Fig. 8
From: Pharmacological rescue of cognitive function in a mouse model of chemobrain
Proposed model for the mechanism of paclitaxel-induced cognitive impairment. Paclitaxel binding to NCS1 enhanced NCS1 binding to the InsP3R resulting in increased calcium release from the ER into the cytoplasm. The increase in calcium concentration, as well as an upregulation of PKCα, leads to PKC hyperactivity. PKCα, in turn, phosphorylates MARCKS into pMARCKS, leading to actin instability. This instability subsequently leads to loss of spines and dendrites, and hence cognitive impairment. Lithium, through inhibiting InsP3R-dependent calcium release and PKCα, and chelerythrine (Chel), through inhibiting PKCα, can rescue paclitaxel-induced cognitive impairment