VPC-23019 and Brain-Edema

Although sphingosine 1-phosphate (S1P) receptor activation by FTY720 (fingolimod) has been suggested to improve the prognosis of experimental stroke, the effect of the drug in early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the precise mechanism of the effect are undetermined. In this study, we investigated the protective effect of systemic administration of FTY720 in EBI after SAH and assessed the mechanism using intracerebroventricular infusion of VPC23019 which is the S1P receptor antagonist.. SAH rats were produced by the endovascular perforation model and injected saline or 1mg/kg FTY720 intraperitoneally at 30 minutes after SAH induction. Neurological function, cerebral blood flow, amount of subarachnoid blood, and brain edema were evaluated to confirm the protective effect of systemic administration of FTY720. SAH rats also received VPC23019 intraventricularly before SAH induction to abolish the central S1P receptor activation.. Systemic administration of FTY720 significantly ameliorated SAH-induced neurological deficits and brain edema without modulation of CBF and the amount of subarachnoid blood. Blockage of central S1P receptor with VPC23019 did not abolish the protective effects of FTY720.. The present study suggests that systemic administration of FTY720 reduces EBI after SAH and that the effect might not come from central S1P activation but be associated with pleiotropic actions of the drug.

Topics: Animals; Brain; Brain Edema; Disease Models, Animal; Fingolimod Hydrochloride; Male; Neuroprotective Agents; Phosphoserine; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Subarachnoid Hemorrhage

Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals killed at 4 weeks post-GMH received low- or high-dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals killed at 72 h post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 h post-surgery. At 72 h post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 h post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway.

Topics: Animals; Body Water; Brain; Brain Chemistry; Brain Edema; Cognition; Female; Fingolimod Hydrochloride; Intracranial Hemorrhages; Leukocyte Count; Male; Neuroprotective Agents; Oxadiazoles; Phosphoserine; Pregnancy; Pyrones; Quinolines; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Thiophenes; Tight Junction Proteins