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FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia.

Liesz A, Sun L, Zhou W, Schwarting S, Mracsko E, Zorn M, Bauer H, Sommer C, Veltkamp R - PLoS ONE (2011)

Bottom Line: Additionally, we did not measure a significant reduction in infarct volume at 24 h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment.Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL-1β and IFN-γ at 24 h after MCAO.This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Heidelberg, Heidelberg, Germany. Arthur.Liesz@med.uni-heidelberg.de

ABSTRACT

Background: The contribution of neuroinflammation and specifically brain lymphocyte invasion is increasingly recognised as a substantial pathophysiological mechanism after stroke. FTY720 is a potent treatment for primary neuroinflammatory diseases by inhibiting lymphocyte circulation and brain immigration. Previous studies using transient focal ischemia models showed a protective effect of FTY720 but did only partially characterize the involved pathways. We tested the neuroprotective properties of FTY720 in permanent and transient cortical ischemia and analyzed the underlying neuroimmunological mechanisms.

Methodology/principal findings: FTY720 treatment resulted in substantial reduction of circulating lymphocytes while blood monocyte counts were significantly increased. The number of histologically and flow cytometrically analyzed brain invading T- and B lymphocytes was significantly reduced in FTY720 treated mice. However, despite testing a variety of treatment protocols, infarct volume and behavioural dysfunction were not reduced 7d after permanent occlusion of the distal middle cerebral artery (MCAO). Additionally, we did not measure a significant reduction in infarct volume at 24 h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment. Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL-1β and IFN-γ at 24 h after MCAO. Also, serum cytokine levels of IL-6 and TNF-α were increased in FTY720 treated animals compared to controls.

Conclusions/significance: In the present study we were able to detect a reduction of lymphocyte brain invasion by FTY720 but could not achieve a significant reduction of infarct volumes and behavioural dysfunction. This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia.

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FTY720 changes serum cytokine levels.Serum cytokine concentrations of the pro-inflammatory cytokines IL-6, IFN-γ and TNF-α (A–C) and anti-inflammatory cytokines TGF-β and IL-10 (D,E) were measured in naïve mice and at 24 h and 5d after FTY720 or control treatment. Each assay was performed in duplicate (n = 5, serum sampling as 2–3 individual experiments, assays as one experiment). * P<0.05 between treatment groups at the respective time point.
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pone-0021312-g008: FTY720 changes serum cytokine levels.Serum cytokine concentrations of the pro-inflammatory cytokines IL-6, IFN-γ and TNF-α (A–C) and anti-inflammatory cytokines TGF-β and IL-10 (D,E) were measured in naïve mice and at 24 h and 5d after FTY720 or control treatment. Each assay was performed in duplicate (n = 5, serum sampling as 2–3 individual experiments, assays as one experiment). * P<0.05 between treatment groups at the respective time point.

Mentions: We also analyzed serum cytokine levels in naïve animals and at 24 h and 5d after MCAO in PBS- and FTY720-treated animals to control for systemic humoral alterations. We measured cytokine concentrations of the pro-inflammatory cytokines IL-6, IFN-γ and TNF-α (Fig. 8A-C) as well as the anti-inflammatory cytokines TGF-β and IL-10 (Fig. 8D,E). Interestingly, we detected a significant increase of serum concentrations of IL-6 and TNF-α in naïve animals after FTY720 treatment compared to control animals (Fig. 8A,C). At 24 h after MCAO we also measured an increase of IL-6 levels (Fig. 8A) but a reduction of IFN-γ concentrations in FTY720 treated animals (Fig. 8B). Cytokine levels of the anti-inflammatory cytokines TGF-β and IL-10 were not altered by the treatment (Fig. 8D,E). Taken together, these results might indicate a partial early activation of the systemic immune system by FTY720 administration.


FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia.

