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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 protein expression in spleen and plasma.IL-1-alpha, TNF-alpha and IL-10 were measured by Cytometric bead array analysis in spleen (A–C) and plasma (D–F) samples 1 h postintervention. Surgery and LPS-treatment resulted in an increased protein expression of IL-1alpha and TNF-alpha in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1alpha in the spleen. In plasma, surgery accompanied by LPS-treatment caused an increased protein expression of TNF-alpha and IL-10. TNF-alpha concentration was significantly diminished by physostigmine and neostigmine application, whereas the expression of IL-10 did not change significantly. Additionally, IL-1beta expression was quantified by western blot analysis in spleen samples extracted 1 h postintervention (G–H). Surgery and LPS-treatment resulted in an increased protein expression of IL-1beta in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1beta in the spleen. Results of Cytometric bead array and western blot analysis are shown as mean ± SEM (n = 8 per group). ***P<0.001, **P<0.01 represent the difference between LPS and saline treated groups. #P<0.05, ##P<0.01 represent the difference between LPS and physostigmine or neostigmine treated groups.
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pone-0062679-g004: Physostigmine and neostigmine reduce surgery combined with LPS-induced IL-1beta and TNF-alpha protein expression in spleen and plasma.IL-1-alpha, TNF-alpha and IL-10 were measured by Cytometric bead array analysis in spleen (A–C) and plasma (D–F) samples 1 h postintervention. Surgery and LPS-treatment resulted in an increased protein expression of IL-1alpha and TNF-alpha in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1alpha in the spleen. In plasma, surgery accompanied by LPS-treatment caused an increased protein expression of TNF-alpha and IL-10. TNF-alpha concentration was significantly diminished by physostigmine and neostigmine application, whereas the expression of IL-10 did not change significantly. Additionally, IL-1beta expression was quantified by western blot analysis in spleen samples extracted 1 h postintervention (G–H). Surgery and LPS-treatment resulted in an increased protein expression of IL-1beta in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1beta in the spleen. Results of Cytometric bead array and western blot analysis are shown as mean ± SEM (n = 8 per group). ***P<0.001, **P<0.01 represent the difference between LPS and saline treated groups. #P<0.05, ##P<0.01 represent the difference between LPS and physostigmine or neostigmine treated groups.

Mentions: Cytometric bead array analysis in samples from the spleen extracted 1 h postintervention confirmed the upregulation of pro-inflammatory cytokines IL-1alpha (Fig. 4A) and TNF-alpha protein expression after 1 h (Fig. 4B) as well as the inhibition of IL-1alpha by physostigmine and neostigmine. No upregulation of IL-10 protein expression 1 h following surgery treatment with LPS was detectable in the spleen (Fig. 4C). As shown in Fig. 4D, surgery accompanied by LPS-treatment did not trigger an increased IL-1alpha protein expression in the plasma. However, TNF-alpha protein expression was elevated after 1 h (Fig. 4E). The enhanced expression of TNF-alpha after 1 h was significantly decreased by physostigmine and neostigmine. Following surgery and LPS-treatment, IL-10 protein expression in the plasma was detectable after 1 h postintervention and did not change significantly using physostigmine and neostigmine (Fig. 4F). After 24, 72 h or 7 days no increase of pro- or anti-inflammatory protein expression was detectable (data not shown). Additionally, IL-1beta expression was quantified by western blot analysis in spleen samples extracted 1 h postintervention (Fig. 4G–H). Surgery and LPS-treatment resulted in an increased protein expression of IL-1beta in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1beta in the spleen.


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 protein expression in spleen and plasma.IL-1-alpha, TNF-alpha and IL-10 were measured by Cytometric bead array analysis in spleen (A–C) and plasma (D–F) samples 1 h postintervention. Surgery and LPS-treatment resulted in an increased protein expression of IL-1alpha and TNF-alpha in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1alpha in the spleen. In plasma, surgery accompanied by LPS-treatment caused an increased protein expression of TNF-alpha and IL-10. TNF-alpha concentration was significantly diminished by physostigmine and neostigmine application, whereas the expression of IL-10 did not change significantly. Additionally, IL-1beta expression was quantified by western blot analysis in spleen samples extracted 1 h postintervention (G–H). Surgery and LPS-treatment resulted in an increased protein expression of IL-1beta in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1beta in the spleen. Results of Cytometric bead array and western blot analysis are shown as mean ± SEM (n = 8 per group). ***P<0.001, **P<0.01 represent the difference between LPS and saline treated groups. #P<0.05, ##P<0.01 represent 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-g004: Physostigmine and neostigmine reduce surgery combined with LPS-induced IL-1beta and TNF-alpha protein expression in spleen and plasma.IL-1-alpha, TNF-alpha and IL-10 were measured by Cytometric bead array analysis in spleen (A–C) and plasma (D–F) samples 1 h postintervention. Surgery and LPS-treatment resulted in an increased protein expression of IL-1alpha and TNF-alpha in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1alpha in the spleen. In plasma, surgery accompanied by LPS-treatment caused an increased protein expression of TNF-alpha and IL-10. TNF-alpha concentration was significantly diminished by physostigmine and neostigmine application, whereas the expression of IL-10 did not change significantly. Additionally, IL-1beta expression was quantified by western blot analysis in spleen samples extracted 1 h postintervention (G–H). Surgery and LPS-treatment resulted in an increased protein expression of IL-1beta in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1beta in the spleen. Results of Cytometric bead array and western blot analysis are shown as mean ± SEM (n = 8 per group). ***P<0.001, **P<0.01 represent the difference between LPS and saline treated groups. #P<0.05, ##P<0.01 represent the difference between LPS and physostigmine or neostigmine treated groups.
Mentions: Cytometric bead array analysis in samples from the spleen extracted 1 h postintervention confirmed the upregulation of pro-inflammatory cytokines IL-1alpha (Fig. 4A) and TNF-alpha protein expression after 1 h (Fig. 4B) as well as the inhibition of IL-1alpha by physostigmine and neostigmine. No upregulation of IL-10 protein expression 1 h following surgery treatment with LPS was detectable in the spleen (Fig. 4C). As shown in Fig. 4D, surgery accompanied by LPS-treatment did not trigger an increased IL-1alpha protein expression in the plasma. However, TNF-alpha protein expression was elevated after 1 h (Fig. 4E). The enhanced expression of TNF-alpha after 1 h was significantly decreased by physostigmine and neostigmine. Following surgery and LPS-treatment, IL-10 protein expression in the plasma was detectable after 1 h postintervention and did not change significantly using physostigmine and neostigmine (Fig. 4F). After 24, 72 h or 7 days no increase of pro- or anti-inflammatory protein expression was detectable (data not shown). Additionally, IL-1beta expression was quantified by western blot analysis in spleen samples extracted 1 h postintervention (Fig. 4G–H). Surgery and LPS-treatment resulted in an increased protein expression of IL-1beta in the spleen after 1 h. Treatment with the AChE inhibitors physostigmine and neostigmine significantly reduced the expression of IL-1beta in the spleen.

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