 7711 (R.A. Johns). Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongtinan Road, Chaoyang District, Beijing 100020, China. Tel.: +86 10 85231463 (Y. Yue). E-mail addresses: [email protected] (R.A. Johns), [email protected] (Y. Yue). 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.11.041
of epigenetic factors in POCD, there is an increasing line of experimental evidence that epigenetic signals play a critical role in synaptic plasticity, learning and memory [3,4]. Epigenetic dysregulation has been implicated to abnormal brain function and neurodegenerative diseases [5,6]. POCD is a prolonged change in cognition, with clinical manifestations similar to those seen in neurodegenerative disorders. Therefore, we speculate that similar epigenetic dysregulation might be also involved in the development of POCD and become an attractive drug target. The hypothesis The hypothesis we propose here is that the epigenetic regulation of chromatin remodeling might be a critical mechanism underlying POCD, which might lead to a new therapeutic strategy of epigenetic intervention for POCD. Evaluation of the hypothesis A series of studies demonstrate that the changes in the epigenetic modification of chromatin may be the molecular basis for memory decline [7]. Until now a number of DNA binding transcription factors involved in gene expression regulation during learning have been described [8]. The chromatin modification (remodeling) is necessary for the gene expression induced by activation of transcription factors [9]. Some processes of chromatin remodeling are considered to be epigenetic. Histone phosphorylation, methylation and acetylation, as well as DNA methylation play the most
250
Y. Wang et al. / Medical Hypotheses 80 (2013) 249–251
important role in chromatin remodeling [10]. Dysfunction of these processes leads to the inability to form long-term memory. Pharmacologic inhibitors of epigenetic processes have had documented effects on long-term potentiation (LTP), an increase in efficiency of synaptic transmission, in the mammalian brain. The DNA methyltransferase (DNMT) inhibitors, such as zebularine, impair induction of LTP in mouse hippocampus, while histone deacetylase (HDAC) inhibitors, such as sodium butyrate and trichostatin A (TSA), have been shown to enhance LTP in rat hippocampus and amygdala [11–13]. Peleg et al. [14] showed that intrahippocampal infusion of mice with suberoylanilide hydroxamic acid, an HDAC, increased memory-associated histone H4 lysine 12 (H4K12) acetylation in the central nervous system, restored memory-associated transcriptional regulation, and improved behavioral memory function in aged animals. Elevation of histone acetylation via administration of HDAC inhibitors is currently being pursued as a novel therapeutic avenue to treat memory impairment linked to Alzheimer’s disease (AD) [6]. Taken together, these experimental evidence suggest that epigenetic regulation is essential for neural and brain functioning. Some risk factors contributing to POCD have been identified, including exposure to general anesthesia, hypotension, hypoxia, psychoactive drugs, hippocampal inflammation induced by the surgical intervention, etc. It is possible that epigenetic regulation might be the common downstream pathway of these risk factors, since the chromatin remodeling is necessary for the memoryassociated gene transcription and expression. Recently, our unpublished data showed that the commonly-used volatile agent, isoflurane, significantly inhibited the H3 acetylation level in the aged rat hippocampus and caused the cognitive impairment after emerge from anesthesia, suggesting exposure to general anesthesia might contribute to POCD through epigenetic mechanism. Hypoxia, an important risk factor of POCD, has been demonstrated to increase the cellular amyloid b production when used combined with desflurane and the increased amyloid b production in the brain might be associated with POCD [15,16]. In the recent study, Wang et al. [17] showed that hypoxia might induce the downregulation of neprilysin, an enzyme to degrade amyloid b, by increasing H3K9 demethylation and decreasing H3 acetylation modulation in mouse primary cortical and hippocampal neurons, suggesting hypoxia might be associated with POCD through histone remodeling. Cognitive decline accompanies surgical trauma, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response, which may alter the permeability of blood–brain barrier via release of inflammatory factors and facilitates the migration of macrophages into the hippocampus [18]. Accumulated evidence has suggested that surgery-related neuroinflammation is another pivotal trigger of POCD [18,19]. The studies in different tissues have shown that inflammation might induce the changes of chromatin modification. For example, in mouse colonic epithelial cells, inflammation could induce aberrant trimethylation of H3K27 [20]. However, so far, no study indicates the direct evidence that surgery-induced hippocampal inflammation may trigger epigenetic dysregualtions of memory-associated genes. It deserves our future investigation. Based on these data, we may propose an emerging hypothesis that risk-factors-induced changes in the epigenetic modification of chromatin remodeling in the central nervous system drive cognitive decline following surgery.
