LIM kinase inhibitor T56-LIMKi protects mouse brain from photothrombotic stroke

ABSTRACT

Primary Objective: In an ischemic stroke, the damage spreads from the infarction core to surrounding tissues. The present work was aimed at the search of effective neuroprotectors that restrict injury propagation. Research Design: We studied possible protective effects of inhibitors of protein kinases LIMK2 (T56-LIMKi), DYRK1A (harmine), and tryptophan hydroxylase (4-chlorophenylalanine) on infarction size and morphology of peri-infarct area after photothrombotic stroke (a model of ischemic stroke) in mouse brain. Methods and Procedures: Photothrombotic stroke was induced by laser irradiation of mouse cortex after administration of photosensitizer Bengal Rose, which does not penetrate cells and remains in blood vessels. Under light exposure, it induces vessel occlusion. Infarct volume and histological changes in the cerebral cortex were evaluated 3, 7 and 14 days after photothrombotic impact. Main Outcomes and Results: Harmine and 4-chlorophenylalanine did not influence infarct volume and morphology of peri-infarct area in the mouse brain cortex after photothrombotic stroke. However, LIMK2 inhibitor T56-LIMKi significantly reduced infarct volume 7 and 14 days after photothrombotic stroke. It also increased the percent of normochromic neurons and decreased the fraction of altered cortical cells (hypochromic, hyperchromic and pyknotic neurons). Conclusions: T56-LIMK2i may be considered as a promising anti-stroke agent.

KEYWORDS:

• Stroke
• photothrombosis
• neuroprotector
• LIM kinase
• T56-LIMKi

Acknowledgments

The authors are very grateful to Professor Andrey Abramov (Institute of Neurology, UCL, London) for the valuable help in the manuscript preparation.

Anatoly Uzdensky was born in 1947. Graduated Leningrad Politechnical Institute in Biophysics. Got PhD in physiology in 1980 and Dr. Sci in Biophysics in 2005. Main research topics: Stroke, Neurotrauma, Neurodegeneration, Neuroprotection, Signalling, Epigenetics. Published 130 papers and 3 books. Member of European Society for Neurochemistry (ESN), International Society for Neurochemistry (ISN), Federation of European Neuroscience Societies (FENS).

Svetlana Demyanenko was born in 1973. Graduated from Rostov State University in 1998 in biochemistry. Got PhD in biochemistry in 2009. Main research topics: Stroke, Epigenetics, Neurodegeneration, Neuroprotection. Published 25 papers and 1 book.

Declaration of interest

The authors declare no conflict of interests.

Additional information

Funding

The work was supported by the Russian Science Foundation, grant #18-15-00110.