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

Constanze Schanbacher, Michael Bieber, Yvonne Reinders, Deya Cherpokova, Christina Teichert, Bernhard Nieswandt, Albert Sickmann, Christoph Kleinschnitz, Friederike Langhauser, Kristina Lorenz

International journal of molecular sciences 2022 Jan 09

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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.

Citation

Constanze Schanbacher, Michael Bieber, Yvonne Reinders, Deya Cherpokova, Christina Teichert, Bernhard Nieswandt, Albert Sickmann, Christoph Kleinschnitz, Friederike Langhauser, Kristina Lorenz. ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke. International journal of molecular sciences. 2022 Jan 09;23(2)