Abstract
The bioactive, signaling lipid, sphingosine-1-phosphate (S1P), and its analog, fingolimod (FTY720), have previously shown neuroprotective effects against ischemic brain injury. However, the underlying mechanisms have not yet been fully clarified. The roles of autophagy in ischemic stroke are being increasingly recognized. In the present study, we sought to determine whether the S1P pathway is involved in neuronal autophagy and investigate its possible mechanisms following stroke. Interestingly, we found that FTY720 significantly attenuates infarct volumes and reduces neuronal apoptosis on days 1 and 3 post stroke, accompanied by amelioration of functional deficits. Additionally, FTY720 was found to decrease the induction of autophagosome proteins, microtubule-associated protein 1 light chain 3(LC3-II) and Beclin1, following ischemic stroke in a dose-dependent manner. Meanwhile, protein levels of the mammalian target of rapamycin (mTOR) and the 70-kDa ribosomal protein, S6 kinase1 (p70S6K), were also up-regulated in FTY720-treated animals, and the nonspecific SphK inhibitor, N,N-dimethylsphingosine (DMS), was found to cause a reverse effect. Our results indicate that modulation of the S1P signaling pathway by FTY720 could effectively decrease neuronal autophagy through the mTOR/p70S6K pathway and attenuate ischemic brain injury in mice.
Highlights
Ischemic stroke is a devastating disease that is a major cause of death and disability, worldwide [1]
Infarct volumes by Magnetic Resonance Imaging (MRI) detection were significantly reduced at day 1 and 3 after photothrombotic ischemia (PT) in the ischemia+FTY720 group, compared to that in the ischemia+vehicle group (Fig 1A and 1B)
Our results showed that the recovery of neurological deficits was accelerated by FTY720 administration (Fig 1C), indicating that the application of FTY720 could attenuate ischemiainduced brain injury
Summary
Ischemic stroke is a devastating disease that is a major cause of death and disability, worldwide [1]. There is a need to develop novel and effective therapies; especially, for patients with acute cerebral ischemia. Ischemic stroke triggers many detrimental cascades that mediate pathological changes including excitotoxicity, oxidative stress, inflammation, and apoptosis [2]. Recent experimental studies suggest a pivotal role of autophagy in post-ischemic changes of various organs, including the brain [3].
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