Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion.

Olga Yu Sudarkina,Ivan B Filippenkov,Nikolai F Myasoedov,Svetlana A Limborska,Alina E Denisova,Veronika G Dmitrieva,Vadim V Yuzhakov,Liya V Valieva,Larisa E Sevan’Kaeva,Leonid V Gubsky,Lyudmila V Dergunova,Julia A Remizova,Vasily V Stavchansky

doi:10.3390/ijms22126179

Abstract

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.

Highlights

To further investigate the mechanisms underlying the neuroprotective action of Semax under the conditions of the transient middle cerebral artery occlusion (tMCAO) model, the expression of the phospho-(Thr183/Tyr185)-SAPK/JNK kDa and kDa (pJNK), matrix metalloproteinase 9 (MMP-9), c-Fos, and pCREB proteins, which are actively involved in the pathogenesis of ischemic stroke, was analyzed by immunodetection in the subcortical structures and the frontoparietal cortex of the rat ipsilateral hemisphere
We showed that pJNK was upregulated in this region of the brain during ischemia, followed by its downregulation after the administration of Semax; in contrast, pCREB was downregulated during ischemia and upregulated under the effect of Semax
The general effect of the drug on both brain tissues occurred via its ability to compensate for the expression profiles of these proteins, which were disturbed by ischemia

Summary

Introduction

Ischemic stroke has been one of the main causes of mortality and disability among the populations of many developed countries. The search for new therapeutic strategies for stroke treatment remains an urgent problem. A significant contribution to the solution can be made by a detailed study of the mechanisms of action of drugs that have a neuroprotective effect against cerebral ischemia. Peptides of the melanocortin family are actively involved in the functioning of the central nervous system because they act as neuroprotective agents [1]

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