0

BK Channel Blocker Paxilline Attenuates Thalidomide-Caused Synaptic and Cognitive Dysfunctions in Mice

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

Sci Rep. 2018 Dec 5;8(1):17653.

PMID: 30518785

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP2614064 (+)-Thalidomide (+)-Thalidomide 2614-06-4 Price
AP57186251 Paxilline Paxilline 57186-25-1 Price
qrcode