Impact of an immune modulator fingolimod on acute ischemic stroke

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (51), p.18315-18320
• Main Authors: Fu, Ying, Zhang, Ningnannan, Ren, Li, Yan, Yaping, Sun, Na, Li, Yu-Jing, Han, Wei, Xue, Rong, Liu, Qiang, Hao, Junwei, Yu, Chunshui, Shi, Fu-Dong
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological Sciences; Blood; Brain; Brain Ischemia - drug therapy; Case-Control Studies; Central nervous system; Dosage; Female; Fingolimod Hydrochloride; Health outcomes; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Infections; Lesions; Lymphocyte Subsets; Lymphocytes; Male; Medical treatment; Middle Aged; NMR; Nuclear magnetic resonance; Permeability; Propylene Glycols - adverse effects; Propylene Glycols - therapeutic use; Single-Blind Method; Sphingosine - adverse effects; Sphingosine - analogs & derivatives; Sphingosine - therapeutic use; Stroke - drug therapy; Strokes; T lymphocytes; Tissues
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1416166111

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. Significance In patients with acute ischemic stroke (AIS), the abrupt and massive influx of lymphocytes from the periphery to the ischemic region orchestrates focal inflammatory responses, catalyzes tissue death, and worsens clinical outcomes. In this early phase clinical study, we reduced lymphocyte migration to the brain during the first 72 h of AIS via oral administration of three doses of fingolimod. This administration led to a significant reduction of secondary lesion enlargement, microvascular permeability, and better clinical outcomes during the acute phase and 3-mo follow-up visit. This study will provoke new investigations on the efficacy of modulation of brain inflammation in AIS.