Potential molecular targets of peroxynitrite in mediating blood–brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment

Abstract

Tissue plasminogen activator (t-PA) remains to be the only FDA-approved drug for ischaemic stroke, but it has a restrictive therapeutic window with 4.5 hours. Beyond the golden time window, thrombolytic treatment carries the risk of haemorrhagic transformation (HT). The blood–brain barrier (BBB) disruption is a critical step in the t-PA-mediated HT. Although large efforts are made to explore the mechanisms of the BBB disruption and HT, the underlying mechanisms are largely unknown. Thrombolytic treatment for recanalization could produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) and mediate cerebral ischaemia–reperfusion injury. RNS, including nitric oxide (NO) and peroxynitrite (ONOO⁻), are important players in cerebral ischaemia–reperfusion injury. In particular, ONOO⁻ and its derivatives could mediate neurovascular unit damages and induce the BBB disruption and HT possibly through interacting with different cellular signalling pathways including matrix metalloproteinase (MMPs), high mobility group Box 1 (HMGB1), toll-like receptor2/4, poly(ADP-ribose) polymerase, Src, ROCK, and GSK-3β. Herein, we review current progress about the roles of ONOO⁻ in mediating those signalling pathways and their impacts on the t-PA-induced BBB disruption and HT. Subsequently, we discuss the values of natural compounds with the properties of scavenging ONOO⁻ as adjunctive therapies to extend the therapeutic window of t-PA and attenuate haemorrhage transformation in ischaemic stroke.

Keywords:

• GSK-3β
• HMGB1
• HT
• MMP-9
• peroxynitrite
• rock
• Src
• stroke
• tissue plasminogen activator

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work is supported by Hong Kong General Research Fund [GRF No. 17102915, GRF No. 17118717], Research Grant Council, Hong Kong SAR and Health and Medical Research Fund, Hong Kong SAR [No. 13142901], Areas of Excellence Scheme, RGC, Hong Kong SAR [AoE/P-705/16]; Shenzhen Basic Research Plan Project [SIRI/04/04/2015/06], and Innovation and Technology Fund, HKSAR [UIM/289].