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Vinpocetine Inhibits NF-κB-Dependent Inflammation in Acute Ischemic Stroke Patients

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Abstract

Immunity and inflammation play critical roles in the pathogenesis of acute ischemic stroke. Therefore, immune intervention, as a new therapeutic strategy, is worthy of exploration. Here, we tested the inflammation modulator, vinpocetine, for its effect on the outcomes of stroke. For this multi-center study, we recruited 60 patients with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h but lasted less than 48 h. These patients, after random division into two groups, received either standard management alone (controls) or standard management plus vinpocetine (30 mg per day intravenously for 14 consecutive days, Gedeon Richter Plc., Hungary). Vinpocetine treatment did not change the lymphocyte count; however, nuclear factor kappa-light-chain-enhancer of activated B cell activation was inhibited as seen not only by the increased transcription of IκBα mRNA but also by the impeded phosphorylation and degradation of IκBα and subsequent induction of pro-inflammatory mediators. These effects led to significantly reduced secondary lesion enlargement and an attenuated inflammation reaction. Compared to controls, patients treated with vinpocetine had a better recovery of neurological function and improved clinical outcomes during the acute phase and at 3-month follow-up. These findings identify vinpocetine as an inflammation modulator that could improve clinical outcomes after acute ischemic stroke. This study also indicated the important role of immunity and inflammation in the pathogenesis of acute ischemic stroke and the significance of immunomodulatory treatment. Clinical Trial Registration Information: www.clinicaltrials.gov. Identifier: NCT02878772

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Acknowledgements

We thank our patients for participating this study and to Yao YR and Lu HY for facilitating recruitment of the patients; we also thank Shi HL for technical support. This work was financially supported by the National Basic Research Program of China (2013CB966900 to FDS), the National Natural Science Foundation of China (81571600, 81322018, 81273287, and 81100887 to JWH), the Youth Top-Notch Talent Support Program, and the National Key Clinical Specialty Construction Project of China.

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Authors and Affiliations

  1. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road, Heping District, Tianjin, 300052, China

    Fang Zhang, Changjuan Wei, Yang Yao, Xiaofeng Ma, Fu-Dong Shi & Junwei Hao

  2. Aab Cardiovascular Research Institute and Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA

    Chen Yan

  3. Department of Neurology, Tianjin First Central Hospital, Tianjin, 300192, China

    Zhongying Gong & Dawei Zang

  4. Department of Neurology, Tianjin Huanhu Hospital, Tianjin, 30006, China

    Shoufeng Liu

  5. Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA

    Jieli Chen

  6. Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 85013, USA

    Fu-Dong Shi

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  1. Fang Zhang
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Correspondence to Junwei Hao.

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The authors declare that they have no conflict of interest.

Funding

This work was financially supported by the National Basic Research Program of China (2013CB966900 to FDS), the National Natural Science Foundation of China (81571600, 81322018, 81273287, and 81100887 to JWH), the Youth Top-Notch Talent Support Program, and the National Key Clinical Specialty Construction Project of China.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

Electronic Supplementary Material

Supplemental Figure 1

Comparison of infection rates in recipients of vinpocetine or standard treatment. In another retrospective study of infection associated with stroke, we collected records from 200 patients with acute ischemic stroke who received only standard treatment, then compared the scores with those from 200 age-, gender- and infarct volume-matched patients with acute ischemic stroke (control vs vinpocetine: Female, n, 74 vs 79; age, year, 61.3 ± 16.7 vs 65.1 ± 19.2) who received standard treatment and vinpocetine (30 mg per day intravenously for 14 consecutive days). The inclusion and exclusion criteria were as follows: Inclusions: (1) >18 years of age; (2) Anterior-circulation ischemic stroke: All patients had symptoms of focal neurological deficits and radiological evidence (nuclear magnetic resonance, NMR) of a concurrent ischemic brain lesion; (3) measurable neurological deficit (NIHSS ≥3). Exclusion criteria were (1) evidence of other diseases of the central nervous system (CNS); (2) diabetes mellitus; (3) tumor and hematological system diseases; (4) any infection before acute ischemic stroke; (5) concomitant use of antineoplastic or immune modulating therapies. (A) The infection rate of vinpocetine group (13%) was lower than that of the control group (28%). Statistically significant differences were found between these groups (P = 0.014 Chi-square text). (B) Among the infected patients of vinpocetine group, 88% were respiratory infection and the last 12% were urinary infection. In the control group, respiratory infections account for 74%, urinary infections account for 20%, oral and ocula infections account for 3% respectively. (DOCX 48.1 kb).

Supplemental Figure 2

Dynamics of lymphocyte subsets during vinpocetine treatment. The dynamic changes of lymphocyte subsets were monitored at baseline (<48 h after stroke onset) in whole-blood samples from all patients to receive vinpocetine, preceding the first dose, and then at days 3 and 7 after the first vinpocetine dose. These values were compared with those from control patients (no vinpocetine) at the same time points. Peripheral blood mononuclear cells were isolated from the whole-blood specimens and stained with antibodies to CD4-FITC, CD8-PE, CD3-PerCP, CD19-APC, CD11c-FITC and CD56-APC (BD Biosciences, Franklin Lakes, NJ, USA). Data were acquired using a FACS Calibur (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA) and analyzed with Flow Jo software (Tree Star, Ashland, OR, USA). At baseline, day 3 and day 7 after symptom onset, the lymphocyte counts and percentages of CD4+ T, CD8+ T, CD19+ B, CD56+ NK and CD11c+ DC cells in the vinpocetine group were similar to those of controls. These results suggest that vinpocetine exerts anti-inflammatory effects but not by decreasing the number of lymphocytes. Data represent means ± SE (DOCX 68.9 kb).

Supplementary Figure 3

Baseline characteristics. (a) NIHSS score and (b) lesion volume of two goups at baseline. Values are means ± SE. (DOCX 67.3 kb).

Supplementary Figure 4

Lesion volumes compared between two groups. Lesion volumes did not differ significantly between the vinpocetine-treated group and control group at baseline and day 7. Values are means ± SE. (DOCX 46.4 kb).

Supplemental Table 1

(DOCX 30 kb).

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Zhang, F., Yan, C., Wei, C. et al. Vinpocetine Inhibits NF-κB-Dependent Inflammation in Acute Ischemic Stroke Patients. Transl. Stroke Res. 9, 174–184 (2018). https://doi.org/10.1007/s12975-017-0549-z

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