Leptomycin B attenuates neuronal death via PKA- and PP2B-mediated ERK1/2 activation in the rat hippocampus following status epilepticus.

Abstract

Leptomycin B (LMB), originally developed as an anti-fungal agent, has potent neuroprotective properties against status epilepticus (SE, a prolonged seizure activity). However, the pharmacological profiles and mechanisms of LMB for neuroprotection remain elusive. In the present study, we found that LMB increased phosphorylation levels of protein kinase A (PKA) catalytic subunits, protein phosphatase 2B (PP2B, calcineurin) and extracellular signal-regulated kinase 1/2 (ERK1/2) under normal condition, and abolished SE-induced neuronal death. Co-treatment of H-89 (a PKA inhibitor) with LMB could not affect the seizure latency and its severity in response to pilocarpine. However, H-89 co-treatment abrogated the protective effect of LMB on SE-induced neuronal damage. Cyclosporin A (CsA, a PP2B inhibitor) co-treatment effectively prevented SE-induced neuronal death without altered seizure susceptibility in response to pilocarpine more than LMB alone. H-89 co-treatment inhibited LMB-mediated ERK1/2 phosphorylation, but CsA enhanced it. U0126 (an ERK1/2 inhibitor) co-treatment abolished the protective effect of LMB on SE-induced neuronal death without alterations in PKA and PP2B phosphorylations. To the best of our knowledge, the present data demonstrate a previously unreported potential neuroprotective role of LMB against SE via PKA- and PP2B-mediated ERK1/2 activation.

• Authors: Su-Ji Min, Hye-Won Hyun, Tae-Cheon Kang
• Journal: Brain research (Brain Res) Vol. 1670 Pg. 14-23 (Sep 01 2017) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 28601633 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Fatty Acids, Unsaturated
• Isoquinolines
• Neuroprotective Agents
• Sulfonamides
• Cyclosporine
• Cyclic AMP-Dependent Protein Kinases
• Calcineurin
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
• leptomycin B

Topics

• Animals
• Calcineurin (metabolism)
• Cell Death (drug effects)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Cyclosporine (pharmacology)
• Disease Models, Animal
• Fatty Acids, Unsaturated (pharmacology)
• Hippocampus (drug effects, enzymology, pathology)
• Isoquinolines (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Neurons (drug effects, enzymology, pathology)
• Neuroprotective Agents (pharmacology)
• Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced)
• Status Epilepticus (enzymology, metabolism, pathology, prevention & control)
• Sulfonamides (pharmacology)
• Temporal Lobe (metabolism)