1.Introduction
Acute ischemic stroke (AIS) is the most common type of stroke. It has the characteristics of high morbidity, high mortality, and high disability, which seriously endangers the health and life of patients. (1) Effective treatment after AIS will directly affect the prognosis of patients. (1)
The devastating, often crippling aftermath of stroke makes it second only to cardiac ischemia as a cause of death worldwide. Therapy for AIS centers first on rapid revascularization of arterial territories, with additional focus on managing blood pressure and cerebral edema.(2)Revascularization is currently achieved by the intravenous administration of tissue plasminogen activator (tPA) and intravascular therapy. However, the benefit of tPA is highly time-dependent, considering that pooled analysis has documented loss of benefit beyond 4.5 h from onset of symptoms.(2-4). Despite numerous clinical trials conducted to salvage cells from death, no significant breakthrough has been made to improve the outcome of stroke patients.(2, 5, 6)
Cerebral ischemia-induced cell death swiftly activates the immune system and initiates inflammation within the brain.(7-11)In an early phase, these immune responses appear to exacerbate neurovascular dysfunction by promoting thrombus formation, and accumulation of blood components in the cerebral microvasculature.(11-13)These changes subsequently exacerbate the ischemic cascade catalyzing neural cell death in the penumbra, resulting in the extension of infarction, which potentially limits the efficacy of pharmacologic or mechanical reperfusion. (11, 14-16)
Fingolimod is a sphingosine analog that acts on sphingosine-1-phosphate receptors(S1PR). It was approved by the US. Food and Drug Administration in 2010 as the first oral disease-modifying therapy for the relapsing-remitting form of multiple sclerosis (MS). (17, 18) Fingolimod inhibits the egress of lymphocytes from lymph nodes and limits their recirculation.(18, 19) Additional effects on the integrity of the blood-brain barrier(BBB) and direct action on neurons and glia that bear sphingosine-1-phosphate receptor may also contribute to its beneficial attributes in MS.(18, 20-22) Recently, the safety and efficacy of fingolimod in both patients with intracerebral hemorrhage and patients with AIS have been investigated in proof-of-concept trials.(2, 18) Fingolimod limited the expansion of infarct volume and ameliorated hemorrhagic transformation in patients with acute ischemic stroke who received intravenous alteplase within 4.5 hours after stroke onset(11, 18), Meanwhile, in patients with acute anterior circulation occlusion who are >4.5 hours after disease onset, fingolimod significantly improved the clinical outcome, reduced secondary lesion growth, and decreased microvascular permeability. (18) In this systematic review, we performed a meta-analysis to evaluate the efficacy and safety of fingolimod for acute ischemic stroke.