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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 suberoylanilide hydroxamic acid (SAHA) treatment on the cognitive performance in the 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 the fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.
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Figure 3: Impact of suberoylanilide hydroxamic acid (SAHA) treatment on the cognitive performance in the 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 the fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.

Mentions: The poor hippocampus-dependent LTM with histone acetylation down-regulation in the 16-month old mice exposed to the surgery guided us to further investigate the effect of SAHA on these mice. The results didn’t showed any significant differences in the total distance traveled (Psurg = 0.984, Fsurg(1,60) = 0.000388; Pdrug = 0.955, Fdrug(1,60) = 0.00318; Pint = 0.847, Fint(1,60) = 0.0375), time spent in the center (Psurg = 0.676, Fsurg(1,60) = 0.177; Pdrug = 0.904, Fdrug(1,60) = 0.0148; Pint = 0.899, Fint(1,60) = 0.0163), or ability of memory acquirement when calculating the freezing time in the pre-stimulation (Psurg = 0.984, Fsurg(1,60) = 0.000388; Pdrug = 0.955, Fdrug(1,60) = 0.00318; Pint = 0.847, Fint(1,60) = 0.0375) and post-stimulation (Psurg = 0.774, Fsurg(1,60) = 0.0833; Pdrug = 0.866, Fdrug(1,60) = 0.0287; Pint = 0.812, Fint(1,60) = 0.0573) among the four groups (Figures 3A–C). In the STM test, no significant difference was found in the context (Psurg = 0.620, Fsurg(1,28) = 0.251; Pdrug = 0.905, Fdrug(1,28) = 0.0146; Pint = 0.816, Fint(1,28) = 0.0554) or tone test (Psurg = 0.872, Fsurg(1,28) = 0.0265; Pdrug = 0.837, Fdrug(1,28) = 0.0429; Pint = 0.403, Fint(1,28) = 0.721) among the four groups (Figure 3D). In the LTM test, the percent of freezing time in the context test decreased in the Laparotomy + Vehicle group compared with the Sham + Vehicle group, whereas SAHA diminished the decrease in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Psurg = 0.014, Fsurg(1,28) = 6.802; Pdrug = 0.049, Fdrug(1,28) = 4.254; Pint = 0.021, Fint(1,28) = 5.991; Figure 3E). No significant difference was observed in the tone test of LTM test among the four groups (Psurg = 0.803, Fsurg(1,28) = 0.0632; Pdrug = 0.701, Fdrug(1,28) = 0.150; Pint = 0.898, Fint(1,28) = 0.0167; Figure 3E).


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 suberoylanilide hydroxamic acid (SAHA) treatment on the cognitive performance in the 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 the fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585136&req=5

Figure 3: Impact of suberoylanilide hydroxamic acid (SAHA) treatment on the cognitive performance in the 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 the fear conditioning tests 2- or 24-h after laparotomy. Data are presented as the mean ± S.E.M. (n = 8). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.
Mentions: The poor hippocampus-dependent LTM with histone acetylation down-regulation in the 16-month old mice exposed to the surgery guided us to further investigate the effect of SAHA on these mice. The results didn’t showed any significant differences in the total distance traveled (Psurg = 0.984, Fsurg(1,60) = 0.000388; Pdrug = 0.955, Fdrug(1,60) = 0.00318; Pint = 0.847, Fint(1,60) = 0.0375), time spent in the center (Psurg = 0.676, Fsurg(1,60) = 0.177; Pdrug = 0.904, Fdrug(1,60) = 0.0148; Pint = 0.899, Fint(1,60) = 0.0163), or ability of memory acquirement when calculating the freezing time in the pre-stimulation (Psurg = 0.984, Fsurg(1,60) = 0.000388; Pdrug = 0.955, Fdrug(1,60) = 0.00318; Pint = 0.847, Fint(1,60) = 0.0375) and post-stimulation (Psurg = 0.774, Fsurg(1,60) = 0.0833; Pdrug = 0.866, Fdrug(1,60) = 0.0287; Pint = 0.812, Fint(1,60) = 0.0573) among the four groups (Figures 3A–C). In the STM test, no significant difference was found in the context (Psurg = 0.620, Fsurg(1,28) = 0.251; Pdrug = 0.905, Fdrug(1,28) = 0.0146; Pint = 0.816, Fint(1,28) = 0.0554) or tone test (Psurg = 0.872, Fsurg(1,28) = 0.0265; Pdrug = 0.837, Fdrug(1,28) = 0.0429; Pint = 0.403, Fint(1,28) = 0.721) among the four groups (Figure 3D). In the LTM test, the percent of freezing time in the context test decreased in the Laparotomy + Vehicle group compared with the Sham + Vehicle group, whereas SAHA diminished the decrease in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Psurg = 0.014, Fsurg(1,28) = 6.802; Pdrug = 0.049, Fdrug(1,28) = 4.254; Pint = 0.021, Fint(1,28) = 5.991; Figure 3E). No significant difference was observed in the tone test of LTM test among the four groups (Psurg = 0.803, Fsurg(1,28) = 0.0632; Pdrug = 0.701, Fdrug(1,28) = 0.150; Pint = 0.898, Fint(1,28) = 0.0167; Figure 3E).

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