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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 NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. (A) The protein levels of NR2A, NR2B were determined by western blot. Representative image is shown at the top and quantitative result at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The protein levels of CaMKIIα and CaMKIIβ. Representative image is shown at the top and quantitative result 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 6: Impact of SAHA treatment on protein expressions of NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. (A) The protein levels of NR2A, NR2B were determined by western blot. Representative image is shown at the top and quantitative result at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The protein levels of CaMKIIα and CaMKIIβ. Representative image is shown at the top and quantitative result 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 NR2A (Psurg = 0.007, Fsurg(1,8) = 12.823; Pdrug = 0.048, Fdrug(1,8) = 5.428; Pint = 0.029, Fint(1,8) = 7.055), NR2B (Psurg < 0.001, Fsurg(1,8) = 26.202; Pdrug = 0.025, Fdrug(1,8) = 7.533; Pint = 0.037, Fint(1,8) = 6.217), CaMKIIα (Psurg < 0.001, Fsurg(1,8) = 28.352; Pdrug = 0.007, Fdrug(1,8) = 12.744; Pint < 0.001, Fint(1,8) = 27.711), and CaMKIIβ (Psurg = 0.037, Fsurg(1,8) = 6.203; Pdrug = 0.020, Fdrug(1,8) = 8.463; Pint = 0.029, Fint(1,8) = 7.001) were up-regulated in the Laparotomy +Vehicle group compared with the Sham + Vehicle group, whereas SAHA inhibited the up-regulation in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Figure 6). The gene expression level changes at the protein level measured by western blot were consistent to those at mRNA level measured by RT-real time PCR (Figure 7). The statistical results were as follows: iNOS (Psurg < 0.001, Fsurg(1,8) = 89.695; Pdrug < 0.001, Fdrug(1,8) = 50.714; Pint < 0.001, Fint(1,8) = 39.864), BDBF (Psurg = 0.019, Fsurg(1,8) = 8.523; Pdrug = 0.256, Fdrug(1,8) = 1.499; Pint = 0.019, Fint(1,8) = 8.523), synapsin 1 (Psurg = 0.013, Fsurg(1,8) = 10.257; Pdrug = 0.030, Fdrug(1,8) = 6.956; Pint = 0.021, Fint(1,8) = 8.254), PSD95 (Psurg = 0.003, Fsurg(1,8) = 16.908; Pdrug = 0.004, Fdrug(1,8) = 15.535; Pint = 0.033, Fint(1,8) = 6.646), CaMKIIβ (Psurg = 0.037, Fsurg(1,8) = 6.203; Pdrug = 0.020, Fdrug(1,8) = 8.463; Pint = 0.029, Fint(1,8) = 7.001), NR2A (Psurg < 0.001, Fsurg(1,8) = 27.121; Pdrug = 0.021, Fdrug(1,8) = 8.224; Pint = 0.037, Fint(1,8) = 6.253), NR2B (Psurg < 0.001,Fsurg(1,8) = 43.819; Pdrug = 0.002, Fdrug(1,8) = 21.952; Pint = 0.002, Fint(1,8) = 20.371), CaMKIIα (Psurg < 0.001, Fsurg(1,8) = 64.159; Pdrug < 0.001, Fdrug(1,8) = 31.208; Pint < 0.001, Fint(1,8) = 47.622), and CaMKIIβ (Psurg < 0.001, Fsurg(1,8) = 65.655; Pdrug < 0.001, Fdrug(1,8) = 25.505; Pint < 0.001, Fint(1,8) = 39.780).


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 NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. (A) The protein levels of NR2A, NR2B were determined by western blot. Representative image is shown at the top and quantitative result at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The protein levels of CaMKIIα and CaMKIIβ. Representative image is shown at the top and quantitative result 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 6: Impact of SAHA treatment on protein expressions of NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. (A) The protein levels of NR2A, NR2B were determined by western blot. Representative image is shown at the top and quantitative result at the bottom. Data are presented as the mean ± S.E.M. (n = 3). (B) The protein levels of CaMKIIα and CaMKIIβ. Representative image is shown at the top and quantitative result 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 NR2A (Psurg = 0.007, Fsurg(1,8) = 12.823; Pdrug = 0.048, Fdrug(1,8) = 5.428; Pint = 0.029, Fint(1,8) = 7.055), NR2B (Psurg < 0.001, Fsurg(1,8) = 26.202; Pdrug = 0.025, Fdrug(1,8) = 7.533; Pint = 0.037, Fint(1,8) = 6.217), CaMKIIα (Psurg < 0.001, Fsurg(1,8) = 28.352; Pdrug = 0.007, Fdrug(1,8) = 12.744; Pint < 0.001, Fint(1,8) = 27.711), and CaMKIIβ (Psurg = 0.037, Fsurg(1,8) = 6.203; Pdrug = 0.020, Fdrug(1,8) = 8.463; Pint = 0.029, Fint(1,8) = 7.001) were up-regulated in the Laparotomy +Vehicle group compared with the Sham + Vehicle group, whereas SAHA inhibited the up-regulation in the Laparotomy + SAHA group compared with the Laparotomy + Vehicle group (Figure 6). The gene expression level changes at the protein level measured by western blot were consistent to those at mRNA level measured by RT-real time PCR (Figure 7). The statistical results were as follows: iNOS (Psurg < 0.001, Fsurg(1,8) = 89.695; Pdrug < 0.001, Fdrug(1,8) = 50.714; Pint < 0.001, Fint(1,8) = 39.864), BDBF (Psurg = 0.019, Fsurg(1,8) = 8.523; Pdrug = 0.256, Fdrug(1,8) = 1.499; Pint = 0.019, Fint(1,8) = 8.523), synapsin 1 (Psurg = 0.013, Fsurg(1,8) = 10.257; Pdrug = 0.030, Fdrug(1,8) = 6.956; Pint = 0.021, Fint(1,8) = 8.254), PSD95 (Psurg = 0.003, Fsurg(1,8) = 16.908; Pdrug = 0.004, Fdrug(1,8) = 15.535; Pint = 0.033, Fint(1,8) = 6.646), CaMKIIβ (Psurg = 0.037, Fsurg(1,8) = 6.203; Pdrug = 0.020, Fdrug(1,8) = 8.463; Pint = 0.029, Fint(1,8) = 7.001), NR2A (Psurg < 0.001, Fsurg(1,8) = 27.121; Pdrug = 0.021, Fdrug(1,8) = 8.224; Pint = 0.037, Fint(1,8) = 6.253), NR2B (Psurg < 0.001,Fsurg(1,8) = 43.819; Pdrug = 0.002, Fdrug(1,8) = 21.952; Pint = 0.002, Fint(1,8) = 20.371), CaMKIIα (Psurg < 0.001, Fsurg(1,8) = 64.159; Pdrug < 0.001, Fdrug(1,8) = 31.208; Pint < 0.001, Fint(1,8) = 47.622), and CaMKIIβ (Psurg < 0.001, Fsurg(1,8) = 65.655; Pdrug < 0.001, Fdrug(1,8) = 25.505; Pint < 0.001, Fint(1,8) = 39.780).

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