Abstract
Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset.
Highlights
Stroke is a leading global cause of mortality and disability
We generated an experimental stroke model induced by middle cerebral artery occlusion (MCAO) for 1 h followed by various periods of reperfusion
Because JNK is activated by a number of upstream stress-related activators, including ASK1 and MKK4/7, we examined whether ASK1 activation was altered; we observed an B36% decrease in the expression of active, phosphorylated ASK1 (p-ASK1), concurrent with inhibition of the MKK/JNK pathway (Fig. 5a)
Summary
Neuronal TRAF1 expression is upregulated after stroke. We generated an experimental stroke model induced by middle cerebral artery occlusion (MCAO) for 1 h followed by various periods of reperfusion. Ligation of the common carotid artery resulted in a comparable reduction in blood flow in both experimental groups, and rCBF in the MCA territory returned to baseline levels after reperfusion (Supplementary Fig. S2e) Because both hypertension and arrhythmia are notable stroke risk factors[2], we measured blood pressure and heart rate in both strains; no differences in systolic blood pressure, diastolic blood pressure or heart rate were observed between the groups (Supplementary Table S1); and no significant changes were noted in blood gases, pH or body weight. TUNEL assays and NeuN dual-immunofluorescence staining 24 h after transient focal ischaemia and found an increase of B41% in the apoptotic rate in TG2-TRAF1 mice compared with that in NTG mice (Fig. 2f) These data demonstrate that neuronal TRAF1 has a detrimental effect on both histological cerebral ischaemic injury and behavioural neurological dysfunction, which is most likely attributable to the enhancement of delayed neuronal apoptosis. These neuroprotective effects on the infarct and oedema volumes persisted until 71 h after reperfusion
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