Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis

Nikolaos Memos, Alex Betrosian, Evangelos Messaris, Maria Boutsikou, Agapi Kataki, Emmy Chatzigianni, Marilena Nikolopoulou, Emmanuel Leandros, Manousos Konstadoulakis

Research output: Contribution to journalArticle

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Abstract

Activated Protein C renders anti-apoptotic properties in neurons and endothelial cells. The aim of the present study was to evaluate the in vivo cytoprotective role of Protein C zymogen (PC) administration in septic rat brain. Male Wistar rats (n = 60) were subjected to sepsis via Cecal Ligation and Puncture (CLP). Animals were randomly divided either to receive 100 IU/kg human PC concentrate at 1, 7 and 13 h post CLP (CLP + PC group) or placebo treatment (CLP group). At pre-specified time points (6, 12, 24, 36, 48 and 60 h post CLP) five animals from either group were euthanized and the brain tissue was removed. Apoptosis in both neurons (Neu-N+) and astroglia (GFAP+) was assessed by flow cytometry using 7-aminoactinomycin D (7AAD). Immunohistochemical detection of cleaved caspase 3, bax, bcl-2, cytochrome c and caspase 8 was also performed. PC treated animals had significantly reduced apoptosis in neurons at 6 and 24 h post CLP (p = 0.04 and p = 0.016 respectively) and necrosis at 6, 12 and 60 h post CLP (p = 0.008, p = 0.012 and p = 0.032 respectively). Astrocyte necrosis was also decreased in septic rats receiving PC (6, 12 and 60 h post CLP p = 0.008, p = 0.016 and p = 0.008 respectively). In addition, active caspase 3, bax, cytochrome c and caspase 8 expression was significantly decreased during early sepsis (6-36 h) while bcl-2 expression was increased (24 h p = 0.001 and 60 h p = 0.001) in the PC treated animals compared to placebo. PC concentrate administration in experimental sepsis produced a time dependent inhibition of apoptosis in rat neurons and astrocytes. The inhibition of sepsis related apoptosis concerned both the mitochondrial and caspase 8 dependent pathways.

Original languageEnglish (US)
Pages (from-to)119-126
Number of pages8
JournalBrain research
Volume1264
DOIs
StatePublished - Apr 6 2009

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Brain Death
Enzyme Precursors
Protein C
Punctures
Sepsis
Cell Death
Ligation
Caspase 8
Astrocytes
Apoptosis
Neurons
Cytochromes c
Caspase 3
Necrosis
Placebos
Brain
Wistar Rats
Flow Cytometry
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

Memos, N., Betrosian, A., Messaris, E., Boutsikou, M., Kataki, A., Chatzigianni, E., ... Konstadoulakis, M. (2009). Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis. Brain research, 1264, 119-126. https://doi.org/10.1016/j.brainres.2009.01.053
Memos, Nikolaos ; Betrosian, Alex ; Messaris, Evangelos ; Boutsikou, Maria ; Kataki, Agapi ; Chatzigianni, Emmy ; Nikolopoulou, Marilena ; Leandros, Emmanuel ; Konstadoulakis, Manousos. / Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis. In: Brain research. 2009 ; Vol. 1264. pp. 119-126.
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abstract = "Activated Protein C renders anti-apoptotic properties in neurons and endothelial cells. The aim of the present study was to evaluate the in vivo cytoprotective role of Protein C zymogen (PC) administration in septic rat brain. Male Wistar rats (n = 60) were subjected to sepsis via Cecal Ligation and Puncture (CLP). Animals were randomly divided either to receive 100 IU/kg human PC concentrate at 1, 7 and 13 h post CLP (CLP + PC group) or placebo treatment (CLP group). At pre-specified time points (6, 12, 24, 36, 48 and 60 h post CLP) five animals from either group were euthanized and the brain tissue was removed. Apoptosis in both neurons (Neu-N+) and astroglia (GFAP+) was assessed by flow cytometry using 7-aminoactinomycin D (7AAD). Immunohistochemical detection of cleaved caspase 3, bax, bcl-2, cytochrome c and caspase 8 was also performed. PC treated animals had significantly reduced apoptosis in neurons at 6 and 24 h post CLP (p = 0.04 and p = 0.016 respectively) and necrosis at 6, 12 and 60 h post CLP (p = 0.008, p = 0.012 and p = 0.032 respectively). Astrocyte necrosis was also decreased in septic rats receiving PC (6, 12 and 60 h post CLP p = 0.008, p = 0.016 and p = 0.008 respectively). In addition, active caspase 3, bax, cytochrome c and caspase 8 expression was significantly decreased during early sepsis (6-36 h) while bcl-2 expression was increased (24 h p = 0.001 and 60 h p = 0.001) in the PC treated animals compared to placebo. PC concentrate administration in experimental sepsis produced a time dependent inhibition of apoptosis in rat neurons and astrocytes. The inhibition of sepsis related apoptosis concerned both the mitochondrial and caspase 8 dependent pathways.",
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Memos, N, Betrosian, A, Messaris, E, Boutsikou, M, Kataki, A, Chatzigianni, E, Nikolopoulou, M, Leandros, E & Konstadoulakis, M 2009, 'Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis', Brain research, vol. 1264, pp. 119-126. https://doi.org/10.1016/j.brainres.2009.01.053

Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis. / Memos, Nikolaos; Betrosian, Alex; Messaris, Evangelos; Boutsikou, Maria; Kataki, Agapi; Chatzigianni, Emmy; Nikolopoulou, Marilena; Leandros, Emmanuel; Konstadoulakis, Manousos.

In: Brain research, Vol. 1264, 06.04.2009, p. 119-126.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis

AU - Memos, Nikolaos

AU - Betrosian, Alex

AU - Messaris, Evangelos

AU - Boutsikou, Maria

AU - Kataki, Agapi

AU - Chatzigianni, Emmy

AU - Nikolopoulou, Marilena

AU - Leandros, Emmanuel

AU - Konstadoulakis, Manousos

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