Interferon-β alleviates delayed tPA-induced adverse effects via modulation of MMP3/9 production in ischemic stroke

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-β (IFNβ), an FDA-approved drug for the treatment of multiple sclerosis, is a cytokine with immunomodulatory properties. Previous studies, including ours, demonstrated that IFNβ or type I IFN receptor signaling conferred protection against ischemic stroke in preclinical models, suggesting IFNβ might have translational therapeutic potential for the treatment of ischemic stroke. Currently, whether IFNβ could be coadministered with tPA to alleviate delayed tPA-induced adverse effects remains unknown. To elucidate that, IFNβ 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, IFNβ ameliorated delayed tPA–exacerbated brain injury and alleviated adverse effects. Mechanistic studies revealed IFNβ suppressed tPA-enhanced neuroinflammation and MMP3/9 production in the ischemic brain. Furthermore, we identified IFNβ 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 IFNβ 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.

Circular RNA circPHC3 Promotes Cell Death and Apoptosis in Human BMECs After Oxygen Glucose Deprivation via miR-455-5p/TRAF3 Axis in vitro

“… 24 Now, thrombolytic therapy using tissue type plasminogen activator is regarded as the only globally approved treatment for ischemic stroke, but this therapy is limited by a short treatment window of time and low recanalization rates. 25 Thus, refraining from ischemic-reperfusion injury is critical for the treatment of patients with stroke.…”

The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets

“…IFN-b also plays an anti-inflammatory role in cerebrovascular diseases. IFN-b attenuates tight junction protein degradation in brain endothelial cells and affords protection against ischaemic stroke (Kuo et al, 2020). In intracranial hemorrhage, elevated levels of IFN-b and signal transducer and activator of transcription (STAT) 1 are accompanied by reduced levels of NLRP3 inflammasomes, caspase-1, and IL-1b (Wang, Nowrangi, et al, 2018).…”

Thinking Outside the Ischemia Box: Advancements in the Use of Multiple Sclerosis Drugs in Ischemic Stroke

“…The studies employed mice, rats, or rabbits in various stroke models and the majority of these showed a positive effect regarding infarct volume [42][43][44] (additional source: poster of Veldhuis et al at the 2002 ISMRM-10th scientific meeting and exhibition in Honolulu, "Delayed treatment with interferon-beta protects against ischemic stroke", available online) and neurological function regain [44], while one did not show a protective effect and raised safety concerns for the substance [45]. Very recently, Kuo et al (2020) showed that IFN-b reduced the rates of mortality, of hemorrhagic transformation, and of adverse events induced by delayed rTPA administration, which has been associated with aggravated brain injury in a murine IS model [46].…”