FTY720 treatment in the convalescence period improves functional recovery and reduces reactive astrogliosis in photothrombotic stroke.
BACKGROUND
The Sphingosine-1-phosphate (S1P) signaling pathway is known to influence pathophysiological processes within the brain and the synthetic S1P analog FTY720 has been shown to provide neuroprotection in experimental models of acute stroke. However, the effects of a manipulation of S1P signaling at later time points after experimental stroke have not yet been investigated. We examined whether a relatively late initiation of a FTY720 treatment has a positive effect on long-term neurological outcome with a focus on reactive astrogliosis, synapses and neurotrophic factors.


METHODS
We induced photothrombotic stroke (PT) in adult C57BL/6J mice and allowed them to recover for three days. Starting on post-stroke day 3, mice were treated with FTY720 (1 mg/kg b.i.d.) for 5 days. Behavioral outcome was observed until day 31 after photothrombosis and periinfarct cortical tissue was analyzed using tandem mass-spectrometry, TaqMan®analysis and immunofluorescence.


RESULTS
FTY720 treatment results in a significantly better functional outcome persisting up to day 31 after PT. This is accompanied by a significant decrease in reactive astrogliosis and larger post-synaptic densities as well as changes in the expression of vascular endothelial growth factor α (VEGF α). Within the periinfarct cortex, S1P is significantly increased compared to healthy brain tissue.


CONCLUSIONS
Besides its known neuroprotective effects in the acute phase of experimental stroke, the initiation of FTY720 treatment in the convalescence period has a positive impact on long-term functional outcome, probably mediated through reduced astrogliosis, a modulation in synaptic morphology and an increased expression of neurotrophic factors.
Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany. robert.brunkhorst@kgu.de
Robert
R
Brunkhorst
Nathalie
N
Kanaan
Alexander
A
Koch
Nerea
N
Ferreirós
Ana
A
Mirceska
Pia
P
Zeiner
Michel
M
Mittelbronn
Amin
A
Derouiche
Helmuth
H
Steinmetz
Christian
C
Foerch
Josef
J
Pfeilschifter
Waltraud
W
Pfeilschifter
D000446:Aldehyde-Lyases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003289:Convalescence; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression / Q000187:drug effects; D005911:Gliosis / Q000503:physiopathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D020767:Intracranial Thrombosis / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057907:Post-Synaptic Density / Q000187:drug effects; D011409:Propylene Glycols / Q000378:metabolism / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D020521:Stroke / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D042461:Vascular Endothelial Growth Factor A; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D000068876:Fingolimod Hydrochloride; D013110:Sphingosine