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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 mRNA abundances of iNOS, BDNF, synapsin 1, PSD95, NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. The real-time PCR results were normalized by those of genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The results from each group were then normalized by those from the group of vehicle-treated mice subjected to sham surgery. 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 7: Impact of SAHA treatment on mRNA abundances of iNOS, BDNF, synapsin 1, PSD95, NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. The real-time PCR results were normalized by those of genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The results from each group were then normalized by those from the group of vehicle-treated mice subjected to sham surgery. 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 mRNA abundances of iNOS, BDNF, synapsin 1, PSD95, NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. The real-time PCR results were normalized by those of genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The results from each group were then normalized by those from the group of vehicle-treated mice subjected to sham surgery. 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 7: Impact of SAHA treatment on mRNA abundances of iNOS, BDNF, synapsin 1, PSD95, NR2A, NR2B, CaMKIIα, and CaMKIIβ in the 16-month old mice after surgery. The real-time PCR results were normalized by those of genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The results from each group were then normalized by those from the group of vehicle-treated mice subjected to sham surgery. 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