Abstract P800: Liposomal Delivery of PICK1 Inhibitor, FSC231, Prevents Ischemic/Reperfusion-Induced Degradation of GluA2 AMPA Receptor Subunit

Abstract

Stroke remains to be a leading cause of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity, eventually leading to delayed neuronal death. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death. AMPA receptors (AMPARs) are homo- or hetero-tetramers composed of GluA1-4 subunits. The majority of AMPARs are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 AMPAR subunit. Calcium-permeable AMPARs lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen-glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C Kinase-1 (PICK1). We hypothesize that disrupting the PICK1—GluA2 interaction will prevent the degradation of GluA2, thereby protecting neurons within the hippocampus from AMPAR-mediated delayed neuronal death. Pretreatment with liposome-encapsulated FSC231, an inhibitor of PICK1, in acute rodent hippocampal slices prevents the OGD/R-induced association of PICK1—GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This work is the first to utilize a liposomal drug delivery system for the delivery of a small molecule in ex vivo acute rodent hippocampal slices exposed to ischemia/reperfusion injury. These results suggest that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels and is a potential therapeutic target for the treatment of ischemic stroke.