The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia.

Abstract

Cerebral ischemia is accompanied by fulminant cellular and humoral inflammatory changes in the brain which contribute to lesion development after stroke. A tight interplay between the brain and the peripheral immune system leads to a biphasic immune response to stroke consisting of an early activation of peripheral immune cells with massive production of proinflammatory cytokines followed by a systemic immunosuppression within days of cerebral ischemia that is characterized by massive immune cell loss in spleen and thymus. Recent work has documented the importance of T lymphocytes in the early exacerbation of ischemic injury. The lipid signaling mediator sphingosine 1-phosphate-derived stable analog FTY720 (fingolimod) acts as an immunosuppressant and induces lymphopenia by preventing the egress of lymphocytes, especially T cells, from lymph nodes. We found that treatment with FTY720 (1mg/kg) reduced lesion size and improved neurological function after experimental stroke in mice, decreased the numbers of infiltrating neutrophils, activated microglia/macrophages in the ischemic lesion and reduced immunohistochemical features of apoptotic cell death in the lesion.

• Authors: Bozena Czech, Waltraud Pfeilschifter, Niloufar Mazaheri-Omrani, Marc André Strobel, Timo Kahles, Tobias Neumann-Haefelin, Abdelhaq Rami, Andrea Huwiler, Josef Pfeilschifter
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 389 Issue 2 Pg. 251-6 (Nov 13 2009) ISSN: 1090-2104 [Electronic] United States
• PMID: 19720050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Inducing Factor
• Immunosuppressive Agents
• Lysophospholipids
• Neuroprotective Agents
• Propylene Glycols
• sphingosine 1-phosphate
• Fingolimod Hydrochloride
• Sphingosine

Topics

• Active Transport, Cell Nucleus
• Animals
• Apoptosis (drug effects)
• Apoptosis Inducing Factor (metabolism)
• Blood-Brain Barrier (drug effects)
• Brain (drug effects, pathology)
• Brain Ischemia (drug therapy, immunology, pathology)
• Fingolimod Hydrochloride
• Immunosuppressive Agents (therapeutic use)
• Lysophospholipids (therapeutic use)
• Macrophages (drug effects, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, immunology)
• Neuroprotective Agents (therapeutic use)
• Neutrophils (drug effects, immunology)
• Propylene Glycols (therapeutic use)
• Sphingosine (analogs & derivatives, therapeutic use)