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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 neurodegeneration and activity of acetylcholinesterase in the cortex.Representative photomicrographs (original magnification X200) of Hoechst 33342 (left panel) and Fluoro-Jade B (right panel) staining from the cortex (Scale bar = 20 µm) of adult rats which were treated with saline (A), surgery combined with LPS-treatment+saline (B), surgery combined with LPS-treatment+physostigmine (C) or surgery combined with LPS-treatment+neostigmine (D). (E) Comparison of the number of Fluoro-Jade B-positive cells from the cortex of adult rats. (F) Activity of acetylcholinesterase in the cortex after 1 h. Surgery combined with LPS-treatment triggered the number of degenerated neurons and the activity of acetylcholinesterase in the cortex after 1 h. Physostigmine and neostigmine led to significantly reduced neuronal damage and activity of acetylcholinesterase. Number of Fluoro-Jade B-positive cells are shown as mean ± SEM (n = 5–6 per group). **P<0.01 represents the difference between surgery combined with LPS-treatment and saline treated groups. #P<0.05 represents the difference between surgery together with LPS-treatment and in combination with physostigmine or neostigmine treated groups.
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pone-0062679-g005: Physostigmine and neostigmine reduce surgery combined with LPS-induced neurodegeneration and activity of acetylcholinesterase in the cortex.Representative photomicrographs (original magnification X200) of Hoechst 33342 (left panel) and Fluoro-Jade B (right panel) staining from the cortex (Scale bar = 20 µm) of adult rats which were treated with saline (A), surgery combined with LPS-treatment+saline (B), surgery combined with LPS-treatment+physostigmine (C) or surgery combined with LPS-treatment+neostigmine (D). (E) Comparison of the number of Fluoro-Jade B-positive cells from the cortex of adult rats. (F) Activity of acetylcholinesterase in the cortex after 1 h. Surgery combined with LPS-treatment triggered the number of degenerated neurons and the activity of acetylcholinesterase in the cortex after 1 h. Physostigmine and neostigmine led to significantly reduced neuronal damage and activity of acetylcholinesterase. Number of Fluoro-Jade B-positive cells are shown as mean ± SEM (n = 5–6 per group). **P<0.01 represents the difference between surgery combined with LPS-treatment and saline treated groups. #P<0.05 represents the difference between surgery together with LPS-treatment and in combination with physostigmine or neostigmine treated groups.

Mentions: To examine if neuroinflammation is associated with neurodegeneration, brain sections were stained with Fluoro-Jade B, a marker for neurons that undergo cell death and additionally with Hoechst 33342, a marker for DNA. Compared to the control group (Fig. 5A) surgery in combination with LPS-treatment resulted in an increased number of neuronal damage in the cortex after 24 h (Fig. 5B). Treatment with physostigmine (Fig. 5C) and neostigmine (Fig. 5D) led to significantly reduced neuronal damage. The comparison of the number of Fluoro-Jade B-positive cells in the cortex is shown in Fig. 5E. Compared to the control group surgery together with LPS-treatment caused an increased activity of acetylcholinesterase in the cortex after 24 h, which could be diminished by physostigmine and neostigmine (Fig. 5F).


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 neurodegeneration and activity of acetylcholinesterase in the cortex.Representative photomicrographs (original magnification X200) of Hoechst 33342 (left panel) and Fluoro-Jade B (right panel) staining from the cortex (Scale bar = 20 µm) of adult rats which were treated with saline (A), surgery combined with LPS-treatment+saline (B), surgery combined with LPS-treatment+physostigmine (C) or surgery combined with LPS-treatment+neostigmine (D). (E) Comparison of the number of Fluoro-Jade B-positive cells from the cortex of adult rats. (F) Activity of acetylcholinesterase in the cortex after 1 h. Surgery combined with LPS-treatment triggered the number of degenerated neurons and the activity of acetylcholinesterase in the cortex after 1 h. Physostigmine and neostigmine led to significantly reduced neuronal damage and activity of acetylcholinesterase. Number of Fluoro-Jade B-positive cells are shown as mean ± SEM (n = 5–6 per group). **P<0.01 represents the difference between surgery combined with LPS-treatment and saline treated groups. #P<0.05 represents the difference between surgery together with LPS-treatment and in combination with physostigmine or neostigmine treated groups.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3643957&req=5

pone-0062679-g005: Physostigmine and neostigmine reduce surgery combined with LPS-induced neurodegeneration and activity of acetylcholinesterase in the cortex.Representative photomicrographs (original magnification X200) of Hoechst 33342 (left panel) and Fluoro-Jade B (right panel) staining from the cortex (Scale bar = 20 µm) of adult rats which were treated with saline (A), surgery combined with LPS-treatment+saline (B), surgery combined with LPS-treatment+physostigmine (C) or surgery combined with LPS-treatment+neostigmine (D). (E) Comparison of the number of Fluoro-Jade B-positive cells from the cortex of adult rats. (F) Activity of acetylcholinesterase in the cortex after 1 h. Surgery combined with LPS-treatment triggered the number of degenerated neurons and the activity of acetylcholinesterase in the cortex after 1 h. Physostigmine and neostigmine led to significantly reduced neuronal damage and activity of acetylcholinesterase. Number of Fluoro-Jade B-positive cells are shown as mean ± SEM (n = 5–6 per group). **P<0.01 represents the difference between surgery combined with LPS-treatment and saline treated groups. #P<0.05 represents the difference between surgery together with LPS-treatment and in combination with physostigmine or neostigmine treated groups.
Mentions: To examine if neuroinflammation is associated with neurodegeneration, brain sections were stained with Fluoro-Jade B, a marker for neurons that undergo cell death and additionally with Hoechst 33342, a marker for DNA. Compared to the control group (Fig. 5A) surgery in combination with LPS-treatment resulted in an increased number of neuronal damage in the cortex after 24 h (Fig. 5B). Treatment with physostigmine (Fig. 5C) and neostigmine (Fig. 5D) led to significantly reduced neuronal damage. The comparison of the number of Fluoro-Jade B-positive cells in the cortex is shown in Fig. 5E. Compared to the control group surgery together with LPS-treatment caused an increased activity of acetylcholinesterase in the cortex after 24 h, which could be diminished by physostigmine and neostigmine (Fig. 5F).

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