Liesz A, Sun L, Zhou W, Schwarting S, Mracsko E, Zorn M, Bauer H, Sommer C, Veltkamp R - PLoS ONE (2011)

FTY720 changes serum cytokine levels.Serum cytokine concentrations of the pro-inflammatory cytokines IL-6, IFN-γ and TNF-α (A–C) and anti-inflammatory cytokines TGF-β and IL-10 (D,E) were measured in naïve mice and at 24 h and 5d after FTY720 or control treatment. Each assay was performed in duplicate (n = 5, serum sampling as 2–3 individual experiments, assays as one experiment). * P<0.05 between treatment groups at the respective time point.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119049&req=5

pone-0021312-g008: FTY720 changes serum cytokine levels.Serum cytokine concentrations of the pro-inflammatory cytokines IL-6, IFN-γ and TNF-α (A–C) and anti-inflammatory cytokines TGF-β and IL-10 (D,E) were measured in naïve mice and at 24 h and 5d after FTY720 or control treatment. Each assay was performed in duplicate (n = 5, serum sampling as 2–3 individual experiments, assays as one experiment). * P<0.05 between treatment groups at the respective time point.
Mentions: We also analyzed serum cytokine levels in naïve animals and at 24 h and 5d after MCAO in PBS- and FTY720-treated animals to control for systemic humoral alterations. We measured cytokine concentrations of the pro-inflammatory cytokines IL-6, IFN-γ and TNF-α (Fig. 8A-C) as well as the anti-inflammatory cytokines TGF-β and IL-10 (Fig. 8D,E). Interestingly, we detected a significant increase of serum concentrations of IL-6 and TNF-α in naïve animals after FTY720 treatment compared to control animals (Fig. 8A,C). At 24 h after MCAO we also measured an increase of IL-6 levels (Fig. 8A) but a reduction of IFN-γ concentrations in FTY720 treated animals (Fig. 8B). Cytokine levels of the anti-inflammatory cytokines TGF-β and IL-10 were not altered by the treatment (Fig. 8D,E). Taken together, these results might indicate a partial early activation of the systemic immune system by FTY720 administration.

Bottom Line: Additionally, we did not measure a significant reduction in infarct volume at 24 h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment.Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL-1β and IFN-γ at 24 h after MCAO.This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Heidelberg, Heidelberg, Germany. Arthur.Liesz@med.uni-heidelberg.de

ABSTRACT

Background: The contribution of neuroinflammation and specifically brain lymphocyte invasion is increasingly recognised as a substantial pathophysiological mechanism after stroke. FTY720 is a potent treatment for primary neuroinflammatory diseases by inhibiting lymphocyte circulation and brain immigration. Previous studies using transient focal ischemia models showed a protective effect of FTY720 but did only partially characterize the involved pathways. We tested the neuroprotective properties of FTY720 in permanent and transient cortical ischemia and analyzed the underlying neuroimmunological mechanisms.

Methodology/principal findings: FTY720 treatment resulted in substantial reduction of circulating lymphocytes while blood monocyte counts were significantly increased. The number of histologically and flow cytometrically analyzed brain invading T- and B lymphocytes was significantly reduced in FTY720 treated mice. However, despite testing a variety of treatment protocols, infarct volume and behavioural dysfunction were not reduced 7d after permanent occlusion of the distal middle cerebral artery (MCAO). Additionally, we did not measure a significant reduction in infarct volume at 24 h after 60 min filament-induced MCAO, and did not see differences in brain edema between PBS and FTY720 treatment. Analysis of brain cytokine expression revealed complex effects of FTY720 on postischemic neuroinflammation comprising a substantial reduction of delayed proinflammatory cytokine expression at 3d but an early increase of IL-1β and IFN-γ at 24 h after MCAO. Also, serum cytokine levels of IL-6 and TNF-α were increased in FTY720 treated animals compared to controls.

Conclusions/significance: In the present study we were able to detect a reduction of lymphocyte brain invasion by FTY720 but could not achieve a significant reduction of infarct volumes and behavioural dysfunction. This lack of neuroprotection despite effective lymphopenia might be attributed to a divergent impact of FTY720 on cytokine expression and possible activation of innate immune cells after brain ischemia.

Show MeSH
Related in: MedlinePlus