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Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model.

Kalb A, von Haefen C, Sifringer M, Tegethoff A, Paeschke N, Kostova M, Feldheiser A, Spies CD - PLoS ONE (2013)

Bottom Line: Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine.Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha.Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité, Universitätsmedizin Berlin, Germany.

ABSTRACT
Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF-alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD.

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Physostigmine and neostigmine reduce surgery combined with LPS-induced IL-1beta and TNF-alpha gene expression in the spleen.IL-1beta (A) and TNF-alpha (B) expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h postintervention. Surgery combined with LPS-treatment resulted in an increased gene expression of IL-1beta and TNF-alpha after 1 h and was reduced by physostigmine and neostigmine treatment. IL-10 expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h (C) and 24 h (D) postintervention. Surgery in combination with LPS-treatment led to an increased gene expression of IL-10 after 1 and 24 h and is enhanced by physostigmine and neostigmine application after 1 h. Results of Real-Time PCR quantification are shown as mean ± SEM and normalized to levels of saline treated rats (Control = 100%, n = 8 per group). ***P<0.001 represents the difference between LPS and saline treated groups. ###P<0.001, #P<0.05 represents the difference between LPS and physostigmine or neostigmine treated groups.
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pone-0062679-g003: Physostigmine and neostigmine reduce surgery combined with LPS-induced IL-1beta and TNF-alpha gene expression in the spleen.IL-1beta (A) and TNF-alpha (B) expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h postintervention. Surgery combined with LPS-treatment resulted in an increased gene expression of IL-1beta and TNF-alpha after 1 h and was reduced by physostigmine and neostigmine treatment. IL-10 expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h (C) and 24 h (D) postintervention. Surgery in combination with LPS-treatment led to an increased gene expression of IL-10 after 1 and 24 h and is enhanced by physostigmine and neostigmine application after 1 h. Results of Real-Time PCR quantification are shown as mean ± SEM and normalized to levels of saline treated rats (Control = 100%, n = 8 per group). ***P<0.001 represents the difference between LPS and saline treated groups. ###P<0.001, #P<0.05 represents the difference between LPS and physostigmine or neostigmine treated groups.

Mentions: As shown in Fig. 3, surgery accompanied by LPS-treatment augmented IL-1beta (Fig. 3A) and TNF-alpha (Fig. 3B) gene expression in the spleen after 1 h. The cholinergic activation by physostigmine and neostigmine lowered levels of IL-1beta and TNF-alpha in the spleen. In comparison, after 24 h, 3 days and 7 days (data not shown) no increase of IL-1beta or TNF-alpha was detectable.


Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model.

Kalb A, von Haefen C, Sifringer M, Tegethoff A, Paeschke N, Kostova M, Feldheiser A, Spies CD - PLoS ONE (2013)

Physostigmine and neostigmine reduce surgery combined with LPS-induced IL-1beta and TNF-alpha gene expression in the spleen.IL-1beta (A) and TNF-alpha (B) expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h postintervention. Surgery combined with LPS-treatment resulted in an increased gene expression of IL-1beta and TNF-alpha after 1 h and was reduced by physostigmine and neostigmine treatment. IL-10 expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h (C) and 24 h (D) postintervention. Surgery in combination with LPS-treatment led to an increased gene expression of IL-10 after 1 and 24 h and is enhanced by physostigmine and neostigmine application after 1 h. Results of Real-Time PCR quantification are shown as mean ± SEM and normalized to levels of saline treated rats (Control = 100%, n = 8 per group). ***P<0.001 represents the difference between LPS and saline treated groups. ###P<0.001, #P<0.05 represents the difference between LPS and physostigmine or neostigmine treated groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643957&req=5

pone-0062679-g003: Physostigmine and neostigmine reduce surgery combined with LPS-induced IL-1beta and TNF-alpha gene expression in the spleen.IL-1beta (A) and TNF-alpha (B) expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h postintervention. Surgery combined with LPS-treatment resulted in an increased gene expression of IL-1beta and TNF-alpha after 1 h and was reduced by physostigmine and neostigmine treatment. IL-10 expression was measured by quantitative Real-Time PCR in spleen samples extracted 1 h (C) and 24 h (D) postintervention. Surgery in combination with LPS-treatment led to an increased gene expression of IL-10 after 1 and 24 h and is enhanced by physostigmine and neostigmine application after 1 h. Results of Real-Time PCR quantification are shown as mean ± SEM and normalized to levels of saline treated rats (Control = 100%, n = 8 per group). ***P<0.001 represents the difference between LPS and saline treated groups. ###P<0.001, #P<0.05 represents the difference between LPS and physostigmine or neostigmine treated groups.
Mentions: As shown in Fig. 3, surgery accompanied by LPS-treatment augmented IL-1beta (Fig. 3A) and TNF-alpha (Fig. 3B) gene expression in the spleen after 1 h. The cholinergic activation by physostigmine and neostigmine lowered levels of IL-1beta and TNF-alpha in the spleen. In comparison, after 24 h, 3 days and 7 days (data not shown) no increase of IL-1beta or TNF-alpha was detectable.

Bottom Line: Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine.Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha.Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité, Universitätsmedizin Berlin, Germany.

ABSTRACT
Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF-alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD.

Show MeSH
Related in: MedlinePlus