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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 does not affect basal cardiovascular parameters.Mean arterial pressure (A) and cerebral blood flow (B) were recorded for 10 min before and 180 min after oral administration of 1 mg/kg FTY720 in 100 µl PBS or 100 µl PBS alone. Values are expressed as relative units in relation to baseline values before the respective treatment (n = 3 per group, each mouse was an individual experiment).
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pone-0021312-g005: FTY720 does not affect basal cardiovascular parameters.Mean arterial pressure (A) and cerebral blood flow (B) were recorded for 10 min before and 180 min after oral administration of 1 mg/kg FTY720 in 100 µl PBS or 100 µl PBS alone. Values are expressed as relative units in relation to baseline values before the respective treatment (n = 3 per group, each mouse was an individual experiment).

Mentions: We investigated the effect of FTY720 on basal physiological parameters to exclude major cardiovascular side effects of the treatment. Therefore, we continuously measured mean intra-arterial pressure (MAP) after catherization of the femoral artery (Fig. 5A) and relative cerebral blood flow by laser doppler analysis (Fig. 5B) for 10 min before and 180 min after oral FTY720 administration. We did not detect a significant alteration of those parameters between treatment groups.


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 does not affect basal cardiovascular parameters.Mean arterial pressure (A) and cerebral blood flow (B) were recorded for 10 min before and 180 min after oral administration of 1 mg/kg FTY720 in 100 µl PBS or 100 µl PBS alone. Values are expressed as relative units in relation to baseline values before the respective treatment (n = 3 per group, each mouse was an individual experiment).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0021312-g005: FTY720 does not affect basal cardiovascular parameters.Mean arterial pressure (A) and cerebral blood flow (B) were recorded for 10 min before and 180 min after oral administration of 1 mg/kg FTY720 in 100 µl PBS or 100 µl PBS alone. Values are expressed as relative units in relation to baseline values before the respective treatment (n = 3 per group, each mouse was an individual experiment).
Mentions: We investigated the effect of FTY720 on basal physiological parameters to exclude major cardiovascular side effects of the treatment. Therefore, we continuously measured mean intra-arterial pressure (MAP) after catherization of the femoral artery (Fig. 5A) and relative cerebral blood flow by laser doppler analysis (Fig. 5B) for 10 min before and 180 min after oral FTY720 administration. We did not detect a significant alteration of those parameters between treatment groups.

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