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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 SAHA treatment on protein expressions of cleaved caspase-3, iNOS, BDNF, synapsin 1 and PSD95 in the 16-month old mice after surgery. (A) The protein levels of cleaved caspase-3 and iNOS were determined by western blot. Representative image is at the top and quantitative result is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The result of western blot for BDNF, synapsin 1, and PSD95. Representative image is shown at the top and quantitation is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.
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Figure 5: Impact of SAHA treatment on protein expressions of cleaved caspase-3, iNOS, BDNF, synapsin 1 and PSD95 in the 16-month old mice after surgery. (A) The protein levels of cleaved caspase-3 and iNOS were determined by western blot. Representative image is at the top and quantitative result is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The result of western blot for BDNF, synapsin 1, and PSD95. Representative image is shown at the top and quantitation is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.

Mentions: The hippocampal protein levels of cleaved caspase-3 (Psurg < 0.001, Fsurg(1,8) = 49.285; Pdrug < 0.001, Fdrug(1,8) = 37.549; Pint < 0.001, Fint(1,8) = 38.197) and iNOS (Psurg = 0.038, Fsurg(1,8) = 6.139; Pdrug = 0.036, Fdrug(1,8) = 6.356; Pint = 0.015, Fint(1,8) = 9.508) increased in the Laparotomy + Vehicle group compared with the Sham + Vehicle group, whereas SAHA eliminated the increases in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Figure 5A). The hippocampal protein levels of BDNF (Psurg = 0.010, Fsurg(1,8) = 11.409; Pdrug = 0.007, Fdrug(1,8) = 13.191; Pint = 0.006, Fint(1,8) = 13.434), synapsin 1 (Psurg = 0.039, Fsurg(1,8) = 6.070; Pdrug = 0.049, Fdrug(1,8) = 5.387; Pint = 0.035, Fint(1,8) = 6.418), and PSD95 (Psurg = 0.024, Fsurg(1,8) = 7.708; Pdrug = 0.060, Fdrug(1,8) = 4.786; Pint = 0.069, Fint(1,8) = 4.401) decreased in the Laparotomy + Vehicle group compared with the Sham + Vehicle group, whereas SAHA reversed the decreases in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Figure 5B).


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 SAHA treatment on protein expressions of cleaved caspase-3, iNOS, BDNF, synapsin 1 and PSD95 in the 16-month old mice after surgery. (A) The protein levels of cleaved caspase-3 and iNOS were determined by western blot. Representative image is at the top and quantitative result is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The result of western blot for BDNF, synapsin 1, and PSD95. Representative image is shown at the top and quantitation is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.
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Related In: Results  -  Collection

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Figure 5: Impact of SAHA treatment on protein expressions of cleaved caspase-3, iNOS, BDNF, synapsin 1 and PSD95 in the 16-month old mice after surgery. (A) The protein levels of cleaved caspase-3 and iNOS were determined by western blot. Representative image is at the top and quantitative result is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The result of western blot for BDNF, synapsin 1, and PSD95. Representative image is shown at the top and quantitation is at the bottom. Data are presented as the mean ± S.E.M. (n = 3). *p < 0.05 compared with the Sham + Vehicle group; #p < 0.05 compared with the Laparotomy + Vehicle group.
Mentions: The hippocampal protein levels of cleaved caspase-3 (Psurg < 0.001, Fsurg(1,8) = 49.285; Pdrug < 0.001, Fdrug(1,8) = 37.549; Pint < 0.001, Fint(1,8) = 38.197) and iNOS (Psurg = 0.038, Fsurg(1,8) = 6.139; Pdrug = 0.036, Fdrug(1,8) = 6.356; Pint = 0.015, Fint(1,8) = 9.508) increased in the Laparotomy + Vehicle group compared with the Sham + Vehicle group, whereas SAHA eliminated the increases in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Figure 5A). The hippocampal protein levels of BDNF (Psurg = 0.010, Fsurg(1,8) = 11.409; Pdrug = 0.007, Fdrug(1,8) = 13.191; Pint = 0.006, Fint(1,8) = 13.434), synapsin 1 (Psurg = 0.039, Fsurg(1,8) = 6.070; Pdrug = 0.049, Fdrug(1,8) = 5.387; Pint = 0.035, Fint(1,8) = 6.418), and PSD95 (Psurg = 0.024, Fsurg(1,8) = 7.708; Pdrug = 0.060, Fdrug(1,8) = 4.786; Pint = 0.069, Fint(1,8) = 4.401) decreased in the Laparotomy + Vehicle group compared with the Sham + Vehicle group, whereas SAHA reversed the decreases in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Figure 5B).

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