Interferon-ß alleviates delayed tPA-induced adverse effects via modulation of MMP3/9 production in ischemic stroke.
Blood Adv
; 4(18): 4366-4381, 2020 09 22.
Article
em En
| MEDLINE
| ID: mdl-32926126
ABSTRACT
Tissue plasminogen activator (tPA) is the only US Food and Drug Administration (FDA)-approved drug for ischemic stroke. However, delayed tPA administration is associated with increased risk of blood-brain barrier (BBB) disruption and hemorrhagic transformation (HT). Interferon-ß (IFNß), an FDA-approved drug for the treatment of multiple sclerosis, is a cytokine with immunomodulatory properties. Previous studies, including ours, demonstrated that IFNß or type I IFN receptor signaling conferred protection against ischemic stroke in preclinical models, suggesting IFNß might have translational therapeutic potential for the treatment of ischemic stroke. Currently, whether IFNß could be coadministered with tPA to alleviate delayed tPA-induced adverse effects remains unknown. To elucidate that, IFNß was coadministered with delayed tPA to ischemic stroke animals, and the severity and pathology of ischemic brain injury were assessed. We found delayed tPA treatment exacerbated ischemic brain injury, manifested by aggravated BBB disruption and HT. Notably, IFNß ameliorated delayed tPA-exacerbated brain injury and alleviated adverse effects. Mechanistic studies revealed IFNß suppressed tPA-enhanced neuroinflammation and MMP3/9 production in the ischemic brain. Furthermore, we identified IFNß suppressed MMP9 production in microglia and attenuated tight junction protein degradation in brain endothelial cells. Moreover, we observed that peripheral immune cells may participate to a lesser extent in delayed tPA-exacerbated brain injury during the early phase of ischemic stroke. In conclusion, we provide the first evidence that IFNß can be coadministered with tPA to mitigate delayed tPA-induced adverse effects of BBB disruption and HT that could potentially extend the tPA therapeutic window for the treatment of ischemic stroke.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Isquemia Encefálica
/
Acidente Vascular Cerebral
/
AVC Isquêmico
Limite:
Animals
País/Região como assunto:
America do norte
Idioma:
En
Revista:
Blood Adv
Ano de publicação:
2020
Tipo de documento:
Article