Inhibition of mitogen‐activated protein kinase 1/2 in the acute phase of stroke improves long‐term neurological outcome and promotes recovery processes in rats

Abstract

It is demonstrated that benefits of early treatment with U0126 persist beyond subacute phase of ischaemic stroke in male rats. Prevention of ERK1/2 activation in the acute phase results in improved long-term functional outcome and enhances later-stage recovery processes. These results expand our understanding of the benefits and promise of using MEK1/2 inhibitors in stroke recovery.

Acute mitogen‐activated protein kinase 1/2 inhibition improves functional recovery and vascular changes after ischaemic stroke in rat‐monitored by 9.4 T magnetic resonance imaging

“…The immunostaining did not double stain with NeuN or overlap with nestin immunolabelling indicating that Ki67 + cells are not neurons or astrocytes. In a previous study, we demonstrated that nestin is expressed in astrocytes because Glial fibrillary acid protein (astrocyte marker) double‐stained with nestin . Similar staining was performed in this study and confirmed our previous results (data not shown).…”

“…This study is the first to demonstrate that there is a clear association between post‐stroke recovery and vascular changes in stroke. In previous studies, it is demonstrated that U0126 acutely did not alter any physiological parameters . Specific blockade of the MEK‐ERK1/2 pathway with U0126 improved long‐term functional outcome, normalized cerebral perfusion and promoted recovery processes despite administration of the inhibitor as late as 6 hours after reperfusion, a clinical relevant time‐point.…”

“…We have recently shown that acute inhibition of the MEK/ERK 1/2 pathway improved long‐term functional outcome, decreased infarct size and promoted recovery processes in 2‐hour MCAO model in male and female rats . The persistence of beneficial effects of new therapeutic strategies for stroke when applied at a clinically relevant time‐point is very important; therefore, we applied the first dose at 6 h after stroke.…”

Targeting mitogen‐activated protein kinase in acute ischaemic stroke

“…Presently, MCAO results in enhanced expression of pERK1/2 in smooth muscle cells of the ischaemic middle cerebral artery and associated small arteries (shown by colocalization with actin) but not in surrounding brain tissue; U0126 blunts this activation in parallel with a reduction in infarct volume and an improved neurological score (Mostajeran et al . ). The other MAPK p38 and JNK were only mildly affected in vessel walls by MCAO; however, as shown before there is enhanced pp38 and pJNK in brain tissue subsequent to stroke that is mainly localized to neurones and glial cells, and this occurs late in the process (Maddahi & Edvinsson ).…”

“…In this issue of Acta Physiologica, Mostajeran and colleagues provide evidence that acute treatment of U0126, a MEK1/2 inhibitor, improved long-term outcome of neurological deficits in a rodent male experimental stroke model (Mostajeran et al 2015). Furthermore, a correlation between infarct size and recovery processes in rats treated with U0126 or vehicle (DMSO) was observed.…”