BK channel blocker paxilline attenuates thalidomide-caused synaptic and cognitive dysfunctions in mice

Tae-Yong Choi,Se-Young Choi,Youhwa Jo,Chul-Seung Park,Seung-Hyun Lee,Soo-Jeong Kim

doi:10.1038/s41598-018-36367-3

Abstract

Thalidomide is a widely prescribed immunomodulatory drug (iMiD) for multiple myeloma, but causes reversible memory loss in humans. However, how thalidomide causes cognitive dysfunction at a cellular and molecular level has not been demonstrated. We studied the effect of thalidomide on synaptic functions and cognitive behaviors using a mouse model. Thalidomide led to cognitive deficits in learning behavior in a passive avoidance test and in a novel object recognition test, increased anxiety in an elevated plus maze test, and increased depressive behaviors in a tail suspension test. Interestingly, thalidomide elevated big- or large-conductance, calcium-activated K+ (BK) channel expression in the plasma membrane and BK channel activity in the hippocampus. Thalidomide also increased the paired pulse ratio of excitatory postsynaptic current (EPSC), which suggests a decreased probability of glutamate release. Furthermore, the changes in the paired pulse ratio and in BK channel activity were blocked by paxilline, a BK channel blocker. Finally, we found that thalidomide-induced cognitive dysfunctions were restored by paxilline treatment. These results suggest that thalidomide-mediated BK channel hyperfunction is responsible for the pathological mechanism of thalidomide-associated reversible memory loss.

Highlights

Thalidomide, which was developed as a sedative but was subsequently determined to be a teratogen that affects limb formation, has recently been re-evaluated as an immunomodulatory drug1,2
We found that thalidomide-treated mice showed a decrease in step-through latency in the passive avoidance test (Fig. 1a, t(11) = 17.013, P < 0.001 by unpaired Student’s t-test)
Thalidomide decreased spontaneous alterations in Y-maze tests (Fig. 1c, t(15) = 2.233, P = 0.0437 by unpaired Student’s t-test). These results suggest that thalidomide aggravates cognitive function in naïve animals to what has been observed in human multiple myeloma patients who were prescribed IMiD

Summary

Introduction

Thalidomide, which was developed as a sedative but was subsequently determined to be a teratogen that affects limb formation, has recently been re-evaluated as an immunomodulatory drug. Thalidomide and its derivatives produce a side effect of reversible memory loss. Thalidomide acts on cereblon (Crbn), a gene on human chromosome 3p26.3 that causes intellectual disability in humans when mutated, and leads to inhibition of CRL4CRBN E3 ubiquitin ligase-related functions. Elucidating the mechanism is important from the perspective of understanding chemotherapy-induced cognitive impairment, and for manipulating the therapeutic efficacy of thalidomide. The mechanism of cognitive impairment due to a loss-of-function mutation in CRBN, a molecular target of thalidomide, has been elucidated. The mechanism of cognitive impairment due to a loss-of-function mutation in CRBN, a molecular target of thalidomide, has been elucidated23–25 These findings provided clues that are important for tracking the mechanism of action of thalidomide. We characterize cognitive dysfunction in thalidomide-treated mice and identify effects of thalidomide on BK channel activity, one of the thalidomide-CRBN functional targets

Methods

Results

Conclusion