Impact of an immune modulator fingolimod on acute ischemic stroke

Abstract

Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. −1, respectively (P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery.acute ischemic stroke | immune modulation | fingolimod

Clinical Trials of Immunomodulation in Ischemic Stroke

“…Candidates for intravenous thrombolysis were excluded. Fingolimod restricted enlargement of the infarct volume on sequential MRI between day 1 and day 7 and reduced blood-brain barrier permeability on contrast MRI [67]. The treatment was also associated with short-term neurological improvements, and no significant excess of adverse events was noted [67].…”

“…In an open-label, 3-center pilot study enrolling 22 patients in China, fingolimod (0.5 mg/day for 3 days) on top of routine medical management or routine management alone was administered to patients within a time window of between at least 4.5 h and 72 h after symptom onset [67]. Candidates for intravenous thrombolysis were excluded.…”

Thromboinflammation in Stroke Brain Damage

“…83 Apart from novel compounds that in the first place counteract thrombus formation, there are several interesting studies on novel immunomodulatory agents in acute stroke therapy. Recently, Fu et al 84 reported that oral fingolimod, a compound that sequesters circulating lymphocytes within their lymphoid organs and that is approved for the treatment of relapsing-remitting multiple sclerosis, administered within 72 hours of stroke onset was safe, limited secondary tissue injury from baseline to 7 days, decreased microvascular permeability, and attenuated neurological deficits. In addition, combination of fingolimod together with alteplase attenuated reperfusion injury and improved clinical outcomes in patients with stroke in another pilot study.…”

Antigen Presentation After Stroke

“…Immunomodulatory drugs that are used in patients with MS are now being tested in stroke. For instance, fingolimod, a drug that induces lymphopenia and prevents lymphocyte access to the brain, has shown beneficial effects in stroke animal models [145] and in small clinical trials in ischemic patients with stroke [146,147]. Also, natalizumab, a drug that inhibits leukocyte infiltration, seems to exert some benefits in human stroke (ACTION trial), and a corresponding mouse anti-CD49d antibody has shown protective effects but only in 1 of 2 experimental models of brain ischemia [148].…”