ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke

Abstract

Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2wt) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIPwt) and its phosphorylation-deficient mutant RKIPS153A, known inhibitors of the ERK1/2 signaling cascade. RKIPwt and RKIPS153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.

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“…This activation process transfers extracellular signals through the cell membrane and cytoplasm to the nucleus to regulate the cell cycle and the physiological and pathological processes of cells [ 35 ]. Studies have shown that the ERK pathway is involved in the regulation of tight junction protein expression and is closely related to blood-brain barrier permeability [ 36 ]. ERK showed continuous overactivation during brain trauma, and its expression duration was significantly prolonged [ 37 , 38 ].…”

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“…In addition, T3 administration after brain ischemia in rodent models stimulates the phosphoinositid-3-kinase/akt pathway (Hiroi et al 2006) and suppresses the mitogen-activated protein kinase (MAPK) pathway (Genovese et al 2013), both of which directly modulate programmed cell death and the inflammatory response. ERK1/2 belongs to the MAPK family and plays a detrimental role in stroke outcome (Schanbacher et al, 2022). ERK is activated by phosphorylation, and this activation was ameliorated by T3 treatment in our stroke model.…”

“…As the inhibition of Erk 1/2 is associated with an improved outcome after stroke (C. Schanbacher et al, 2022), the expression and phosphorylation of Erk1/2 were examined in both the cortex and basal ganglia. The expression of Erk1/2 remained constant in all groups following tMCAO (Fig.…”

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“…Moreover, ERK inhibitors U0126 and PD184161 have shown to decrease infarct volume after an ischemic insult [ 24 ]. A recent study has reported that stimulation of ERK1/2 led to an increase in infarct volume, inflammation, and apoptosis after tMCAO [ 44 ], thus indicating that the activation of this pathway is detrimental and that its inhibition is instead neuroprotective. Our results are in close agreement since ischemia-reperfusion significantly increases ERK1/2 phosphorylation/activation in the ischemic hemisphere.…”