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Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice.

Jia M, Liu WX, Sun HL, Chang YQ, Yang JJ, Ji MH, Yang JJ, Feng CZ - Front Mol Neurosci (2015)

Bottom Line: Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice.SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95).Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University Nanjing, China.

ABSTRACT
Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD.

No MeSH data available.


Related in: MedlinePlus

Impact of the cognition and histone acetylation in the 3- and 16-month old mice after surgery. (A,B) Performance of total distance traveled and time spent in the center during the open field test. Data are presented as the mean ± S.E.M. (n = 16). (C) Performance of freezing time during the fear conditioning training session. Data are presented as the mean ± S.E.M. (n = 16). (D,E) Performance during fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). (F) The acetylation level of histone H3 and H4 in the 3- or 16-month-old mice after laparotomy. Results are mean ± S.E.M. (n = 3). *p < 0.05 compared with the 16-month old mice subjected to sham surgery.
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Figure 2: Impact of the cognition and histone acetylation in the 3- and 16-month old mice after surgery. (A,B) Performance of total distance traveled and time spent in the center during the open field test. Data are presented as the mean ± S.E.M. (n = 16). (C) Performance of freezing time during the fear conditioning training session. Data are presented as the mean ± S.E.M. (n = 16). (D,E) Performance during fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). (F) The acetylation level of histone H3 and H4 in the 3- or 16-month-old mice after laparotomy. Results are mean ± S.E.M. (n = 3). *p < 0.05 compared with the 16-month old mice subjected to sham surgery.

Mentions: To investigate the difference of POCD between adult and aging mice, laparotomy or sham surgery was performed on the 3- and 16-month old mice. Neither the 3- nor the 16-month old mice had significant difference in the total distance traveled (Page = 0.804, Fage(1,28) = 0.0626; Psurg = 0.982, Fsurg(1,28) = 0.00053; Pint = 0.913, Fint(1,28) = 0.00761) or time spent in the center (Page = 0.855, Fage(1,28) = 0.0338; Psurg = 0.839, Fsurg(1,28) = 0.0421; Pint = 0.913, Fint(1,28) = 0.0122) after the laparotomy or sham surgery (Figures 2A,B). Then we used fear conditioning test to determine the associative memory. The laparotomy did not induce the acquirement of associative memory during the training session of pre-stimulation (Page = 0.957, Fage(1,28) = 0.00295; Psurg = 0.985, Fsurg(1,28) = 0.000353; Pint = 0.843, Fint(1,28) = 0.0398) or post-stimulation (Page = 0.825, Fage(1,28) = 0.0498; Psurg = 0.990, Fsurg(1,28) = 0.000176; Pint = 0.948, Fint(1,28) = 0.00432; Figure 2C). In the STM test, no significant difference was found in the context (Page = 0.506, Fage(1,28) = 0.454; Psurg = 0.920, Fsurg(1,28) = 0.0103; Pint = 0.994, Fint(1,28) = 0.0000547) or tone test (Page = 0.593, Fage(1,28) = 0.293; Psurg = 0.925, Fsurg(1,28) = 0.00893; Pint = 0.916, Fint(1,28) = 0.0113) among the four groups (Figure 2D). However, in the LTM test, the laparotomy led to a shorter freezing time in the context (Page = 0.003, Fage(1,28) = 10.750; Psurg = 0.017, Fsurg(1,28) = 6.396; Pint = 0.025, Fint(1,28) = 5.583) but not in the tone test (Page = 0.301, Fage(1,28) = 1.113; Psurg = 0.737, Fsurg(1,28) = 0.115; Pint = 0.736, Fint(1,28) = 0.116) compared with the sham surgery in 16-month, but not 3-month old mice (Figure 2E).


Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice.

Jia M, Liu WX, Sun HL, Chang YQ, Yang JJ, Ji MH, Yang JJ, Feng CZ - Front Mol Neurosci (2015)

Impact of the cognition and histone acetylation in the 3- and 16-month old mice after surgery. (A,B) Performance of total distance traveled and time spent in the center during the open field test. Data are presented as the mean ± S.E.M. (n = 16). (C) Performance of freezing time during the fear conditioning training session. Data are presented as the mean ± S.E.M. (n = 16). (D,E) Performance during fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). (F) The acetylation level of histone H3 and H4 in the 3- or 16-month-old mice after laparotomy. Results are mean ± S.E.M. (n = 3). *p < 0.05 compared with the 16-month old mice subjected to sham surgery.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Impact of the cognition and histone acetylation in the 3- and 16-month old mice after surgery. (A,B) Performance of total distance traveled and time spent in the center during the open field test. Data are presented as the mean ± S.E.M. (n = 16). (C) Performance of freezing time during the fear conditioning training session. Data are presented as the mean ± S.E.M. (n = 16). (D,E) Performance during fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). (F) The acetylation level of histone H3 and H4 in the 3- or 16-month-old mice after laparotomy. Results are mean ± S.E.M. (n = 3). *p < 0.05 compared with the 16-month old mice subjected to sham surgery.
Mentions: To investigate the difference of POCD between adult and aging mice, laparotomy or sham surgery was performed on the 3- and 16-month old mice. Neither the 3- nor the 16-month old mice had significant difference in the total distance traveled (Page = 0.804, Fage(1,28) = 0.0626; Psurg = 0.982, Fsurg(1,28) = 0.00053; Pint = 0.913, Fint(1,28) = 0.00761) or time spent in the center (Page = 0.855, Fage(1,28) = 0.0338; Psurg = 0.839, Fsurg(1,28) = 0.0421; Pint = 0.913, Fint(1,28) = 0.0122) after the laparotomy or sham surgery (Figures 2A,B). Then we used fear conditioning test to determine the associative memory. The laparotomy did not induce the acquirement of associative memory during the training session of pre-stimulation (Page = 0.957, Fage(1,28) = 0.00295; Psurg = 0.985, Fsurg(1,28) = 0.000353; Pint = 0.843, Fint(1,28) = 0.0398) or post-stimulation (Page = 0.825, Fage(1,28) = 0.0498; Psurg = 0.990, Fsurg(1,28) = 0.000176; Pint = 0.948, Fint(1,28) = 0.00432; Figure 2C). In the STM test, no significant difference was found in the context (Page = 0.506, Fage(1,28) = 0.454; Psurg = 0.920, Fsurg(1,28) = 0.0103; Pint = 0.994, Fint(1,28) = 0.0000547) or tone test (Page = 0.593, Fage(1,28) = 0.293; Psurg = 0.925, Fsurg(1,28) = 0.00893; Pint = 0.916, Fint(1,28) = 0.0113) among the four groups (Figure 2D). However, in the LTM test, the laparotomy led to a shorter freezing time in the context (Page = 0.003, Fage(1,28) = 10.750; Psurg = 0.017, Fsurg(1,28) = 6.396; Pint = 0.025, Fint(1,28) = 5.583) but not in the tone test (Page = 0.301, Fage(1,28) = 1.113; Psurg = 0.737, Fsurg(1,28) = 0.115; Pint = 0.736, Fint(1,28) = 0.116) compared with the sham surgery in 16-month, but not 3-month old mice (Figure 2E).

Bottom Line: Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice.SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95).Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University Nanjing, China.

ABSTRACT
Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD.

No MeSH data available.


Related in: MedlinePlus