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.
Highlights
Postoperative cognitive dysfunction (POCD) is a cognitive progressive deterioration in memory and concentration following exposure to anesthesia and surgery (Amar et al, 1998; Terrando et al, 2011; Hovens et al, 2012)
Laparotomy Induced the HippocampusDependent Long-Term Cognitive Impairments and Down-Regulation of Hippocampal Acetyl-H3 and Acetyl -H4 Levels in the 16- but not the 3-Month Old Mice 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
We found that the laparotomy-induced hippocampus-dependent long-term memory (LTM) impairments were accompanied by the decreased acetylation levels of hippocampal histone H3 and H4 in 16- but not 3-month old mice
Summary
Postoperative cognitive dysfunction (POCD) is a cognitive progressive deterioration in memory and concentration following exposure to anesthesia and surgery (Amar et al, 1998; Terrando et al, 2011; Hovens et al, 2012) These cognitive deficits result in prolonged hospitalization and decreased quality of life (Moller et al, 1998). Histone acetylation is one of the most common forms of epigenetic modification, which is controlled by the balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs; Fischer et al, 2010; Haggarty and Tsai, 2011; McQuown et al, 2011). A substantial body of evidence suggests that the dysregulation of histone acetylation contributes to the pathogenesis of neurodegenerative diseases, and targeted restoration of histone acetylation by HDAC inhibitors shows neuroprotective effects on neurodegenerative diseases (Petrij et al, 1995; Dash et al, 2010; Kilgore et al, 2010; Haettig et al, 2011; Ji et al, 2014)
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