Consequences of the hypothesis and discussion So far, there is no potent drug for the treatment of POCD in clinical practice. Our hypothesis may lead to a new epigenetic intervention for POCD. Epigenetic drug strategies are currently
employed to treat a collection of cancer subtypes, and these medications are now being considered in the treatment of psychiatric or neurodegenerative disease, as well [21]. The DNMT inhibitor, doxorubicin, has been used to increase reelin and GAD67 expression in neuronal precursor cells, and it was shown that reelin gene expression correlated with the dissociation of DNMT1 and MeCP2 from its promoter, as well as an increased level of histone H3 acetylation [22]. Other studies have shown that HDAC inhibition enhances learning and memory following neurodegeneration induced by traumatic brain injury and also shows some therapeutic efficacy in rodent models of neurodegenerative conditions, such as Huntington’s disease, multiple sclerosis, and Parkinson’s disease [5,21]. Recent successes of therapeutic intervention in chronic inflammatory diseases using epigenetic modifiers such as HDAC inhibitors and inhibitors of DNA methylation suggest that the epigenetic intervention will be very promising for POCD in the near future. A substantial challenge to the epigenetic intervention of POCD involves the identification and verification of inhibitors for specific histone-modifying enzymes [23–25]. Once developed, these compounds should provide higher therapeutic efficiency versus the nonspecific therapeutics that are currently used for cancer treatment. Importantly, epigenetic processes are reversible and may provide an excellent therapeutic target for POCD. In conclusion, epigenetic mechanisms play a critical role in synaptic plasticity, learning and memory. The risk-factors of POCD, such as exposure to isoflurane anesthesia, hypoxia, neuroinflammation, etc., might trigger the epigenetic dysregulation of cognition-associated genes (chromatin remodeling), which would fail to initiate a hippocampal gene expression program associated with memory consolidation and consequently lead to cognitive impairment following surgery. Restoration of abnormal chromatin remodeling will be a viable approach to therapeutic intervention in POCD. Conflict of interest statement None declares. Acknowledgement This work was supported by National Natural Science Foundation of China (81171055/H0903), Natural Science Foundation of Beijing (7112054) and New Century Excellent Talents Program from Ministry of Education, China (NCET-10-0014). References [1] Terrando N, Brzezinski M, Degos V, et al. Perioperative cognitive decline in the aging population. Mayo Clin Proc 2011;86(9):885–93. [2] Moller JT, Cluitmans P, Rasmussen LS, et al. ISPOCD investigators. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998;351(9106):857–61. [3] Haberman RP, Quigley C, Gallagher M. Characterization of CpG island DNA methylation of impairment-related genes in a rat model of cognitive aging. Epigenetics 2012. PMID: 22869088. [4] Kosik KS, Rapp PR, Raz N, Small SA, Sweatt JD, Tsai LH. Mechanisms of agerelated cognitive change and targets for intervention: epigenetics. J Gerontol A Biol Sci Med Sci 2012;67(7):741–6. [5] Dash PK, Orsi SA, Moore AN. Histone deacetylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury. Neuroscience 2009;163(1):1–8. [6] Govindarajan N, Agis-Balboa RC, Walter J, Sananbenesi F, Fischer A. Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression. J Alzheimers Dis 2011;26(1):187–97. [7] Sweatt JD. Epigenetics and cognitive aging. Science 2010;328(5979):701–2. [8] Chwang WB, Arthur JS, Schumacher A, et al. The nuclear kinase mitogen- and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation. J Neurosci 2007;27(46):12732–42. [9] Roth TL, Sweatt JD. Regulation of chromatin structure in memory formation. Curr Opin Neurobiol 2009;19(3):336–42.
Y. Wang et al. / Medical Hypotheses 80 (2013) 249–251 [10] Graff J, Mansuy IM. Epigenetic codes in cognition and behaviour. Behav Brain Res 2008;192(1):70–87. [11] Levenson JM, Roth TL, Lubin FD, et al. Evidence that DNA (sytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 2006;281(23):15763–73. [12] Yeh SH, Lin CH, Gean PW. Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol Pharmacol 2004;65(5):1286–92. [13] Levenson JM, O’Riordan KJ, Brown KD, et al. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 2004;279(39):40545–59. [14] Peleg S, Sananbenesi F, Zovoilis A, et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 2010;328(5979):753–6. [15] Zhang B, Dong Y, Zhang G, et al. The inhalation anesthetic desflurane induces caspase activation and increases amyloid beta levels under hypoxic conditions. J Biol Chem 2008;283(18):11866–75. [16] Xie Z, Tanzi RE. Alzheimer’s disease and postoperative cognitive dysfunction. Exp Gerontol 2006;41(4):346–59. [17] Wang Z, Yang D, Zhang X, et al. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLos One 2011;6(4):e19229.
251
[18] Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA 2010;107(47):20518–22. [19] Cibelli M, Fidalgo AR, Terrando N, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010;68(3):360–8. [20] Takeshima H, Ikegami D, Wakabayashi M, Niwa T, Kim YJ, Ushijima T. Induction of aberrant trimethylation of histone H3 lysine 27 by inflammation in mouse colonic epithelial cells. Carcinogenesis 2012;(12):2384–90. [21] Ptak C, Petronis A. Epigenetic approaches to psychiatric disorders. Dialogues Clin Neurosci 2010;12(1):25–35. [22] Kundakovic M, Chen Y, Costa E, Grayson DR. DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol 2007;71(3):644–53. [23] Kim MS, Akhtar MW, Adachi M, et al. An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J Neurosci 2012;32(32): 10879–86. [24] Kilgore M, Miller CA, Fass DM, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacol 2010;35(4):870–80. [25] Chen S, Shi Y. Small molecules that inhibit a specific subfamily of histone demethylases: A new horizon for epigenetic medicine? Cell Res 2012. PMID:22986503.