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

- LMB attenuated SE-induced neuronal death with increased PKA, PP2B and ERK phosphorylations.
- H-89 diminished the neuroprotective effect of LMB accompanied by reduced EKR phosphorylation.
- CsA enhanced the neuroprotective effect of LMB with increased EKR phosphorylation.
- Co-treatment of U0126 with LMB aggravated SE-induced neuronal death more than LMB.
- LMB protected neurons from SE via PKA- and PP2B-mediated ERK activation.

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.