Protease-independent action of tissue plasminogen activator in brain plasticity and neurological recovery after ischemic stroke

Abstract

Emerging evidence suggests that tissue plasminogen activator (tPA), currently the only FDA-approved medication for ischemic stroke, exerts important biological actions on the CNS besides its well-known thrombolytic effect. In this study, we investigated the role of tPA on primary neurons in culture and on brain recovery and plasticity after ischemic stroke in mice. Treatment with recombinant tPA stimulated axonal growth in culture, an effect independent of its protease activity and achieved through epidermal growth factor receptor (EGFR) signaling. After permanent focal cerebral ischemia, tPA knockout mice developed more severe sensorimotor and cognitive deficits and greater axonal and myelin injury than wild-type mice, suggesting that endogenously expressed tPA promotes long-term neurological recovery after stroke. In tPA knockout mice, intranasal administration of recombinant tPA protein 6 hours poststroke and 7 more times at 2 d intervals mitigated white matter injury, improved axonal conduction, and enhanced neurological recovery. Consistent with the proaxonal growth effects observed in vitro, exogenous tPA delivery increased poststroke axonal sprouting of corticobulbar and corticospinal tracts, which might have contributed to restoration of neurological functions. Notably, recombinant mutant tPA-S478A lacking protease activity (but retaining the EGF-like domain) was as effective as wild-type tPA in rescuing neurological functions in tPA knockout stroke mice. These findings demonstrate that tPA improves long-term functional outcomes in a clinically relevant stroke model, likely by promoting brain plasticity through EGFR signaling. Therefore, treatment with the protease-dead recombinant tPA-S478A holds particular promise as a neurorestorative therapy, as the risk for triggering intracranial hemorrhage is eliminated and tPA-S478A can be delivered intranasally hours after stroke.

In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

“…BDNF is an abundant growth factor that is involved in activity-induced neuroplasticity and is upregulated in the animal brain by exercise. The regulation of neuroplasticity depends on a complex set of interactions between a variety of neural proteins, including postsynaptic density 95 (PSD-95; Wang et al, 2019 ), synapsin I (SYN; Pan et al, 2017 ), growth-associated protein 43 (GAP-43), and microtubule-associated protein (also known as Tau; Biundo et al, 2018 ; Mercerón-Martínez et al, 2018 ; Pu et al, 2019 ). Changes in these neuroplastic factors are related to exercise-induced activation of BDNF (Kim and Leem, 2016 ; Belviranli and Okudan, 2019 ).…”

A Novel Cerebroprotein Hydrolysate, CH1, Ameliorates Chronic Focal Cerebral Ischemia Injury by Promoting White Matter Integrity via the Shh/Ptch-1/Gli-1 Signaling Pathway

“…Therefore, we investigated the impact of CH1 on the microstructural changes in white matter intensity (WMI) 28 days after dMCAO by double-label immunostaining for MBP (a marker of mature myelin oligodendrocytes, indicating myelin) and SMI-32 (a marker of non-phosphorylated neurofilament H, indicating demyelination) in the peri-infarct cortex (CTX) and striatum (STR). 31 …”

“…Therefore, we investigated the impact of CH1 on the microstructural changes in white matter intensity (WMI) submit your manuscript | www.dovepress.com 28 days after dMCAO by double-label immunostaining for MBP (a marker of mature myelin oligodendrocytes, indicating myelin) and SMI-32 (a marker of nonphosphorylated neurofilament H, indicating demyelination) in the peri-infarct cortex (CTX) and striatum (STR). 31 In sham-operated animals, abundant staining with MBP was visible in both CTX and STR, whereas SMI-32 staining was barely detectable in these regions. dMCAO caused an increase in SMI-32 immunofluorescence and a concomitant reduction in MBP in CTX and STR.…”

Neuroprotective effect of a new free radical scavenger HL-008 against ischemia-reperfusion injury

“…The tissue plasminogen activator, tPA dissolves thrombi and restores blood ow by promoting brinolysis. However, there is increasing evidence indicating that an ROS burst caused by reperfusion may aggravate brain injury [27][28][29]. Therefore, timely and effective ROS elimination in the I/R process is favorable for neuroprotection.…”